Rimsulfuron Human Health Risk Assessment DP. No. 408722

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C

. 20460

MEMORANDUM

Date : July 2, 2014 OFFICE OF CHEMICAL SAFETY
AND POLLUT I ON PREVENTION

SUBJECT : Rimsulfuron. Human Health Risk Assessment for Proposed Section 3 Use on Aceto l actase Synthase (ALS) Toleran t Grain Sorghum.

PC Code: 129009
Decision No .: 473406
Petition No .: 2F8131
Assessment Type: Single Chemical/ Aggregate
TXRN o.: NA
MRIDNo .: NA DP Barcode: D408722 Registration Nos.: 352-748,352-816 Regulatory Action: Section 3
Case N o .: NA
CAS No

. : 122931-48-0
40 CFR: §180.478

FROM: 

## "

. : 2-

# vJJ~ Cassi Walls, Ph.D., Risk Assessor**~** / Myron Ottley

, Ph.D

. , Senior Toxicologist

## 1t()J{)t~ Meheret Negussie, Chemist 

### HeAerd-**~t...** Risk Assessment Branch III (RAB 3)
Health Effects Division (H ED; 7509P)

THROUGH : Christine Olinger, Branch Chief

# V#J~ Risk Assessment Branch III (RAB 3g 

# I/)

r RAB3/HED (7509P)

TO: Kable Davis, RM 25
Herbicide Branch (HB) Registration Division (RD; 7505P)

The Registration Division (RD) of Office of Pesticide Programs (OPP) has requested that th e Hea l t h Effects Division (HED) evaluate hazard and exposure data and conduct dietary, occupational

, and aggregate exposure assessments, to estimate the risk to human health that will
result from the proposed use ofrimsulfuron on Acetolactase Syntha s e (ALS) herbicide tolerant sorghum

. The HED team members contributing to this risk assessment include Cassi Walls (risk

assessment and occupational/residential assessments)), Myron Ottle y (hazard reeva l uation), and
Meheret Negussie (residue chemistry and dietary risk assessment).

-

Page 1 of37Rimsulfuron Human H ealth Ri s k Assessment DP. No. 408722

1.0 Executive Summary

........................................... .. .. .. .. ...... .. . ... . ... . .. .. ........... . ... .. .. ...... ... .. ... . 4
2.0 HED Recommenda t ions

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

..... . .... . ... . ... . . . . . ..................... . ............................ 6
2

. 2.2 Recommend e d Tolerances

.. . ..... . ... . .......................... ............. .. .. .... .. ... .. ....... . ......... 6
2.2.3 Revisions to Petitioned-For Tolerances

... . .. .. ................................... . .. .. .... . ......... 7
2.2.4 International Ha rmonization

.. ............. .. .. ......... ....... . ........................... .......... ...... 7
2.3 Label Reco m mendations

......................................................... ........ ..................... 7
2

. 3.1 Recommend at ions from Residue Reviews

................................. ........... .. .. ... . ...... 7
3.0 Introduction

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

.. . ............................................................................................... 8
3.2 Physical and Chemical Properties

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

..... ........... .. .. ...... .. .. .. . ... . .. .. .. . ... . ......... .. .. . ..... . .... . .. .. ... .. ... .. ..... 8
3

. 4 Anticipated E xposure Pathways

............. .. ......... .. .. .. ............... . . .......................... . 9
3.5 Consideration of Environmental Justice

................. .................... ..................... 10 4

. 0 Hazard C haracterization and Dose-Response Assessment..

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

......................................................... .. .......... 10
4.2 Safety Facto r for Infants and C hildren (FQPA Safety Fac tor)

...................... 12
4.2.1 Completeness of the Toxicology Database

........................................................ 12 4.2.2 Evidence of Neurotoxicity

............................ .. .............................. .. .. ........ . ...... ... 12 4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

.. 12 4

. 2.4 Residu a l Uncertainty in the Exposure Database

................... . .... .. .. .. .. .. ............ 13
4

. 3 Toxicity E ndpoint and Point of De parture Selections

.... ........... .... .. ... .. .. .. ... .. .. 1 3 4

. 3.1 Dose-Re sponse Assessment

..................................................... . .......................... 1 3 4.3.2 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment

........................................................ . .............................. .. .. . .... .. ............ 14 5.0 Dietary Ex po s ure and Risk Assessment..

...................................................................... 16 5

. 1 Residues of Concern Summary and Rationale

...................... ........... ... . .. .......... 1 6 5.2 Food Residue Profile

......................... ...... ................................................ 1 6 5.3 Drinking Water Residue Profile

....... . .................................... . ......... ...... 1 6 5.4 Dietary Risk Assessmen t

.......... .......... .. . .... .. .. . ... . . . ..... . .................. .. ...... .... .. .. ...... 17 5.4.1 Description of Residue Data Used i n Dietary Assessment

......... ................ ..... 17 5.4

. 2 Pe rcent C rop Treated Used in Dietary Assessment..

..... .. .. .. .. ................... ....... 17 5.4

. 3 Acute Dietary Risk Assessment

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

..................................................................... 1 7 5.4

. 5 Ca ncer Diet a ry Risk Assessment..

..................................................................... 18 5.4.6 Summary T a ble

.................................. . ..................................... .. ......................... 1 8 6.0 Residential (No n

- Occupational) Exposure/Risk Characterization

............................ 18
6

. 1 Residential Bystander Post

- application Inhalation Ex posure

........................ 1 8 6.2 Spray Drift

............................................... . ...... .. .. .. ... . ...................... .. .. ... . .. .... .. .. .. . 1 9 7.0 Aggregate Exposure/Risk Characterization

................................................................. 1 9 8

. 0 Cumulative Risk Characterization/ Assessment..

......................................................... 19 9.0 Occupational Exp o s ure/Risk Characterization

. ..... .. .................................. .. ............... 20 9 .1 Short-/Intermediate

- Term Handler Risk

......................................................... 20 9.2 Short-Term Post-Application Risk.

................................................................... 22 9.2.1 Dermal Po st -Application Risk

.................. . ..... ... .. ,.,.,., ............... . ..... .. ... .. . ... .. ..... 22 9.2.2 Inhalation Post-Applica t ion Risk

...................................................................... 22 10.0 References

................. .. ...... .... ..................................... .. . . . ................................... . ... . ...... .. . 23

Page 2 of37Rimsulfuron Human Health Risk Assessment DP. No. 408722

Page 3 of 37 Appendix A: Physical and Chemical Properties

................................ ................................ ...... 24 Appendix B: Toxicity Profile and Executive Summaries

................................ ....................... 25 B.1 Toxicology Data Requirements

................................ ................................ .............. 25 B.2 Toxicity Profile Tables

................................ ................................ ............................ 26
B.3 Executive Summaries

................................ ................................ ............................. 33 Ap pendix C: Chemical Name and Structures of Rimsulfuron and Metabolites

.................. 36Rimsulfuron Human Health Risk Assessment DP. No. 408722

Page 4 of 37 1.0 Executive Summary

Rimsulfur on is a sulfonylurea herbicide that works via inhibition of acetolactate synthase (ALS). It is currently regis tered to E. I. du Pont de Nemours and Co. (DuPont) for use on bushberries, caneberries, chickory, soybeans, potatoes, field corn, tomatoes, grapes, various tree fruits, and

tree nuts for pre

- and post

- emergence control of annual grasses, broadleaf weeds, and yellow nutsedge. Permanent rimsulfuron tolerances are currently established in 40 CFR §180.478. The previous risk assessment for rimsulfuron was conducted on May 4, 201 2 ( D391083, C. Walls,
05/04/12 )

.

DuPont has submitted an application to modify the DuPont Resolve SG Herbicide label (EPA Reg. No. 352

- 748) and the DuPont Steadfast XP Herbicide label (EPA Reg. No. 352

- 816) to include use on ALS tolerant sorghum.

Use Profile DuPont Resolve SG Herbicide (EPA Reg. No. 352

- 748) and DuPont Steadfast XP Herbicide (EPA Reg. No. 352

- 816) end

- use products (EPs) are water dispersible granular (WG) formulations containing 25% and 15% rimsulfuron by weight, respectively. DuPontTM
Steadfast ® XP herbicide (EPA Reg. No. 352

- 816) also contains the active ingredient (ai)
nicosulfuron. This assessment addresses the potential exposure and risk of rimsulfuron only

. Exposure to nicosulfuron from the proposed use on sorghum will be evalua ted 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 and dermal exposure

to rimsulfuron 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 rimsulfuron. There are no existing or proposed uses for rimsulfuron in residential settings.

Hazard Characterization For the proposed new use, the toxicological database for rimsulfuron is sufficient for risk assessment p urposes. All required toxicity studies have been submitted or waived.

