Nicos ul fur on H ealth Risk Assessmen t DP N o

. D 408756

UNITED STATE S ENVIRONMENTAL PROTEC TI ON AGENCY
WASHINGTON, D.C. 20460

MEM ORAND UM

D ate : J une 26, 20 14 O FFIC E O F C H EM ICAL SA FETY AND PO L LUTION PREVENTION

SU BJECT : Ni co su l f uron: H uman H ea l t h Ri s k Ass e s sment f or Pr o p ose d Use on A L S Inhibit o r T o l e r a nt So rghum

.

PC Co de: 129008 Dec i s i o n N o .: 473409 Pe tit io n N o .: 2F8132 D P B a rc o de: 0408756 Re g i s tr a ti o n No s

. : 352-560

, 352-8 1 6

, 352-535 Reg ulat ory Ac tio n : Section 3Registratio n Case N o.: 7227 R i s k Ass e ss m e n t Type: Single Chemical Agg r ega t e Risk Assessment T XR No.: NA
MRIDNo

. : N A CA S No.: 111991

- 09

- 4 4 0 C FR : § 180 .454

FROM : Kr i s t i n Rury, Risk Assessor

# ¥-~**/--;** M i nerva Mercado, Tox i cologis t 

# !Jf/. 

# #

Mehe r et Neguss i e, R esidue

# Che~**1** 

## Heitd:-c:/-

# ~~**e..** R isk Assessment Br anc h III (RAB III) H ea l th Effects D i vis i on (7509P)

T H R O U G H : Chr i st i ne O li nger, Bra nc h Ch i ef //// ./

- Ri s k Assessme nt Branch III (RA B II I )**~/-- ~**  H ea l th Effects Di v i si on (7 5 0 9 P )

TO : K able Davis, Ri s k M anager Mindy Ond i sh, Risk Manager R eviewer Herb i c i de Branch Registration Division ( 7 505P)

P age 1 of3 1Nicosulfuron 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 Revis io ns to Petitioned-For Tolerances

.......................... .. ........................... .. . ... .. .. .. . 7 2.2.4 International H armonization

........... . .. . . .............. ...... .. . ... . .. ...................................... .. 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 P esticide Use Pattern

...................................................................................................... 8 3.4 Anticipated Exposure Pathways

.......................................................... ......................... 9 3

. 5 Consideration of Environmental Justice

.......... . .................. . .. .. ....... . .......................... 10 4.0 

### Haza r d Characterization and Dose-Response Assessment..

........................................ 10 

### 4.1 Summ a ry 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 f or 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 Profi l e

................................... .. . .. ...... .. .. .. .. .. .. .. ............ ................. ........... 15 

### 5.3 Water Residue Profile

................................... . ... . .......................................................... 15 

### 5

. 4 D ietary Risk Assessment

...... .. ...... . ................................................ .. . . ......... .. .. .. .. ....... . .. 16 

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

............................. ... . .. 16 

### 5.4

. 2 Percent Crop Treated Us ed in Dietary Assessment

.............................................. 16 

### 5.4.3 Acute Dietary Risk Assessment

............................................. .. .. .. .. .. . ............ . ... ....... 16 

### 5.4

. 4 Chron i c Dietary Risk Assessment

..................................................................... .. .... 17 

### 5.4.5 Cance r Dietary Risk Assessment

.. .......... ...... ........ ............... ...... .. ........ . ..... .. .. .. ........ 17 

### 5 .4.6 Summary Table

......................................................................................................... 17
6.0 

### Residential (Non-Occupational) Exposure/Risk Characterization

.......... .. ... .............. 18 

### 6

. 1 Residential Bystander Pos t -application Inhalation Exposure

....................... .. . ....... 18 

### 6.2 Spray Drift

..................... .. . ......... . .............. ............ .......... .. .. ..................... . .................... 18 7.0 

### Aggregate E xposure/Risk Characterization

........................ ....... . .. ...... .. .. .. .. .. ................ 18 8 .0 

### Cumulative Exposure/Risk Characterization

..... .. ........................................................ 19 

### 9.0 Occupational Exposure/Risk Charac t erization

... .. .. .. .. .. . .. ................................. ........... 19 

### 9

. 1 Short-/Intermediate- Term Handler Risk.

