UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY

AND
POLLUTION PREVENTION

November 4, 2011

MEMORANDUM

SUBJECT: Rimsulfuron. Human Health Risk Assessment for Proposed Section 3 Uses on

Caneberry and B ush berry

.

PC Code: 129009 DP Barcode: D384623, D386178

Decision No.: 4 427470 and 443815 Registration No.: 352

- 768

Petition No.: 0E7809 Regulatory Action: Section 3 Assessment Type: Single Chemical Aggregate Registration Case

No.: N A

TXR No.: N A CAS No.: 122931

- 48

- 0

MRID No.: N A 40 CFR: §180. 478

FROM: Elizabeth Holman

, Chemist /Risk Assessor S. Oonnithan, Biologist

Risk Assessment Branch II

Health Effects Division (HED) (7509P)

THROUGH: Karlyn Middleton, Toxicologist

Christina Swartz, Branch Chief

Risk Assessment Branch II Health Effects Division (7509P)

TO: Sidney Jackson, Review Manager

Barbara Madden, Minor Use Team Leader Risk Integration Minor Use, and Emergency Response Branch Registration Division (7508P)

The Registration Division (RD) requested that the Health Effects Divis i on (HED) conduct a risk

assessment for the active ingredient rimsulfuron to estimate the risk to human health t hat will result from the proposed use to control broadleaf weeds in b ush berry and caneberry.Rimsulfuron Risk Assessment Document D384623, D386178

Page 2 of 37 Table of Contents

1.0 Executive Summary

................................ ................................ ................................ .......... 4

2.0 Ingredient Profile

................................ ................................ ................................ .............. 9

2.1 Propos ed Use Directions

................................ ................................ ....................... 9

2.2 Structure and Nomenclature

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

2.3 Physical and Chemical Properties

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

3.0 Hazard Characterization/Assessment

................................ ................................ ........... 11

3.1 Hazard and Dose

- Response Characterization

................................ .................. 11

3.1.1 Database Summary

................................ ................................ ................. 11

3.1.2 Toxicological Effects

................................ ................................ ............... 12

3.2 Absorption, Distribution, Metabolism, Excretion (ADME)

............................ 13

3.3 FQPA Considerations

................................ ................................ ......................... 13

3.3.1 Adequacy of the Toxicity Database

................................ ....................... 13

3.3.2 Evidence of Neurotoxicity

................................ ................................ ...... 14

3.3.3 Developmental Toxicity

................................ ................................ .......... 14

3.3.4 Reproductive Toxicity

................................ ................................ ............ 14

3.3.5 Pre

- and/or Postnatal Toxicity

................................ ................................ 14

3.3.6 Recommendation for a Developmental Neurotoxicity Study

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

3.3.7 FQPA Safety Factor for Infants and Children

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

3.4 Hazard Identification and Toxicity Endpoint Selection

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

3.4.1 Acute Reference Dose (aRfD)

– Females Ages 13

- 49 and General Population

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

3.4.2 Chronic Reference Dose (cRfD)

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

3.4.3 Dermal Absorption

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

3.4.4 Dermal Exposure (Short

- , Intermediate

- Term)

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

3.4.5 Inhalation Exposure (Short

- , Intermediate

- Term)

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

3.4.6 Level of Concern for Margin of Exposure

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

3.4.7 Recommendation for Aggregate Exposure Risk Assessments

............ 18 When there are potential occupational and residential exposures to a pesticide, the risk assessment must address exposures from three major sources: oral, derma l and inhalation exposures, and determine whether the individual exposures can be combined if they have the same toxicological effects. For rimsulfuron, short

- /intermediate

- term dermal and inhalation exposure and risk are being assessed based on the same endpoint and dose from the oral study in the dog. Therefore, these routes of exposure can be combined.