The target organs for rimsulfuron are the liver and kidney in the rat and dog, along with the testis and blood in the mouse and dog. In the mouse, the stomach was also a target org an. Adverse changes in body weight and food consumption were observed in rats, mice

, and dogs

.

Rimsulfuron has low acute toxicity by the oral, dermal and inhalation routes, but is a moderate eye irritant. It is not a dermal sensitizer. Rimsulfuron is n ot mutagenic and has been classified as “Not Likely to be Carcinogenic to Humans,” based on the lack of evidence for carcinogenicity
in studies conducted in rats and mice.

There is no quantitative or qualitative evidence of increased susceptibility following pre

- and/or postnatal exposures in the developmental and reproduction studies, and there are no concerns orRimsulfuron Human Health Risk Assessment DP. No. 408722

Page 5 of 37 residual uncertainties. There was no evidence of neurotoxici ty or immunotoxicity in the recently submitted studies which have undergone preliminary evaluation and are currently under detailed
review. Therefore, HED has concluded that the Food Quality Protection Act ( FQPA ) Safety
Factor can be reduced to 1X.

An en dpoint for acute dietary risk assessment was not selected because there were no adverse
effects attributable to a single dose. The endpoint for chronic dietary risk assessment was chosen from the rat chronic/carcinogenicity study, and was based on liver a nd body weight
effects. Incidental oral endpoints were not selected because residential exposures are not anticipated. The endpoint for dermal and inhalation risk assessments for occupational workers
was chosen from the 90

- day oral study in the dog, and w as based on kidney effects.

Dietary Risk Estimates (Food and W ater) An acute dietary assessment was not performed, as a toxicological endpoint attributable to a single dose has not been identified for rimsulfuron.

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 rimsulfuron (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 1 .4% of the cPAD for all infants and
children 1

- 2 years old

, the population subgroup s with the hig hest estimated chronic dietary exposure to rimsulfuron . 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 ar e no registered residential uses of rimsulfuron. Therefore, the aggregate risk assessment for rimsulfuron only includes chronic exposures to residues in food and drinking water. The chronic dietary risk assessments for the U.S. population and all populat ion subgroups are not of concern to HED (<100% cPAD).

Occupational Risk
A short

- and intermediate

- term occupational risk assessment was performed for rimsulfuron application using ground and aerial equipment to sorghum; chemigation is not permitted on the proposed labels. There are no occupational handler risk estimates of concern for the proposed uses of rimsulfuron at labeled PPE (baseline + gloves, no respirator). At labeled PPE , all short

and intermediate

- term occupational handler combined (dermal + inhalation) MOEs ranged from 220 to 6,700

. The REI on the proposed label is 4 hours. The occupational short

- term post

application risk estimate resulted in a dermal MOE of 3,400 o n the day of application and is not of concern. Based on the Agency's current practices, a quantitative non

- cancer occupational post

- application inhalation exposure assessment was not performed for rimsulfuron at this time. 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 rimsulfuron.Rimsulfuron Human Health Risk Assessment DP. No. 408722

Page 6 of 37 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.pd f ).

2.0 HED Recommendations

HED has examined the residue chemistry, toxicity, and exposure database s for rimsulfuron and concluded that, provided a revised Section B, a revised Section F are submitted , and a sample of the analytical standard , there are no deficiencies that would preclude granting a Section 3 registration on 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 u ses of rimsulfuron.

860.1550 Proposed Tolerances

 The petitioner needs to submit a revised Section F to reflect the correct commodity
definitions presented in Table 2.2.2

.

860.1650 Submittal of Analytical Reference Standards

 The analytical reference standard for rimsulfuron will expire (04/2014). A 5g standard needs to be supplied to the repository

.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate data collection/enforcement method, the high performance liquid chromatography with tandem mass spectroscopy ( HPLC/MS/MS ) method DuPont

- 32277 , is available for
determination of residues of rimsulfuron on sorghum commodities. Samples of sorghum commodities from the submitted crop field trials were analyzed for residues of rimsulfuron using
the method. The limit of quantification ( LOQ ) of the method for sorghum grain, stover, and forage is 0.01 ppm. An adequate ILV was conducted with re coveries within the acceptable range (70

- 120%). Radiovalidat ion data are not needed since the extraction solvent for the method is
similar to the extraction solvent used in the metabolism studies. This method can be forwarded
to FDA. Note that rimsulfuron is not recovered by FDA Multiresidue Methods.

2.2.2 Recommended TolerancesRimsulfuron Human Health Risk Assessment DP. No. 408722

Page 7 of 37 Tol erances for residues of rimsulfuron, including its metabolites and degradates, are established
in 40 CFR §180.4 78(a)

. Compliance with tolerance levels specified is to be determined by measuring only the parent compound, rimsulfuron. Adequate data

, reflec ting the proposed use pattern

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

. The available field trial data support the proposed tolerances for residues of rim sulfuron on sorghum grain forage, stover, and grai n at 0.01 ppm each

. T he Organisation for Economic
Co

- operation and Development ( OECD ) statistical calculation procedure was not used to
determ ine appropriate tolerance level s since all residues were <LOQ (0.01 ppm).

The propos ed use on sorghum does not result in an increased dietary burden to ruminants or poultry. There is no reasonable expect ation of finite residues of rim sulfuron on livestock commodities (40 CFR §180.6 ( a )( 3 ) ) based on the registered /proposed uses

. The waiver request
for livestock feed ing studies is acceptable. HED notes that if additional uses of rimsulfuron with
livestock feed items are p roposed in the future, livestock feeding studies may be required

.

Table 2.2.2. Tolerance Summary for Rimsulfuron

. Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity

Definition
Sorghum, forage 0.01 0.01 Sorghum, grain, forage
Sorghum, stover 0.01 0.01 Sorghum, grain, stover
Sorghum, grain 0.01 0.01 Sorghum, grain, grain

2.2.3 Revisions to Petitioned

- For Tolerances

Note to PM: T he tolerance expression for rimsulfuron should be revised as follow s :

Under 40 CFR §180. 478(a) : “Tolerances are established for residues of the herbicide
rimsulfuron , including is metabolites and degradates, in or on the commodities in the following table [ below ] . Compliance with the tolerance levels specified in the following table [ below ] is to be determined by measuring only rimsulfuron
, N

- [[(4,6

- dimethoxy

- 2

- pyrim idinyl)amino]carbonyl]

- 3

- (ethylsulfonyl)

- 2

- pyridinesulfonamide

.

2.2.4 International Harmonization

No Codex or Mexican Maximum Residue Limits (MRLs) have been established for residues of
rimsulfuron. There are no MRLs established in Canada for rimsulfur on use on sorghum.

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

The following changes should be made to the proposed labels before granting the rimsulfuron use on sorghum:

860.1200 Directions for UseRimsulfuron Human Health Risk Assessment DP. No. 408722

Page 8 of 37  The label s should indicate that application should be made to “ grain sorghum ” rather than

to “ sorghum ”

.

 Subsequent to completion of the residue chemistry summary document, the registrant proposed amend ing the preharvest intervals (PHI) to plant height and growth sta ges. 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

.

3.0 Introduction

Rimsulfuron is a sulfonylurea herbicide that works via inhibition of ALS . Inhibition of the enzyme leads to rapid cessation of plant growth and visual symptoms such as chlorosis, necrosis,
leaf malformation and discoloration. These e ffects appear a few d ays after treatment in sensitive species. ALS is not found in humans or mammals.

3.1 Chemical Identity

Table 3.1. Rimsulfuron Nomenclature.
Compound

Common name Rimsulfuron
Company experimental name DPX

- E9636

IUPAC name 1

- (4,6

- dimethoxypyrimidin

- 2

- yl)

- 3

- (3

- ethylsulfonyl

- 2

- pyridylsulfonyl)urea

CAS name N

- [[(4,6

- dimethoxy

- 2

- pyrimidinyl)amino]carbonyl]

- 3

- (ethylsulfonyl)

- 2

- pyridinesulfonamide
CAS registry number 122931

- 48

- 0

3.2 Physical and Chemical Properties

The phys ical/chemical properties of rim sulfuron are summarized in Appendix A

. Based on the molecular weight, low vapor pressure (7.5 x 10

- 8 mm Hg at 25 o C) and K OW (<0.0342 at pH 7),
rimsulfuron is not expected to volatilize , pass lipid barriers, or bioaccumulate.