................................... . . .. .. .. ...................... . 19

Page 2 of31Nicosulfuron Health Risk Assessment DP No. D408756

Page 3 of 31 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

................................ ................................ ................ 31Nicosulfuron Health Risk Assessment DP No. D408756

Page 4 of 31 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 a re 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 a reas . 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 i s 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 (E P) 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 A ccent ® 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 t he active ingredient (ai) rimsulfuron. Exposure to rimsulfuron from the proposed use on sorghum will be evaluated in a separate document. The proposed label s require occupational handlers to wear long pants, long sleeved shirts, chemical resistant gloves, shoes , and socks. The restricted entry inter val (REI) on the proposed labels is 4 hours.

Exposure Profile There is a potential for occupational short

- and intermediate

- term inhalation a nd 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 particu larly 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 we ights of males) at the highest doses tested. Recently submitted acute and subchronic neurotoxicity studies andNicosulfuron Health Risk Assessment DP No. D408756

Page 5 of 31 immunotoxicity study did not change the points of departure (PODs) or endpoints from prior

assessments. There were no concerns for developmenta l 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 toxic ity, 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 re duced 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 resul ts 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 assessm ent 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 propose d 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 ha ndler 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

. T he 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 prac tices, 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, theNicosulfuron Health Risk Assessment DP No. D408756

Page 6 of 31 Agency may revisit the need for a quantitative occupationa l 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 Lo w

- 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 database s 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 Secti on 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 definition s 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

av ailable for tolerance enforcement of corn commodities. The methods have been adequately validated for the determination of residues of nicosulfuron in plant s

.
DuPont has proposed an HPLC/MS/MS method (DuPont

- 32277) as an enforcement method for the dete rmination 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 trial s

.

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

,Nicosulfuron Health Risk Assessment DP No. D408756

Page 7 of 31 reflecting the proposed use pattern

, are available for purpo ses of establishing tolerances i n sorghum forage , stover, and grain

. T he 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 a re appropriate. The proposed tolerance of 0.4
ppm in sorgh um 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: T he tolerance expressions for nicosulfuron should be revised as follow s :

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]ami no]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

Subse quent 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 P HI changes supersede those mentioned in the residue chemistry review (M. Negussie, D417854, 02/14/2014).Nicosulfuron Health Risk Assessment DP No. D408756

Page 8 of 31 3.0 In troduction

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 C 15 H 18 N 6 O 6 S Molecular weight 410.40

IUPAC name 2

- [(4,6

- dimethoxypyrimidin

- 2

- ylcarbamoyl)sulfamoyl]

- N

, N

dimethylnicotinamide; 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,N

dimethyl

- 3

- pyridinecarboxamide CAS registry number 111991

- 09

- 4

End

- use product (EP) Dupont TM Accent® Herb icide; EPA File Symbol 352

- 560 and Dupont TM STEADFAST® XP Herbicide; EPA File Sy mbol 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 25 o C) and K OW (< 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

DuPo nt 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 occu pational exposure risk has not been previously evaluated. When applied to sorghum resistant to ALS

- inhibitors, theNicosulfuron Health Risk Assessment DP No. D408756

Page 9 of 31 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 l abels (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 dispers ible 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. Formulatio n

[EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per Season Max.

Seasonal Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations 1

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

re quired (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 settin g, 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 aforement ioned exposure pathways based on the proposed newNicosulfuron Health Risk Assessment DP No. D408756

Page 10 of 31 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 vari ety 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 a nd 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/WWEI A) 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 su bgroups 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 b ystanders 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, 1 0/27/2009). The toxicity endpoints and P o Ds 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.Nicosulfuron Health Risk Assessment DP No. D408756

Page 11 of 31 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 pr oduce 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 ne urotoxic or immunotoxic effects elicited by nicosulfuron in animal studies; this includes recently submitted acute and subchronic neurotoxicity studies and an immunotoxicity stud y

.
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 F actor for Infants and Children (FQPA Safety Factor)

Based on the currently available toxicity and exposure data, the risk assessment team recommend s 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 o f 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 C ouncil (HASPOC) waived the required subchronic inhalation toxicity study based on nicosulfuron ’s physical chemical properties, in cluding 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 N eurotoxicity

Nicosulfuron did not show neur otoxic effects in acute, subchronic, and chronic testing in rats, mice and dogs.