.. 18

3.4.8 Classification of Carcinogenic Potential

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

3.4.9 Summary of Toxicological Doses and Endpoints for Rimsulfuron for

Use in Human Risk Assessments

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

4.0 Public Health and Pesticide Epidemiology Data

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

5.0 Dietary Exposure/Risk Characterization

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

5.1 Pesticide Metabolism and Environmental Degradation

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

5.1.1 Metabolism in Primary Crops and Livestock

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

5.1.2 Metabolism in Rotational Crops

................................ ............................ 20

5.1.3 Analytical Methodology

................................ ................................ .......... 20

5.1. 4 Magnitude in Plants

................................ ................................ ................ 20

5.1.5 Environmental Degradation

................................ ................................ .. 21

5.1.6 Comparative Metabolic Profile

................................ ............................. 22Rimsulfuron Risk Assessment Document D384623, D386178

Page 3 of 37 5.1.7 Pesticide Metabolites and Degradates of Concern

............................... 22

5.1.8 Drinking Water Residue Profile

................................ ............................ 22

5.1.9 Food Residue Profile

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

5.1.10 International Residue Limits

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

5.2 Dietary Exposure and Risk

................................ ................................ ................ 24

5.2.1 Acute Dietary Exposure/Risk

................................ ................................ . 24

5.2.2 Chronic Dietary Exposure/Risk

................................ ............................. 24

5.2.3 Cancer Dietary Risk

................................ ................................ ............... 24

6.0 Re sidential (Non

- Occupational) Exposure/Risk Characterization

............................ 24

6.1 Other (Spray Drift, etc.)

................................ ................................ ..................... 25

7.0 Aggregate Risk Assessments and Risk Characterization

................................ ............ 25

8.0 Cumulative Risk Characterization/Assessment

................................ ........................... 25

9.0 Occupational Exposure/Risk Pathway

................................ ................................ .......... 25

9.1 Short

- Term Handler Risk

................................ ................................ .................. 26

9.2 Postapplication Exposure and Risk

................................ ................................ ... 29

9.3 Restricted Entry Interval (REI)

................................ ................................ ........ 29

10.0 Data Needs and Label Recommendations

................................ ................................ .... 30

10.1 Toxicology

................................ ................................ ................................ ............ 30

10.2 Residue Che mistry

................................ ................................ .............................. 30

10.3 Occupational and Residential Exposure

................................ ........................... 30

References:

................................ ................................ ................................ ................................ ... 30 Appendix A: Toxicology Assessment

................................ ................................ ....................... 31 A.1 Toxicity Profiles

................................ ................................ ................................ ....... 31 A.2 Rationale for Toxicology Data Requirements.

................................ ..................... 34 Appendix B: Tolerance Setting

................................ ................................ ................................ .. 37 Appendix C: Review of Human Research

................................ ................................ ................ 37Rimsulfuron Risk Assessment Document D384623, D386178

Page 4 of 37 1.0 Executive Summary

Rimsulfuron is a sulfonylurea herbicide (Group 2) that works via inhibition of acetolactate synthase (ALS). Inhibition of the enzyme leads to rapid cessation of growth and visual symptoms such as chlorosis, necrosis, leaf malformation and discoloration. These effects appear a few days after treatment in sensitive species.

The Interregional Project N o. 4 (IR

- 4) has submitted a petition supporting the use of rimsulfuron

on caneberry and blueberry (PP# OE7809 ) , and has proposed the establishment permanent

tolerances for residues of rimsulfuron in the caneberry subgroup (13

- 07A) and the blueberry subgroup (13

- 07B), both at 0.01 ppm.

The proposed uses to be added to Dupont’s Matrix ® SG Herbicide (EPA Reg. No. 352

- 768)

include b roadcast spray and band treatment applications of rimsulfuron to be applied to

bushber ry and caneberry at a maximum single application rate of 0.063 lb ai/A (4 .0 oz/A). For band treatments, a n additional application is permitted 30 days after the original application but the total application rate cannot exceed 0 .063 lb ai/A/yr (4 .0 oz/A/y r ) . A maximum of two split applications are allowed per year

. Handlers may apply rimsulfuron using ground equipment. Based on the proposed use pattern, HED has assessed short

- and intermediate

- term occupational

exposure for handlers ; however, post applic ation exposure was not assessed due to the low expectation for exposure via dermal and inhalation routes for workers who re

- enter treated areas.