3.3 Pesticide Use Pattern

Rimsulfuron is currently regis tered to DuPont for use on bushberries; caneberries; chickory; field corn; grapes; potatoes; soybeans; tomatoes; and various tree fruits and tree nuts; for pre

- and post

- emergence c ontrol of annual grasses, broadleaf weeds, and yellow nutsedge. DuPont
submitted a petition to allow rimsulfuron use on sorghum tolerant to ALS herbicides. When applied to sorghum resistant to ALS

- inhibitors, the surrounding weeds will be controlled.
Ho wever, when applied to sorghum that is not resistant to ALS

- inhibitor herbicides, the plantRimsulfuron Human Health Risk Assessment DP. No. 408722

Page 9 of 37 itself will be eliminated. Rim sulfuron has no registered residential uses. The formulations relevant to the sorghum use request are formulated EP labels DuPontTM Steadfast ® XP herbicide, (EPA Reg. No. 352

- 816) and DuPont Resolve SG Herbicide (EPA Reg. No. 352

- 748). Both
formulated end

- use products are WG formulations containing 15% and 25% rimsulfuron by weight, respectively. The proposed use on sorghum is summar ized in Table 3 .3

.

T able 3

. 3 Summa ry of Directions for Use of Rim sulfuron. Application Timing; Type; Equipment Formulation

[EPA Reg.
No. ] Use Rate

(lb ai/A) Max.

Uses per
Season
RTI (days) Max.

Seasonal
Use Rate (lb ai/A) PHI

(Days) Use Directions and

Limitations 1

Sorghum C ontaining the DuPontTM INZENTM Z Tolerance T rait

Post

- emergence

Aerial
Ground DupontTM

Resolve ®
25% DF [352

- 748] 1.0

- 2.0 oz/A

(0.016

- 0.031) 2

(7

- days) 2.0 oz/A

(0.031) Mature

Stage (forage, grain, stover) Application is to be made to

emerged sorghum that is up to 20 inches tall. Applications
made to 4

- 20 inch tall sorghum (V3

- V7 stage) are
recommended for best weed control and crop tolerance.
Best results are obtained when applications are made to young ac tively growing weeds. Do not apply to sorghum taller than 20
inches. Use of a spray adjuvant is required (NIS at 0.25%

- 0.5% v/v, or COC at 1%

- 2% v/v, or a combination adjuvant containing NIS, COC, MSO and/or ammonium nitrogen fertilizer). For aerial appl ication using COC use at
0.5% v/v DupontTM
Steadfast
XP Herbicide
15%
Rimsulfuron [352

- 816] 1.25

- 1.67

oz/A

(0.012

- 0.016) 1.67 oz/A

(0.016)

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

Subsequent to completion of the residue chemistry summary document, the registrant proposed amending the preharvest intervals (PHI) 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.

3.4 Anticipated Exposure Pathways

Humans may be exposed to rimsulfuron in food and drinking water, since rimsulfuron may be applied directly to growing crops and application may result in rimsulfuron 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

- app lication exposure for workers re

- entering treated fields. This risk assessment considers all of the aforementioned exposure pathways based on the proposed newRimsulfuron Human Health Risk Assessment DP. No. 408722

Page 10 of 37 uses of rimsulfuron, 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 Lo w

- Income Populations," http://www.epa.gov/environmentaljustice/resources/policy/exec_order_12898.pdf

. As a part of every pesticide risk assessment, O PP 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

consump tion, 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 t o 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 childr en 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
th at 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

Rimsulfuron is a sulfonylurea herbicide that works via inhibition of acetolactate synthase (ALS) an enzyme found in plants and micro

- organisms. The relevance of this mode of action to
humans has not been established.

4.1 Summary of Toxicological Effects

The toxicity database indicates that target organs for rimsulfuro n are the liver and kidney in the rat and dog, along with the testis and blood in the mouse and dog. In the mouse, the stomach was also a target organ. Adverse changes in body weight and food consumption were observed in rats, mice and dogs.

In subchronic toxicity studies in rats, decreased body weight, body weight gain, increased relative liver and absolute kidney weights, and diuresis were observed; in the dog subchronic study decreased liver enzymes and bilirubin, fatty change, and hepatoce llular hypertrophy were observed. In chronic rat studies, decreased body weight gain, and increased liver weights were observed in both sexes, with increased mortality at higher dose levels in males. In a subchronic study in mice, increased red blood cell (RBC) and hemoglobin, and decreased body weight gain and food efficiency were observed. After mouse chronic exposure, decreased body weight,Rimsulfuron Human Health Risk Assessment DP. No. 408722

Page 11 of 37 increased incidences of dilation and cysts in the glandular stomach, and degeneration of the testicular artery and tunica albuginea were observed. In dogs, diuresis indicated by increased urinary volume, platelet concentration and kidney weights accompanied by decreased urinary osmolality was observed after 90 days. Chronic exposure led to increased absolute liver a nd kidney weights and increased incidence of seminiferous tubule degeneration and increased numbers of spermatid giant cells present in epididymides in males at in males, while in both

sexes decreased mean body weight and body weight gain, increased serum cholesterol levels and alkaline phosphatase activity, increased absolute liver weight, and increased relative liver and kidney weights were observed.

In the developmental toxicity study in rats, no developmental toxicity was seen at the highest
dose teste d. In the developmental toxicity study in rabbits (in which both maternal and fetal death were observed), and in the two

- generation study in rats (in which decreases in body weight gain were observed in both parents and offspring, developmental and offspr ing effects were seen in the presence of maternal/systemic toxicity at the same dose levels. Consequently, there is no evidence of quantitative or qualitative increased susceptibility following pre

- and/or postnatal exposures and there are no concerns or residual uncertainties.

Rimsulfuron did not demonstrate neurotoxicity in the acute or subchronic neurotoxicity studies, nor did it suppress the immune response in the immunotoxicity study.

HED classified rimsulfuron as “Not Likely to be Carcinogenic to H umans” based on the lack of evidence for carcinogenicity in rats and mice in the long term carcinogenicity studies. Rimsulfuron is not considered to be a mutagen or clastogen. It has low acute oral, dermal and inhalation toxicity, but is a moderate eye i rritant. It is not a dermal sensitizer.

In standard metabolism studies, there were no remarkable differences in the excretion pattern of either males or females in the low, high or repeat dose groups. Within the first 72 hours, greater
than 90% of the ad ministered radioactivity was excreted. Urinary elimination predominated, accounting for approximately 64% of the dose; approximately 30% was eliminated in the feces. Monitoring of the expired air indicated that less than 0.08% of the radiolabel was present in expired CO 2 . For all of the treatment groups, 93 to 96% of the radioactivity administered was recovered in either the feces (20 to 33%) or urine (58 to 67%). After 72 hours, the animals were
sacrificed and the tissue distribution of labeled residues wa s determined. Low, but detectable amounts of radioactivity were found in the heart, lung, liver, kidney, and muscle; animals in the repeat dose groups also showed some accumulation in the spleen. Hepatic accumulation, although low, was slightly higher than other organs; within each treatment group, the males showed more accumulation in the liver than the females. The metabolic profiles were determined on pooled urinary and fecal samples. The highest percentage of the urinary (42 to 55%) and fecal (5 to 16% ) radioactivity was attributed to unmetabolized parent compound. Metabolism largely involved either the contraction or cleavage of the sulfonylurea bridge. Following contraction of the sulfonylurea bridge, demethylation to metabolite P5 and subsequent hydr oxylation to metabolite P4 occurred. Data on enzymatic (β

- glucuronidase) or acid hydrolysis were not presented. Therefore, the contribution of Phase II biotransformation reactions to the
detoxification of DPX

- E9636 could not be assessed.Rimsulfuron Human Health Risk Assessment DP. No. 408722

Page 12 of 37 No dermal absorption or dermal toxicity data are available for this chemical, and the dermal absorption factor of 100% is used for risk assessment.

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

The rimsulfuron database is considered complete and sufficient for risk assessment. There are no concerns for neurotoxicity or susceptibility, and t here are no residual uncertainties in the exposure database. Therefore, HED determined that the FQPA SF can be reduced to 1x.

4.2.1 Completeness of the Toxicology Database

The toxicity database for rimsulfuron is considered to be complete and sufficient for endpoint selection for exposure/risk assessment scenarios and for evaluation of the requirements under FQPA, and an additional database uncertainty f actor does not need to be applied.

The required inhalation toxicity study for rimsulfuron has been waived based on rimsulfuron’s use pattern (MOEs > 4,400), physical chemical properties, low acute inhalation toxicity, and a
lack of evidence that a point o f departure ( POD ) from a subchronic inhalation toxicity study would be more protective than the available POD from an oral study for inhalation risk

assessment. (K. Rury, TXR#0056438, 09/17/2012). In absence of a route specific inhalation toxicity study, a POD for inhalation exposure risk assessment as been extrapolated from an oral study.

4.2.2 Evidence of Neurotoxicity

An acute neurotoxicity study was conducted in rats at dose levels up to 2000 mg/kg. No significant adverse effects on neurologic tissu e or function were observed. Functional observation battery , motor activity, gross and microscopic pathology, all failed to show an increased incidence of adverse effects that could be related to treatment. The neurotoxicity
lowest observed adverse effect level ( LOAEL ) was not established. The no observed adverse effect level ( NOAEL ) was 2000 mg/kg, the highest dose level in the study, and the limit dose.