4.2.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Animal

The current database does not provide evidence of sensitivity/susceptibility in the developin g 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

-Nicosulfuron Health Risk Assessment DP No. D408756

Page 12 of 31 generation reproductive study, lower gestational body weight ga in 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 Datab ase

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 D eparture 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 POD s: 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
p rotective of the effects seen in the rabbit developmental toxicity stud y

.

The toxicity e ndpoints and points of departures are presented in Table s 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 Exposur es 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 populatio n 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 ni cosulfuron, 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, t here have been no changes to the prior dose

response assessment or recommendations for combining routes of exposu re and/or cancer classification ( M. Doherty, D360807, 10/27/2009 )

.Nicosulfuron Health Risk Assessment DP No. D408756

Page 13 of 31 For short and intermediate

- term dermal and inhalation ris k 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 stain ing 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 si milar; 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 deve lopmental effects and female workers.

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

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

Table 4

. 3

. 3. 1 Su mmary 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) N o hazard was identified from appropriate oral toxicity studies including developmental

toxicity studies in rats and rabbits.

Acute Dietary (Females 13

- 49 years of age) N o 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 UF A = 10 x

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

= 1.25 mg/kg/day

cPAD = 1.25 mg/kg/day C hronic 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 relev ant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of th e human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose.Nicosulfuron Health Risk Assessment DP No. D408756

Page 14 of 31 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% UF A =10x

UF H =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 Intermediate

term (1

- 6 months)

Term NOAEL

=125 mg/kg/day UF A =10x

UF H =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. S upported 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 lev el. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. N/A = not applicable. DAF = dermal absorption factor. IAF = Inhalation absorption factor. Toxicity via the inh alation 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 re sidues 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 m ethod 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 NicosulfuronNicosulfuron Health Risk Assessment DP No. D408756

Page 15 of 31 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 includ es milk, and the meat, fat and meat byproducts of cattle, goats, horses, and sheep.

Adequate crop field trial data have been submitted to suppor t the requested use on ALS tolerant grain sorghum. The trials reflect the proposed use pattern and t he 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 propos ed use on grain sorghum does not result in an increased dietary burden to ruminants and poultry. Therefore, n o change s 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 ) an d incorporated directly into this dietary assessment. Water residues were incorpor ated in DEEM

FCID 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 co ncentration, 2.80 μg/L (2.80 ppb) for the chronic concentration, and 2.15 μg/L (2.15 ppb) for the cancer concentration.Nicosulfuron Health Risk Assessment DP No. D408756

Page 16 of 31 Ground water estimates of concentrations are estimated using the PRZM

- GW. PRZM

- GW model estimates upper

- bound concentrations of nico sulfuron, 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 estimate d 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 a t 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 (o f 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

I t 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

.Nicosulfuron Health Risk Assessment DP No. D408756

Page 17 of 31 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 wi th 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 popula tion 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 boldedNicosulfuron Health Risk Assessment DP No. D408756

Page 18 of 31 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 Sci entific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 1 . 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, subseque ntly, 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 nicos ulfuron.

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 qualitati vely 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.htmNicosulfuron Health Risk Assessment DP No. D408756

Page 19 of 31 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 populati on 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 E xposure/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 ni cosulfuron 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 reg arding 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 determinati ons 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

T here 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 post

application activities (via the dermal route) based on the pro posed uses.

9.1 Short

- /Intermediate

- Term Handler Risk

HED has evalu ated 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, th e 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 o ccupational handlers. However , for both dermal and inhalation exposures, the PODs selected are considered protective of both durations. The proposed label s 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 accountNicosulfuron Health Risk Assessment DP No. D408756

Page 20 of 31 for variability within species. The total u ncertainty 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 e stimates 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 i n 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 short

and intermediate

- term occupational handler combined (dermal + inhalation) MOEs ranged from 490 to 56 ,000

.Nicosulfuron Human Health Risk Assessment DP No. D408756

Page 21 of 31 Table 9 .1. 1. Occupational Handler Short

- and Intermediate

- Term Exposure and Risk Estimates for Nicosulfuron

.