Toxicity/Hazard

For the proposed new uses, t he toxicological database for rimsulfuron is adequate for risk

assessment purposes

. However, in accordance with the new part 158 guidelines, acute and subchronic neurotoxicity, immunotoxicity and 21/28 day dermal toxicity studies are required. In the available toxicity studies, there was no ev idence of neurotoxicity or treatment

- related effects on the immune system. Additionally, there is no concern for increased susceptibility of the young and a developmental neurotoxicity study in not required at this time. Based on the weight of the eviden ce, HED does not believe that the submission of the required studies will result in lower points of departure (POD) than those currently used for overall risk assessment. Therefore, the available studies are considered adequ ate for the purposes of dose/ en dpoint

selection and hazard characterization and additional safety factors are not needed.

In subchronic and chronic toxicity studies in rats, toxic effects included decreased body weight,

decreased body weight gain, increased relative liver and absolut e kidney weights, and diuresis (increased urine) at ≥ 375 mg/kg bw/day . At 500 mg/kg bw/day , decreased liver enzymes and bilirubin, fatty change, and hepatocellular hypertrophy were observed. In chronic rat studies, decreased body weight gain and increa sed liver weights were observed at ≥ 121/568 mg/kg bw/day (M/F) . Increased mortality was observed at 414 mg/kg bw/day in males . In a subchronic study in mice, increased red blood cell ( RBC ) and hemoglobin, and decreased body weight gain

and food efficien cy were observed at ≥ 225 mg/kg bw/day . After chronic exposure at 1127/1505 mg/kg bw/day (M/F) , decreased body weight, 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 kidneyRimsulfuron Risk Assessment Document D384623, D386178

Page 5 of 37 weights accompanied by decreased urinary osmolality was observed ≥ 125 mg/kg bw/day after 90 days. Chronic exposure led to 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 at ≥ 81.8 mg/kg bw/day in males . At 342.4/358.5 mg/kg bw/day (M/F)

, decreased mea n 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 devel opmental toxicity was seen at the highest dose tested. In the developmental toxicity study in rabbits, and in the two generation study in rats, developmental/offspring toxicity w as seen in the presence of maternal/systemic toxicity and

at similar dose lev els . Consequently, there is no quantitative or qualitative evidence of increased susceptibility following pre

- and/or postnatal exposures

, and there are no concerns or residual

uncertainties. Although the acute and sub chronic neurotoxicity studies are no w required, there was no evidence of potential neurotoxicity in the submitted studies, and HED has concluded that a developmental neurotoxicity study is not needed. Based on the low concerns for pre

- and/or postnatal susceptibility and the lack of potenti al immunotoxic effects

, HED has concluded that the FQPA Safety Factor should be reduced to 1X.

The endpoint for chronic dietary risk assessment was chosen from the rat chronic/carcinogenicity study, and was based on liver and body weight effects. The end point for dermal and inhalation risk assessment for occupational workers was chosen from the 90

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

It was determined that rimsulfuron should be classified as “Not Likely a Human Carcinogen

, ”

based on the lack of evidence for carcinogenicity in studies conducted in rats and mice. Rimsulfuron is not mutagenic. It has low acute oral, dermal and inhalation , but is a moderate eye

irritant. It is not a dermal sensitizer.

Residue Chemistry

The residue chemistry database is complete and there are no residue chemistry issues associated with the requested new uses on caneberry and bushberry. The nature of the residue in plant s and livestock is adequately understood based on acceptable metabolism studies conducted with rimsulfuron, labeled in the pyridine or pyrimidine ring, in field corn, potatoes, tomatoes, lactating goat, and laying hen. HED previously c oncluded that rimsulfuron is the residue of concern for both regulatory and risk assessment purposes in both plant and animal commodities. HED is recommending for the establishment of permanent tolerances for the requested crops. No quantifiable residues were observed in the submitted crop field trials for the proposed uses. Therefore, the recommended tolerances of 0.01 ppm are based on the limit of quantitation (LOQ) of the analytical method. Suitable analytical methods are available to enforce tolerances for

residues of rimsulfuron.

Under a separate submission (DP 386178, Decision No. 443815), th e registrant has submitted revised analytical enforcement methods in order to fulfill conditional data requirements previously identified (DP 326655). HED has reviewed these revised methods, which wereRimsulfuron Risk Assessment Document D384623, D386178

Page 6 of 37 needed to address problems identified by the independ ent laboratory validation, and determined that all issues have been addressed. Thus, this conditional data requirement has been met.