A subchronic neurotoxicity study was conducted in rats at dose levels up to 7500 ppm (438/507 mg/kg/d ay in Males/Females). There were no treatment related effects on mortality, clinical signs, body weight, brain weight or gross and histologic pathology or neuropathology. Functional operational battery (FOB) and motor activity testing revealed no treatment

- related
effects. The LOAEL was not established. The NOAEL was 7500 ppm, equivalent to 438 and 507 mg/kg/day in males and females, respectively.

The available neurotoxicity battery, therefore, did not raise concern for neurotoxicity. Similarly,
the subchronic and chronic data in the database did not show any adverse effects that could be considered as neurotoxicity.

4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young AnimalRimsulfuron Human Health Risk Assessment DP. No. 408722

Page 13 of 37 In the developmental toxicity study in rats, no developmental toxicity was seen at the hig hest dose tested. In the developmental toxicity study in rabbits, and in the two generation study in rats, developmental and offspring toxicity (see Section 4.3) were seen only in the presence of maternal/systemic toxicity. Consequently, there is no evid ence of quantitative or qualitative increased susceptibility following pre

- and/or postnatal exposures.

4.2.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database. Since the dietary and non

- dietary

e xposure estimates were based on several conservative assumptions, HED does not believe that the exposure estimates are underestimated. The chronic dietary assessment utilized tolerance

level residues for all crops. In addition, default processing factors were incorporated into the assessment, and 100% crop treated was assumed for all commodities. The DEEM analysis also assumed that all drinking water will contain rimsulfuron at the highest EDWC levels modeled by EFED for groundwater or surface water. Fo r these reasons it can be concluded that the dietary

exposure analysis does not underestimate risk from chronic exposure to rimsulfuron.

4.3 Toxicity Endpoint and Point of Departure Selections

4.3.1 Dose

- Response Assessment

Endpoint selection and points of departure have been presented in a previous risk assessment (E. Holman, D384623, 11/04/11), and are summarized in Table 4.3.4.

For acute dietary exposure, there were no toxicological effects attributable to a single dose

o bserved in oral toxicity studies including the acute neurotoxicity study in rats (currently under review) and developmental toxicity studies in rats and rabbits. Therefore, a dose and endpoint
were not selected for this risk assessment.

For chronic dieta ry exposure, the rat chronic/carcinogenicity study was selected for risk
assessment because the NOAEL from that study represents the lowest available NOAEL for effects of rimsulfuron following long

- term dietary administration, and is protective of all othe r toxic effects seen in the existing database. The study is appropriate for chronic dietary exposure due to the route (oral) and long

- term duration of dosing. Chronic mouse and dog studies were also considered for chronic dietary exposure; however, the c hronic rat study provided the most sensitive endpoints for chronic dietary risk assessment.

No residential exposures are anticipated for the projected use patterns, so residential risk
assessments were not conducted.

For short

- and intermediate

- term dermal and i nhalation exposures, in the absence of route

specific data, the subchronic oral toxicity study in dogs was used for dermal risk assessment. The selected endpoint provides the most sensitive NOAEL available from a study of appropriate duration, i.e. subchronic. Since the endpoint for risk assessment was selected from an oral study, a dermal absorption value of 100% was used for route

- to

- route extrapolation in the riskRimsulfuron Human Health Risk Assessment DP. No. 408722

Page 14 of 37 assessment, and equivalent toxicity via the inhalation and oral routes was ass umed for the purpose of route

- to

- route extrapolation. In the subchronic dog study, the minimal effects seen at the LOAEL, increased urinary volume, kidney weights, and decreased osmolality, are supported by the observations that the kidney is a target or gan in rats and dogs (increased kidney weights, diueresis) following rimsulfuron exposure; also, other sulfonylurea compounds in the HED Integrated Structure, Toxicity, Endpoints and Properties (iSTEP) database produce kidney effects such as nephropathy, k idney weight changes and atrophy in subchronic, chronic and multi

generation reproduction studies. Therefore, the study and endpoint used for short

- and
intermediate

- term dermal and inhalation exposures are considered appropriate for risk

assessment.

Th e dog subchronic study used for s hort

- and intermediate

- term dermal and i nhalation exposures provides a lower NOAEL than the rat chronic rat study used for the Chronic RfD. However, the LOAELs for both studies, 120 mg/kg/day for the rat study versus 125 mg/ kg/day are very similar, suggesting that the difference in NOAELs may just be a matter of dose selection, and thus not toxicologically significant.

4.3.2 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk
Assessment

Table 4.3.4 Sum mary of Toxicological Doses and Endpoints for Rimsulfuron for Use in Dietary, Non

Occupational, and Occupational Human Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty/FQP

A Safety Factors RfD, PAD,

Level of
Concern for
Risk
Assessment Study and Toxicological Effects

Acute Dietary (All Populations) An appropriate endpoint attributable to a single dose was not identified.

Chronic Dietary (All Populations) NOAEL=

11.8 mg/kg bw/day UF A =10x

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

= 0.118 mg/kg/day

cPAD =
0.118 mg/kg/day Combined Chronic/Carcinogenicity

- Rat

LOAEL= 121 mg/kg/day in males; 568mg/kg/day in females (NOAEL=163 mg/kg/day), based on decreased body weight gains and liver effects.

Incidental
Oral Short

Term (1

- 30 days);
I ntermediate

Term (1

- 6 months) Use pattern does not indicate a need for this risk assessment.

Dermal Short

Term (1

- 30 days);
I ntermediate

Term (1

- 6 months) NOAEL=

6.25 mg/kg /day UF A =10x

UF H =10x

DAF=100% Occupational

LOC for
MOE = 100 90 Day Toxicity

- Dog

LOAEL=125 mg/kg/day, based on increased urinary volume, kidney weights, and decreased osmolality.Rimsulfuron Human Health Risk Assessment DP. No. 408722

Page 15 of 37 Table 4.3.4 Sum mary of Toxicological Doses and Endpoints for Rimsulfuron for Use in Dietary, Non

Occupational, and Occupational Human Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty/FQP

A Safety Factors RfD, PAD,

Level of
Concern for
Risk
Assessment Study and Toxicological Effects

Inhalation Term (1

- 30 days);
I ntermediate

Term (1

- 6 months) NOAEL=

6.25 mg/kg /day UF A =10x

UF H =10x Occupational

LOC for
MOE = 100 90 Day Toxicity

- Dog

LOAEL=125 mg/kg/day, based on increased urinary volume, kidney weights, and decreased osmolality.

Cancer (oral, dermal, inhalation) Rimsulfuron is considered “not likely to be carcinogenic to humans” due to the absence of

tumors in rat and mo use carcinogenicity studies.

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. UF A = extrapolation from animal to human (intraspecies). UF H = potential variation in sensitivity among members of the hu man population (interspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. DAF=Dermal absorption factor. I nhalation toxicity considered to be equivalent to toxicity via the oral route

.Rimsulfuron Human Health Risk Assessment DP. No. 408722

Page 16 of 37 5.0 Dietary Exposure and Risk Assessment

5.1 Residues of Concern Summary and Rationale

The residue of concern for enforcement and risk assessm ent is the parent compound,
rim sulfuron. The residues of concern for drinking water include parent rimsulfuron and all major degradates which maintain the sulfonylurea bridge which include d egradates identified as
IN

- 70941 and IN

- 70942 ( structures listed in Appendix C ). Therefore , the total resi due method will be used to estimate exposure in drinking water sources.

Table 5.1

. Compounds to be I ncluded in th e Rimsulfuron Risk Assessment and Tolerance Expression

.

Matrix Residues included in Risk
Assessment Residues included in
Tolerance Expression

Plants Primary Crop R imsulfuron Ri msulfuron

Rotational Crop Rimsulfuron Rimsulfuron

Livestock Ruminant Rimsulfuron Rimsulfuron

Poultry Rimsulfuron Rimsulfuron

Drinking Water Rimsulfuron , IN

- 70941 and
IN

- 70942 Not Applicable

5.2 Food Residue Profile

Permanent tolerances have been established under 40 CFR §180.478(a) for residues of rimsulfuron at 0.01 ppm in/on citrus fruit, pome fruit, stone fruit, grapes, tree nuts, pistachios caneberry and bushberries; 0.05 ppm in/on tomatoes, 0. 09 ppm in/on almond hulls, 0.1 ppm in/on field corn grain, forage, and stover; chicory (roots and tops) is 0.01 ppm. The proposed tolerance associated with the new uses of rimsulfuron on sorghum grain, forage, and stover is
0.01 ppm. B ased on the registe red /proposed ruminant feed items

, t here is no reasonable expect ation of finite residues of rim sulfuron in livestock commodities

. Adequate field trial and storage stability data are available to support the established/recommended tolerances.