Exposure Scenario Crop or Target Dermal Unit

Exposure ( μ g/lb ai) 1 Inhalation Unit

Exposure ( μ g/lb ai) 1 Maximum

Application Rate 2 Area Treated or Amount Handled Daily 3 Dermal Inhalation Total

Baseline* Baseline* Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8

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 ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × 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 ( μ g/lb ai) × Conversion Fac tor (0.001 mg/ μ g) × 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 + In halation Dose.Nicosulfuron Human Health Risk Assessment DP No. D408756

Page 22 of 31 9.2 Short

- Term Post

- Application Risk

9.2.1 Dermal Post

- A pplication 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, o nly exposure from scouting was assessed because nicosulfuron is an herbicide. Hand weed ing, the only other post

application 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 re aches 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

a t a rate of 10% each following day.

A DF R study is not required for nicosulfuron at this time since the dermal MOE s 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 3 0 ,000 on the day of application. Therefore, there are no post

- application risk estimates of concern for nicosulfuron.

Table 9.2. Occupational Po st

- application Non

- Cancer Exposure and Risk Estimates for Nicosulfuron

.
Crop/Site Activities Transfer Coefficient (cm 2 /hr) DFR 1 Dermal Dose (mg/kg/day) 2 MOE 3

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/cm 2 ; where F = 0.25 and D = 0.10 per day

. 2 Daily Dermal Dose = [DFR (μg/cm 2 ) × 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

- A pplication 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 a cute 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 post

application 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, andNicosulfuron Human Health Risk Assessment DP No. D408756

Page 23 of 31 received the SAP’s final report on March 2, 2010 3 . 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 expos ure 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 D rinking Water Assessment.

K. Rury. 0 5 / 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 Tol erances 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 Assessme nts 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.htmlNicosulfuron Human Health Risk Assessment DP No. D408756

Page 24 of 31 A ppendix 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

.. 870.5 385 Mutagenicity

— Structural Chromosomal Aberrations

... 870.5 550 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 Profile sNicosulfuron Human Health Risk Assessment DP No. D408756

Page 25 of 31 Table A.2.1 Acute Toxicity Profile of Nicosulfuron

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

870.1100 Acute oral

– rat 40924205 LD 50 > 5000 mg/kg IV

870.1200 Acute dermal

– rabbit 40924207 LD 50 ≥ 2000 mg/kg III

870.1300 Acute inhalation

– rat 40924209 LC 50 ≥ 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/d ay 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, 5 00 , 1000 or 2000 mg/kg/day Materna l 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 post

implantation loss and decrease in body weight gain. Increased incidence of diarrhea was observed at the next highest dose (1000 mg/kg/day). Developmenta l NOAEL = 1000 mg/kg/day

LOAEL could not be determined

.Nicosulfuron Human Health Risk Assessment DP No. D408756

Page 26 of 31 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 F 1 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 increase d 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.Nicosulfuron Human Health Risk Assessment DP No. D408756

Page 27 of 31 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 /m L Negative for DN A 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 d ose 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 detec ted 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 kidney s. The major excretion product was unchanged parent compound. P yridinesulfonamide was detected in urine (1.1

- 5.7% dose). Pyr idine 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.Nicosulfuron Human Health Risk Assessment DP No. D408756

Page 28 of 31 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 dayNicosulfuron Human Health Risk Assessment DP No. D408756

Page 29 of 31 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/cm 3 relative 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, pK a 4.22 MRID #47632204 Octanol/water partition coefficient, K OW ( 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

- pyridinecarboxamideNicosulfuron Human Health Risk Assessment DP No. D408756

Page 30 of 31 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

- pyridinecarboxamideNicosulfuron Human Health Risk Assessment DP No. D408756

Page 31 of 31 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 Agricultur al Handler Exposure Task Force (AHETF), 2011. The Occupational Handler Unit Exposure Surrogate Reference Table. U.S. EPA. Released June 21, 2011.