Dietary Exposure (food/water) /Risk Characterization :

HED conducted an unrefined chronic dietary assessment, based on the assumption that rimsulfuron residues are present at tolerance levels in all commodities for which tolerances have

been established

, and that 100% of those crops are treated. Risks from this chronic dietary

exposure are <1 %cPAD, and are there fore below the level of concern for the general US population and all population subgroups

. An acute dietary assessment was not performed, as a toxicological endpoint attributable to a single dose has not been identified for rimsulfuron. Also,

rimsulfuro n is classified as “not likely” to be carcinogenic; therefore, there is no cancer risk associated with exposure to rimsulfuron

.

Residential Exposure

There are currently no residential uses for rimsulfuron

, and therefore no non

- occupational exposure is ex pected to result from the proposed and labeled uses.

Aggregate Ri sk

Because there is no residential exposure and no acute dietary endpoints were identified

, the aggregate risk for rimsulfuron is equivalent to chroni c dietary (food and drinking water) risk. As with the chronic dietary risk, the aggregate risk associated with the proposed and registered u ses of rimsulfuron is significantly below HED ’s level of concern.

Occupational Exposure/Risk

No chemical

- specific data were submitted in support of the proposed uses. Therefore, for handlers HED used standard assumptions with respect to the typical work day, the standard adult body weight, area treated per day, and surrogate unit exposures from t he Occupational Pesticide Handler Unit Exposure S urrogate Reference Table (OPHED) and from the Outdoor Residential Exposure Task Force (ORETF) . The amount applied was based on the proposed label rates and

use pattern. A postapplication dermal exposure a ssessment was not conducted because the label recommends using a directed spray application for weed control on berries while minimizing contact with crop foliage. In addition, the labe l recommends timing application with rainfall or watering

- in to maximi ze herbicidal effectiveness. Th erefore negligible dermal exposure is expected for postapplication workers re

- entering treated areas

.

For handlers, the estimated short

- and intermediate

- term combined dermal and inhalation margins of exposure (MOE) ranged from 370 to 3,000. HED's level of concern (LOC) is an MOE less than 100, and therefore the estimated risks for handlers applying rimsu lfuron to bush

and caneberries are not of concern

. A quantitative postapplication inhalation exposure assessment was not conducted, primarily due to the very low exposure expected based on the use pattern and the vapor pressure of rimsulfuron, and there is also no concern for workers who re

-Rimsulfuron Risk Assessment Document D384623, D386178

Page 7 of 37 enter treated areas. Handler MOEs for inhalation exposure are considered to be protective of postapplication exposure and risk via the inhalation route.

Review of Human Research: This risk assessment relies in part o n data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies, which comprise the Occupational Pesticide Handlers Exposure Database (OPHED) (http://www.epa.gov/pesticides/science/handler

- expos ure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html) have been determined to require a review of their ethical conduct, have received that review, and have been determined to be ethically conducted.

HED Recommendations:

T h ere are no residue chemistry , toxicology, or risk issues that would preclude granting a registration for uses of rimsulfuron (25% water dispersible granule (WDG) formulation;

DuPontTM Matrix ® SG Herbicide (EPA No. 352

- 76 8)) on caneberry and blueberry

.

Add itional Data Needs:

Toxicology The following toxicity studies are outstanding : acute and subchronic neurotoxicity, immunotoxicity, and 21/28 day dermal toxicity stud ies

. These data requirements were previously noted in the 2009 risk assessment (DP360852, D. Rate, 13/AUG/2009). Progress towards meeting these requirements is being made, including EPA receipt of the proposal for the rimsulfuron immunotoxicity testing regardi ng species and dose selection to fulfill the 870.7800 guideline study. This proposal has been reviewed by HED (D 384959, J. Kidwell, 5/Jan/2011) and the registrant should incorporate these recommendations into their forthcoming immunotoxicity data submissi on. These additional data requirements do not preclude making the safety finding for this risk assessment, as the toxicological database is adequate to allow a sufficiently protective assessment.

Residue Chemistry

No additional data are needed. Previous ly required conditional data have been reviewed and considered acceptable.

Occupational/Residential

No additional data are needed.