5.3 Drinking Water Residue Profile

The drinking water residues used in the dietary r isk assessment were provided EFED ( M. Barrett, D414506, 03/13/2014)

. Water residues were incorporated directly into the DEEM

- FCID assessment under the food categories “water, direct, all sources” and “water, indirect, all
sources.”

Rimsulfuron foliar applications using ground and aerial sprays impact both surface and ground water drinking water sources given that it possesses similar physical chemical properties and persistence to other chemicals which are known to translocate to these media.

The estimate is based on assessment of all registered uses using the Tier 1 model PRZM

- GW ( Pesticide Root Zone Model

- Ground Water). The models and their descriptions are available atRimsulfuron Human Health Risk Assessment DP. No. 408722

Page 17 of 37 the EPA internet site: http://www.epa.gov/oppefed1/models/water/ . The maximum estimated drinking water concentrations (EDWCs) are presented below in Table 5.3

.

In this updated drinking water exposure assessment it has been determined that exposure from the current and proposed uses should not exceed 22.2 μg/L (ppb) for acute exposure and 19.7 μg/L (ppb) for chronic and cancer exposure. The values in Table 5.3 ar e based on uses from several crop sites with higher single and seasonal maximum application rates than proposed for
the new use on ALS inhibit or tolerant sorghum. These values reflect a predicted higher potential exposure level from groundwater sourced dr inking water supplies than surface water supplies.

Table 5.3. Maximum Ti er I Rimsulfuron ROC EDWCs for Drinking Water Based on A pplication to Crops with Highest Rates and Exposure P otential.

Crops (scenario) Highest Daily Value (Acute) Post

- Breakthrough Average (Chronic and Cancer)

All 22.2 19.7

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Existing and recommended tolerance

- level residues [40 CFR §180.478(a)] have been used for all
food commodities in this assessment. Permanent tolerances are established for residues of rimsulfuron at levels ranging from 0.01 ppm to 4.5 ppm . For the propos ed new use on sorghum, a tolerance level of 0.01 ppm is recommended ( D 418153 , M. Negussie, 03/ 17 /2014 ).

DEEMTM Version 7.81 default processing factors were applied to all processed commodities for which they were available. In the processing study for soybean oil, residues did not concentrate. Therefore, the processing factor was left at 1.0.

5.4.2 Perce nt Crop Treated Used in Dietary Assessment

It was assumed that 100% of foods in the assessment had residues of rimsulfuron ( i.e. , 100% crop treated).

5.4.3 Acute Dietary Risk Assessment

No acute dietary toxicity endpoint could be identified based on t he toxicology data currently
available for rimsulfuron; therefore, an acute assessment was not performed

.

5.4.4 Chronic Dietary Risk Assessment

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 cPAD for the general U.S. population and
1.4% of the cPAD for all infants and children 1

- 2 years old, the most high ly expose d population subgroup

. Therefore, the chronic dietary risk is not of concern (i.e., <100% of the cPAD).Rimsulfuron Human Health Risk Assessment DP. No. 408722

Page 18 of 37 5.4.5 Cancer Dietary Risk Assessment

Rimsulfuron 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 . Chronic Aggregate Dietary (Food + Drinking Water) Exposure and Risk for Rimsulfuron

Population Subgroup Exposure (mg/kg/day) % cPAD

General U.S. Population 0.000807 <1

All Infants (< 1 year old) 0.001710 1.4

Children 1

- 2 years old 0.001658 1.4

Children 3

- 5 years old 0.001473 1.2

Children 6

- 12 years old 0.001002 <1

Youth 13

- 19 years old 0.000724 <1

Adults 20

- 49 years old 0.000743 <1

Adults 50

- 99 years old 0.000652 <1

Females 13

- 49 years old 0.000724 <1

1 The population subgroup with the highest estimated chronic dietary (food + drinking water) exposure and risk is indicated by bold text.

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no proposed residential us es for rimsulfuron, therefore a non

- occupational exposure
assessment was not 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 rimsulfuron at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV ), low vapor pressure (7.5 x10

- 8 mm Hg at 25 oC), and the low proposed use rate (0.031 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 is sues 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, 2010 1 . The Agency is in the process of evaluating t he 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

1 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlRimsulfuron Human Health Risk Assessment DP. No. 408722

Page 19 of 37 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
rimsulfuron.

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 rim sulfuron. 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 (se e 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 Dr ift 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, exposure s 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
dura tion 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 rimsulfuron. Therefor e, the aggregate risk assessment for rimsulfuron 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 and
1.4% of the cPAD for all infants and children 1

- 2 years old, the most high ly exposed populatio n subgroups

.

8.0 Cumulative Risk Characterization/Assessment

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding for
rimsulfuron and any other substances, and rimsulfuron does not appear to produce a toxic metabolite produced by other substances. For the purposes of this action, therefore, EPA has

2 Available: http://www.epa.gov/opp00001/fac tsheets/spraydrift.htmRimsulfuron Human Health Risk Assessment DP. No. 408722

Page 20 of 37 assumed that rimsulfuron does not have a common mechanism of toxicity with other sub stances. 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 Occupation al Exposure/Risk Characterization

T here is potential for short

- and intermediate

- term occupational exposure to rimsulfuron during both handler [mixing, loading, and application (via the dermal and inhalation routes)] and post

application activities (via t he dermal route) based on the proposed uses.

9.1 Short

- / Intermediate

- Term Handler Risk

HED has evalu ated occupational exposure from the proposed uses of rimsulfuron. Application methods, maximum application rates, and use sites are summarized in Table 3.3. Chemigation application is prohibited on the proposed labels; however, rimsulfuron may be applied with aerial and ground equipment. Based on application rate and label information, only short

- and
intermediate

- term exposure is expected for occupati onal 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 account for variability within species. The total uncertai nty factor that has been applied to the handler

assessment of rim sulfuron 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 and inhalation risk estimates for occupational handlers applying rimsulfuron is provided in Tab le 9. 1. There are no risk estimates of concern for the proposed uses of rimsulfuron at labeled PPE (baseline + gloves, no respirator). At labeled PPE

, all short

- and intermediate

- term occupational handler combined (dermal + inhalation) MOEs ranged from 2 20 to 6,700

.Rimsulfuron Human Health Risk Assessment DP. No. 408722

Page 21 of 37 Table 9.1

. ST and IT Occupational Handler Exposure and Risk Estimates for Rimsulfuron

Exposure Scenario Crop Dermal Unit Exposure ( μ g/lb ai) 1 Inhalation Unit

Exposure ( μ g/lb ai) 1 Maximum

Application
Rate 2
(lb ai/A) Area

Treated Daily 3
(A/day) Dermal Inhalation Total

Baseline + Gloves Baseline

(no respirator) Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8

Mixer/Loader

Aerial (SG form.) Sorghum 51.6 8.96 0.031 1200 0.024 260 0.0042 1,500 220

Groundboom (SG form.) 51.6 8.96 0.031 200 0.0040 1,600 0.00070 9,000 1,400
Applicator
Aerial (liquid form.) Sorghum 2.08 0.0049 0.031 1200 0.00094 6,700 0.0000022 2,800,000 6,700
Groundboom (liquid form.) 16.1 0.34 0.031 200 0.0013 5,000 0.000027 240,000 1,000
Flagger
Flagger Sorghum 12.0 0.35 0.031 350 0.0016 3,800 0.000048 130,000 3,800

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table”

2 Based on registered or proposed label (Reg. No. 352

- 748 and 352

- 816 ).
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) × Ap plication Rate (lb ai/acre ) × Area Treated (A /day) × DAF ( 100 %) ÷ BW ( 80 kg).
5 Dermal MOE = Dermal NOAEL ( 6.25 mg/kg/day) ÷ Dermal Dose (mg/kg/day).
6 Inhalation Dose = Inhalation Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × App lication Rate (lb ai/acre ) × Area Treated (A /day) ÷ BW ( 80 kg).
7 Inhalation MOE = Inhalation NOAEL ( 6.25 mg/kg/day) ÷ Inhalation Dose (mg/kg/d ay).
8 Total MOE = NOAEL ( 6.25 mg/kg/day) ÷ Dermal Dose + Inhalation Dose

.Rimsulfuron Human Health Risk Assessment DP. No. 408722

Page 22 of 37 9.2 Short

- Term Post

- Application Risk

9.2.1 Dermal Post

- Application Risk

Rimsulfuron is applied as a postemergence spray to control weeds in sorghum. Common post

application activities performed on commercially grown sorghum fields are scouting and hand weeding which have the potential for dermal exposure to workers performing such activities. However, hand weeding would not be necessary following application of an herbicide. Therefore, only dermal exposures during scouting activities were assessed. Although s hort

- and
intermediate

- term exposure s could occur for the proposed use rimsulfuron on sorghum, since the
POD is the same for dermal short

- and intermed iate

- term exposures, one assessment is protective
of both durations.

Chemical

- specific dislodgeable foliar residue (DFR) data have not been submitted for
rimsulfuron . 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 DF R study is not required for rimsulfuron at this time
since the dermal MOE s are greater than 4 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 3,400 on the day of application. Therefore, there ar e no post

- application risk estimates of concern for
rimsulfuron.

Table 9.2 presents the results of the occupational post

- application risk assessment when HED default assumptions are used. Using surrogate data, the dermal MOEs from agricultural post

application activities are greater than 100 and are not of concern.

Table 9 .2

. Occupational Post

- application Non

- Cancer Exposure and Risk Estimates for Rimsulfuron

.

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 0.0869 0.0018 3,400

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 ( 80 kg).
3 MOE = POD ( 6.5 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 rim sulfuron at this time primarily because of the low acute inhalation toxicity (Toxicity Categ ory IV), low vapor pressure (7.5 x 10

- 8 mm Hg at 25oC), and the low proposed use rate (0.031 lb ai/A). However, there are multiple potential s ources of post

application inhalation exposure to individuals performing post

- application activities inRimsulfuron Human Health Risk Assessment DP. No. 408722

Page 23 of 37 previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pest icides. 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, 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 inhalatio n expo sure assessment for rim sulfuron.

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 expo sure scenarios.

10.0 References

M. Barrett. 03/13/14. D414506. Tier I Dri nking Water Assessment for the proposed Section 3 ALS inhibition tolerant sorghum crops new use for the chemical Rimsulfuron (P.C. Code: 129009, DP Barcode 414506 )

.

M. Negussie. 03/17/14. D394389. Rimsulfuron Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section 3 Registration on Acetolactase Synthase (ALS) Tolerant Grain Sorghum.

M. Negussie. 03/17/14. D418153. Rimsulfuron . Petition for the Establishment of Permanent
Tolerances for Uses on Acetolactase Synthase (ALS) Tolerant Grain Sorghum. Summary of Analytical Chemistry and Residue Data.

C. Walls. 05/04/12. D391083

. Rimsulfuron. Human Health Risk Assessment for Prop osed Section 3 Use on Chicory.

C. Walls. 05/04/12. D418152. Rimsulfuron: Occupational and Residential Exposure
Assessment for the New Use on ALS

- Tolerant “DuPont INZEN Z” Sorghum

.

3 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlRimsulfuron Human Health Risk Assessment DP. No. 408722

Page 24 of 37 Appendix A: Physical and Chemical Properties

Table A.1

. Physicochemical Properties of Rimsulfuron

Parameter Value Reference Melting point 176

- 178  C Reviewed in DP# 193018, M. Nelson, 23/NOV/1993; All product chemistry requirements reported to be
fulfilled.

Also, MRID No. 475 7 2805. pH 4.32 to 5.89 (1% dilution in water) Density 0.784 ± 0.0016 g/mL Water solubility pH 5: 0.135 ± 0.005 g/L (25°C) pH 7: 7.3 ± 0.03 g/L (25  C) pH 9: 5.56 ± 0.05 g/L (25  C) pH 4

- 4.5: 0.024 ± 0.001 g/L (20  C) Solvent solubility (25°C) N,N

- dimethylformamide 241 ± 1 g/L Dimethyl sulfoxide 113 ± 3 g/L Methylene chloride 35.5 ± 0.4 g/L
Acetonitrile 17.2 ± 0.5 g/L
Acetone 14.8 ± 0.5 g/L Ethyl acetate 2.85 ± 0.17 g/L
Methanol 1.55 ± 0.11 g/L
Toluene 0.363 ± 0.022 g/L Xylenes 0.093 ± 0.008 g/L

n

- Hexane <0.01 g/L Vapor pressure (25°C) <10

- 5 Pa ; 7.5x10

- 8 mmHg Dissociation constant, pK a 4 Octanol/water partition coefficient, Log(K OW ) pH 5: 1.94 pH 7: 0.0342 pH 9: not attempted UV/visible absorption spectrum pH 1.80 at 230 nm, ε = 1.78 x 10 4 (log ε = 4.25) and at 290 mm, ε = 1.81x 10 2 (log ε = 2.26)

pH 2.10 at 290 nm, ε = 2.03 x10 2 (log ε = 2.31)

pH 5.03 at 240 nm, ε = 2.24 x 10 4 (log ε = 4.35) and at 290 nm, ε = 4.81 x 10 2 (log ε = 2.68)Rimsulfuron Human Health Risk Assessment DP. No. 408722

Page 25 of 37 Appendix B : Toxicity Profile and Executive Summaries

B

. 1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for Food Use for Rimsulfuron are in the following table. 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 Primary Eye Irritation

................................ .................... 870.2500 Primary Dermal Irritation

................................ .............. 870.2600 Dermal Sensitization

................................ ..................... yes
yes
yes
yes
yes
yes yes

yes
yes
yes
yes
yes 870.3100 Oral Subchronic (rodent)

................................ ............... 870.3150 Oral Subchronic (nonrodent)

................................ ......... 870.3200 21

- Day Dermal

................................ .............................. 870.3250 90

- Day Dermal

................................ .............................. 870.3465 90

- Day Inhalation

................................ .......................... yes
yes

no

no

no yes

yes waived

-- waived
870.3700a Developmental Toxicity (rodent)

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

............................ 870.3800 Reproduction

................................ ................................ . yes
yes
yes yes

yes
yes 870.4100a Chronic Toxicity (rodent)

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

................................ ........ 870.4200a Oncogenicity (rat)

................................ .......................... 870.4200b Oncogenicity (mouse)

................................ ................... 870.4300 Chronic/Oncogenicity

................................ ................... no
yes

no
yes
yes yes

yes
yes
yes
yes 870.5100 Mutagenicity

— Gene Mutation

- bacterial

..................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

................ 870.5375 Mutagenicity

— Chromosomal Aberrations

................... 870.5395 Mutagenicity

— In Vivo micronucleus

........................... yes
yes
yes
yes yes

yes
yes
yes 870.6100a Acute Delayed Neurotox. (hen)

................................ ..... 870.6100b 90

- Day Neurotoxicity (hen)

................................ .......... 870.6200a Acute Neurotox. Screening Battery (rat)

....................... 870.6200b 90

- Day Neuro. Screening Battery (rat)

......................... 870.6300 Develop. Neuro

................................ ............................. no

no
yes
yes

no - -

- - yes
yes

-- 870.7485 General Metabolism

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

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

................................ ............................. yes

no
yes yes

-- yes Special Studies for Ocular Effects

Acute Oral (rat)

................................ ........................... Subchronic Oral (rat)

................................ .................. Six

- month Oral (dog)

................................ .................. no

no

no --

--

--Rimsulfuron Human Health Risk Assessment DP. No. 408722

Page 26 of 37 B

. 2 Toxicity Profile Tables

Table A.2.1 Acute Toxicity Profile

– Rimsulfuron

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

870.1100 Acute oral Rat

Acute oral Mouse 41356311
41356310
41931634

41931623 LD 50 = > 5000

mg/kg

LD 50 = > 5000 mg/kg IV

IV
870.1200 Acute dermal Rabbit 41356312
41356313
41931624
41931635 LD 50 = > 2000

mg/kg IV

870.1300 Acute inhalation Rat 41356314
41931625
41931637
41931636 LC 50 = >5.4; >

5.0; > 7.5; > 5.4 mg/L IV

870.2400 Acute eye irritation Rabbit 41931626
41356315
41356316
41931638 Moderate eye

irritant III

870.2500 Acute dermal irritation Rabbit 41931627
41356318
41931639
41356317 No irritation IV

870.2600 Skin sensitization Guinea Pig 41931628
41356320
41931641
41931640
41356319 Not a sensitizer IVRimsulfuron Human Health Risk Assessment DP. No. 408722

Page 27 of 37 Table B .2.2 Subchronic, Chronic and Other Toxicity Profile

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

870.3100
90

- Day oral toxicity (rat) 41356321 (1989)

0, 50, 1500, 7500, 2000 ppm 0, 2.5, 75, 375, 1000 mg/kg bw/day

Acceptable

- Guideline NOAEL = 75 mg/kg bw/day
LOAEL = 375 mg/kg bw/day based on reduced body wt. gains.

870.3100
90

- Day oral toxicity (mouse) 41356323 (1989) (90

- day oral toxicity in the mouse is not required under the 1884 Subdivision F guideline requirements.)

0, 50, 375, 1500, 7500 ppm 0, 7.5, 56.25, 225, 1125 mg/kg bw/day

Acceptable

- Nonguideline NOAEL = M: 56.25 ; F: >1125 mg/kg bw/day
LOAEL = M: 225 mg/kg bw/day based on increased RBC and hemoglobin and decreased body weight gain and food efficiency. F: LOAEL not established.

870.3150
90

- Day oral toxicity (dog) 41356322 (1989)

0, 250, 5000, 20000 ppm 0, 6.25, 125, or 500 mg/kg bw/day.

Acceptable

- Guideline NOAEL = 6.25 mg/kg bw/day
LOAEL = 125 mg/kg/day based on urinary volume and osmolarityRimsulfuron Human Health Risk Assessment DP. No. 408722

Page 28 of 37 Table B .2.2 Subchronic, Chronic and Other Toxicity Profile

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

870.3700a
Prenatal developmental in (Rat) 41356324 (1989)

0, 200, 700, 2000, 6000 mg/kg bw/day

Acceptable

- Guideline Maternal NOAEL ≥ 6000 mg/kg bw/day
LOAEL = not established Developmental NOAEL ≥ 6000 mg/kg bw/day
LOAEL = not established

870.3700b
Prenatal developmental in (rabbit) 41356325 (1989)

0, 25, 170, 500, 1500 mg/kg bw/day

Acceptable

- Guideline Maternal NOAEL = 170 mg/kg bw/day LOAEL = 500 mg/kg bw/day based on death and reduced weight gain. Developmental NOAEL = 500 mg/kg bw/day Developmental LOAEL = 1500 mg/kg bw/day based on production of only two
viable fetuses.

870.3800 Reproduction and fertility effects (rat) 41931644 (199 0)

0, 50, 3000, 15000 ppm 0, 2.76, 165, 830 mg/kg bw/day (F 0 males) 0, 3.38, 204, 1021 mg/kg bw/day (F 0 females) 0, 3.66, 217, 1316 mg/kg bw/day (F 1 males) 0, 4.29, 264, 1316 mg/kg bw/day (F 1 females)

Acceptable

- Guideline Parental/Systemic NOAEL = 1 65 mg/kg bw/day in males, 204 mg/kg bw/day in
females Parental/Systemic LOAEL = M: 830; F: 1021mg/kg bw/day based on decreased body weight gain in males and females Reproductive NOAEL =1316 mg/kg bw/day (HDT) Reproductive LOAEL = Not Established.

Offspring NOAEL = M: 217; F; 264 mg/kg bw/day LOAEL = 1316 mg/kg bw/day based on decreased mean body weight in F 1 males, decreased body weight gain in F 1 females and decreased daily food consumption in
F 1 males.Rimsulfuron Human Health Risk Assessment DP. No. 408722

Page 29 of 37 Table B .2.2 Subchronic, Chronic and Other Toxicity Profile

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

870.4100b Chronic toxicity (dog) 41931643( 1991)

0, 50, 2500, 10,000 ppm 0, 1.6, 81.8, 342.4 mg/kg bw/day (males); 0,1.6, 86.5, 358.5 mg/kg bw/day (females)

Acceptable

- Guideline Following re

- evaluation (HED DOC. NO. 012501, HIARC, 19/FEB/1998):

NOAEL = in males 81.8 mg/kg/day and
in females 86.5 mg/kg bw/day. LOAEL = 342.4 mg/kg/day) based on increased absolute liver and kidney weights and increased incidence of seminiferous tubule degeneration and increased numbers of spermatid giant cells present in epididymides in males.
The LOAEL in fem ales is 358.5 mg/kg/day based on decreased mean body weight and body weight gain, increased
serum cholesterol levels and alkaline phosphatase activity, increased absolute liver weight, and increased relative liver and kidney weights.

870.4200 Carcinogenicity (rat) 42047701(1991)

0, 25, 300, 3000, 10,000 ppm 0, 1.0, 11.8, 121, 414 mg/kg bw/day (males) 1.38, 17.1, 163, 568 mg/kg bw/day (females)

Acceptable

- Guideline NOAEL = 11.8 mg/kg bw/day for males and 163 mg/kg/day for females.
LOAEL = 121 mg/kg bw/day for males
and 568 mg/kg bw/day for females, based on decreased body weight gain and liver
effects.

No evidence of carcinogenicity.

870.4300 Carcinogenicity (mouse) 41931642 (1991)

0, 25, 250, 2500, or 7500 ppm 0, 3.47, 35.5, 351, or 1127 mg/kg bw/day (males) 0, 4.99, 50.5, 488, or 1505 mg/kg bw/day (females)

Acceptable

- Guideline NOAEL = 351 mg/kg bw/day (males);
488 mg/kg bw/day (females).
LOAEL = 1127 mg/kg bw/day for males;
and 1505 mg/kg bw/day , females, based

on decreased mean body weight in males and females, increased incidence of dilation and cysts in the glandular stomach and degeneration of the testicular artery and tunica albuginea in males.
No evide nce of carcinogenicity.Rimsulfuron Human Health Risk Assessment DP. No. 408722

Page 30 of 37 Table B .2.2 Subchronic, Chronic and Other Toxicity Profile

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

870.5100
In vitro Bacterial Gene Mutation Assay 42471310 (1992)

Trial 1 5000, 1000, 750, 500, 100, 75, 50, 25, 10, 0 μg/plate

Trial 2 5000, 2500, 1000, 750, 500, 100, 0 μg/plate in the presence and absence of mammalian
metabolic activation with 0.5 ml S

- 9 mix.

Acceptable

- Guideline There was no evidence of induced mutant colonies over background.

870.5300
In Vitro Mammalian
Cells in Culture Gene Mutation assay in
CHO 41356328 (1989)

0, 10, 100, 250, 750, 1300 μg/mL i n the presence and absence of mammalian
metabolic activation with S/9.

Acceptable

- Guideline

41356327 (1989)

0, 0.0008, 0.004, 0.008, 0.04, 0.08, 0.4, 0.8, or 1.1 mg/mL

Acceptable

- Guideline There was no evidence of induced mutant
colonies over background.

There was no evidence that unscheduled DNA synthesis, as determined by radioactive tracer procedures [nuclear silver grain counts] was induced.Rimsulfuron Human Health Risk Assessment DP. No. 408722

Page 31 of 37 Table B .2.2 Subchronic, Chronic and Other Toxicity Profile

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

870.6200a Acute Neurotoxicity (rat) 48710302 (2011) 0, 200, 1000, 2000 mg/kg

Acceptable

- Guide line NOAEL = 2000 mg/kg LOAEL > 2000 mg/kg. No clinical signs, changes in body weight and/or food consumption, gross or microscopic pathology, or
neurobehavioral effects were observed
870.6200b
Subchronic Neurotoxicity (rat) 48710303 (2011) 0, 1000. 3000, 7500 ppm (M/F) 0, 55. 170, 438 mg/kg/day (M) 0, 69, 193, 507 mg/kg/day (F)

Acceptable

- Guideline NOAEL = 438/507 mg/kg/day (M/F)
LOAEL > 438/507 mg/kg/day (M/F) No clinical signs, gross or microscopic pathology, or changes in survival, body weight and/or food consumption,
fore/hind

- limb grip strength, footsplay, body temperature, rearing, FOB measurements or motor activity were
observed.

870.7800
28

- day Immuno

toxicity (mouse) 48710305 (2011) 0, 300, 600, 1800, 6500 ppm 0, 45, 93, 288, 1006 mg/kg/day

Ac ceptable

- Guideline NOAEL = 1006 mg/kg/day LOAEL > 1006 mg/kg/day No clinical signs, gross or microscopic pathology, or changes in body weight and/or food consumption, brain, spleen or thymus weights, or in humoral immune

response were observed.Rimsulfuron Human Health Risk Assessment DP. No. 408722

Page 32 of 37 Table B .2.2 Subchronic, Chronic and Other Toxicity Profile

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

870

- 7485
Metabolism

-- Rat 42540701 (1989)

Low Dose Group: C 14

- pyridine DPX

- E9636 administered once by oral gavage at a dose of 25 mg/kg (4.6 μCi/mg).

High Dose Group: Either C 14

- pyridine

DPX

- E9636 (0.47 μCi/mg) or C 14

- pyrimidine

- DPX

- E9636 (0.45 μCi/mg) was
admi nistered once by oral gavage at a dose of 250 mg/kg.

Repeat Dose: Either Propylene glycol, or unlabeled test compound, was administered by oral gavage for 14 consecutive days. On
the 15 th day treated animals received a single
dose of C 14

- pyridine

- DPX

- E96 36 (25 mg/kg, 0.47 μCi/mg).

Acc e ptable/Guideline There were no remarkable differences in the excretion pattern of either males or females in the low, high or repeat dose groups. Within the first 72 hours, greater
than 90% of the administered radioactivity was excreted. Urinary elimination predominated, accounting for approximately 64% of the dose; approximately 30% was eliminated in the feces. Monitoring of the expired air
indicated that less than 0.08% of the radiolabel was present in expired CO 2

.

For a ll of the treatment groups, 93 to 96% of the radioactivity administered was recovered in either the feces (20 to 33%) or urine (58 to 67%). After 72 hours, the
animals were sacrificed and the tissue
distribution of labeled residues was determined. Low, but detectable amounts of radioactivity were found in the heart, lung, liver, kidney, and muscle; animals in the repeat dose groups also showed some accumulation in the spleen. Hepatic accumulation, although low, was slightly higher than other organs; within each treatment group, the males showed more
accumulation in the liver than the
females.

The metabolic profiles were determined on pooled urinary and fecal samples. The highest percentage of the urinary (42 to 55%) and fecal (5 to 16%) radioactivity

was attributed to unmetabolized parent compound. Metabolism largely involved either the contraction or cleavage of the sulfonylurea bridge. Following contraction of the sulfonylurea bridge, demethylation to metabolite P5 and subsequent hydroxylation to metabol ite P4 occurred. Data on enzymatic (β

glucuronidase) or acid hydrolysis were not presented. Therefore, the contribution
of Phase II biotransformation reactions to
the detoxification of DPX

- E9636 could
not be assessed.Rimsulfuron Human Health Risk Assessment DP. No. 408722

Page 33 of 37 B .3 Executive Summaries

The executi ve summaries of the neurotoxicity and immunotoxicity stud ies represent new data and are presented below; the executive summaries of the other studies used in this risk assessment and/or appearing in Table A.2.2 are presented in a previous Risk Assessment
document. Please refer to D. Rate , D3 3 3 256

, 05 /16/200 7

.

870. 6200 Acute and Subchronic Neurotoxicity Battery (rat)

870.6200a In an acute neurotoxicity study (MRID 48710302 ), rimsulfuron (99.8% a.i., Lot/Batch No. FEB10MA206) was administered to 12 male and 12 female Crl:CD(SD) rats/dose by gavage (single dose) a t dose levels of 0, 200, 1000, or 2000 mg/kg on Study Day One and observed for 14 days. The test vehicle was 5% (w/v) carboxymethylcellulose.

Endpoints evaluated included viability, body weights and body weight gains, food consumption,
and clinical observations. Neurobehavioral assessment (functional observational battery and motor activity testing) was performed in 12 rats/sex/group pre

- test, o n the day of dosing, and on days 7 and 14 post dose. At study termination (day 16), 6 rats/sex/group were euthanized and perfused in situ for neuropathological examination. The control and 300 mg/kg rats were subjected to histopathological evaluation of b rain and peripheral nervous system tissues.

All rats survived to study termination. There were no clinical signs, and body weight and food consumption were comparable among the groups throughout the study in both sexes. No significant adverse effects on neurologic tissue or function were observed. Functional observation battery , motor activity, gross and microscopic pathology, all failed to show an increased incidence of adverse effects that could be related to treatment. Brain weight data were

not reported for the study; however, in the absence of any functional or microscopic findings, this deficiency is not considered to significantly degrade the study.

The neurotoxicity LOAEL was not established. The NOAEL was 2000 mg/kg, the highest dose
level in the study, and the limit dose.

870.6200b In a subchronic neurotoxicity study, (MRID 48710303 ) Rimsulfuron (99.8% a.i., Lot/Batch No.
FEB10MA206 ) was administered to 12 male and 12 female Crl:CD(SD) rats/dose in the diet at dose levels of 0, 1000, 300 0, and 7500 ppm (Males: 0, 55, 170, 438 mg/kg/day, Females: 0, 69, 193, 507 mg/kg/day) for approximately 90 days. Neurobehavioral assessments (functional observational battery and motor activity evaluation) were performed in12 rats/sex/group once

pre

- tes t and at weeks 4, 8, and 13. At study termination (test day 98 or 99), 6 rats/sex/group were euthanized and perfused in situ for neuropathological evaluation. Of the perfused animals. the control and 7500 ppm groups were subjected to a histopathological e valuation of brain and peripheral nervous system tissues. The remaining 6 rats/sex/group were sacrificed and discarded without necropsy on test day 100.Rimsulfuron Human Health Risk Assessment DP. No. 408722

Page 34 of 37 There were no treatment related effects on mortality, clinical signs, body weight, brain weight or

gr oss and histologic pathology or neuropathology. Functional operational battery (FOB) and motor activity testing revealed no treatment

- related effects.

The LOAEL was not established. The NOAEL was 7500 ppm, equivalent to 438 and 507 mg/kg/day in males and females, respectively.

CLASSIFICATION: This study is classified as Acceptable /Guideline and satisfies the guideline requirements for a Subchronic Neurotoxicity study in rats, OPPTS 870.6200b . Although the dose levels could have been higher (no effects were observed), rimsulfuron is a sulfonylurea compound, and there is no indication of neurotoxicity in this class of compounds. Another study would not provide any useful data for risk assessment.

870.7800 Subchronic Immunotoxicity study (mouse)

In an immunotoxicity study (MRID 48710305 ), Rimsulfuron (DPX

- E9636) Technical (99.8% a.i., Lot# DPX

- E9636

- 170) was administered to male Crl:CD

- 1(ICR) mice (10/dose) in the diet at dose levels of 0, 300, 600,1800, or 6500 ppm (equivalent to 0, 45, 93, 288, or 1006 mg/kg bw/day, respectively) for 28 consecutive days. Body weights, food consumption, and clinical observations were recorded during the in

- life period. On test day 23, animals were injected intravenously in the lateral tail vein with 0.2 mL of sheep red blood cells (SRBC, 5 x 10 8 /mL). The positive control animals were injected intraperitoneally with cyclophosphamide monohydrate (25 mg/kg/day) for 5 consecutive days (days 23

- 28). Five days after SRBC injection (test day 28), the animals were euthaniz ed by isoflurane anesthesia and exsanguinations. Blood was collected from each mouse, from the abdominal vena cava while the animal was under isoflurane anesthesia, processed to serum, and frozen at <

- 60°C until analyzed.
Humoral immune function was evalua ted by analyzing sera from individual control and test

substance treated animals for anti

- SRBC IgM levels with an enzyme

- linked immunosorbent assay (ELISA). At sacrifice, each animal was examined grossly and selected organs were weighed (brain, spleen, and thymus).

There were no adverse effects on clinical signs, body weight or nutritional parameters in any of the treated group compared with the control.

The systemic toxicity NOAEL for Rimsulfuron in mice is 6500 ppm (equivalent 1006 mg/kg bw/day), teste d above the limit dose.

For immunotoxicity, there were no treatment

- related effects on serum anti

- SRBC IgM antibody levels as measured by an ELISA. A high inter

- individual variability of anti

- SRBC IgM level was noted in all the treatment groups as well a s in the control group. Evaluation of individual animal data did not show any trend or distribution that would demonstrate significant suppression of the
anti

- SRBC antibody response. Animals in the positive control group showed marked decreases
in the anti

- SRBC IgM response. The positive control group confirmed the validity of the immunotoxicity assay.Rimsulfuron Human Health Risk Assessment DP. No. 408722

Page 35 of 37 The Natural Killer (NK) cells activity was not evaluated in this study. The toxicology database
for Rimsulfuron does not reveal any evidence of treatment

- r elated effects on the immune system. The overall weight of evidence suggests that this chemical does not directly target the immune system. Under HED guidance, a NK cells activity assay is not required at this time.

Under the conditions of this study, t he NOAEL for immunotoxicity is 6500 ppm (equivalent to 1006 mg/kg/day). The LOAEL was not established, tested above the limit dose.

This study is classified as acceptable/guideline and satisfies the guideline requirement for an immunotoxicity study (OPPTS 870.7800) in the mouse.Rimsulfuron Human Health Risk Assessment DP. No. 408722

Page 36 of 37 Appendix C: Chemical Name and Structures of Rimsulfuron and Metabolites

Company code; Chemical name Chemical structure

IN

— 70941
N

- (4 ,6

- Dimetho x y - 2

- pyrimidinyl)

- N

- ((3

- ethylsulfonyl)

- 2

- pyridinyl)

urea

IN

- 70942
N

- ((3

- ethylsulfonyl)

- 2

- pyridinyl)

- 4,6

- dimethoxy

- 2

- pyrimidinamine

IN

- E9260
3

- (Ethylsulfonyl )

- 2

- pyridinesulfonamide.

IN

- T5831
N

- (4,6

- dimethoxy

- 2

- pyrimidinyl)urea

IN

- 69190
2

- amino

- 4,6

- dimethoxy

- 5

- pyrimidinol

IN

- J290
2

- Amino

- 4,6

- dimethoxypyrimidineRimsulfuron Human Health Risk Assessment DP. No. 408722

Page 37 of 37 Company code; Chemical name Chemical structure

IN

- H1043
2

- Amino

- 4,6

- dihydroxypyrimidine

IN

- JF999
N

- [((3

- Ethylsulfonyl)

- 2

- pyridinyl)]

- 4

- hydroxy

- 6

- methoxy

- 2

- pyrimidineamine