Tolerance Considerations

Enforcement Analytical Method

Currently, an HPLC/UV method exists for the enforcement of tolerances for residues of rimsulfuron in/on corn, potato, and tomato commodities. The method, AMR

- 1241

- 88, involves extraction of samples with pH 7 potassium phosphate buffer and methanol (75:25, v:v). TheRimsulfuron Risk Assessment Document D384623, D386178

Page 8 of 37 extract is acidified to pH 2.5

- 3.5 (using concentrated phosphoric acid) and filtered for analysis by HPLC/UV with column switching, using a phenyl column for clean

- up chromatography followed by an R

x column for analytical chromatography. The L OQ is 0.05 ppm.

DuPont also proposed two additional methods using liquid chromatography with tandem mass spectroscopy (LC/MS/MS) for tolerance enforcement: Method DuPont

- 15033 for watery and dry crop matrices, and Method DuPont

- 15027 for oily crop matrice s. These methods were also adequate for data collection, as shown in the submitted studies. The validated LOQ is 0.01 0 ppm in each matrix.

International Harmonization There are no established or proposed Codex maximum residue limits (MRLs) for residues of

rim s u lfu ron. However, there is a Canadian MRL of 0.05 ppm for rimsulfuron residues on blueberry, based on their method LOQ of 0.05 ppm and no residues above LOQ being observed in their reviewed field trials. Given the availability of a more sensitive analytical method with an LOQ of 0.01 ppm, HED recommends proceeding with setting a tolerance for the bushberry crop group of 0.01 ppm, which includes the blueberry commo dity. With PMRA having only a tolerance on blueberry of 0.05 ppm, if USEPA were to harmonize tolerances on this commodity, this would result in an inconsistency with the remaining commodities in the bushberry crop

group.

Recommended Tolerances

HED recom mends for the following permanent tolerances:

Caneberry, subgroup 13

- 07A

................................ ........................ 0.01 ppm Blueberry, subgroup 13

- 07B

................................ ......................... 0.01 ppm

In addition, in order to ensure that legal uses of rimsulfuron under FIFRA do not result in illegal residues in food under the FFDCA, HE D recommends for the following tolerance expression to be implemented for rimsulfuron under 40 CFR 180.478:

(a) General. Tolerances are established for residues of the herbicide rimsulfuron, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only rimsulfuron (N

- ((4,6

- dimethoxypyrimidin

- 2

- yl)aminocarbonyl)

- 3

- (ethylsulfonyl)

- 2

- pyridinesulfonamide).

Revisions to Petitioned

- For Tolerances

The only revision is the recommended change in the tolerance expression

, as described above.

Label Recommendations

The supplemental label for the proposed uses is acceptable and does not require any changes.Rimsulfuron Risk Assessment Document D384623, D386178

Page 9 of 37 The personal protective equipment (PPE) recomm ended on the label is considered appropriate, as is the Restricted Entry Interval (REI) of 4 hours.

2.0 Ingredient Profile

Rimsulfuron is a sulfonylurea herbicide (Group 2) that works via inhibition of acetolactate synthase (ALS). Inhibition of the enzyme l eads to rapid cessation of plant growth and visual symptoms such as chlorosis, necrosis, leaf malformation and discoloration. These e ffects appear a few days after treatment in sensitive species.

2.1 Proposed Use Directions

The IR

- 4 has submitted a Supplemental Label of Matrix ® SG Herbicide for use on bush

- and caneberries. The proposed use pattern is summarized in Table 2.1.

Table 2.1 : Proposed Uses of Rimsulfuron.

Product (EPA Reg. No.) Use Site Application

Method Maximum

Single Application

Rate † Timing of

Application/Specifications

Commercial Products

DUPONT

MATRIX SG

HERBICIDE

(352

- 768)

25% ai

Water Soluble

Granule Bushberry Subgroup 13

- 07B;

Caneberry Subgroup 13

- 07A Ground (Broadcast and band treatments) 0.0625 lb ai/A

(Broadcast = 4.0 oz prod/A)

(Perimeter/Band = 2.0 oz prod/A) Max Application Rate/Yr = 4.0

oz/A/year. Max of 2 apps/year when applied

as band treatment.

REI = 4 hrs. Do not apply this product by air. Use ground application equipment only

. Use a minimum of 10 gallons of

sp ray solution per acre. PHI = 21 days. Allow a minimum of 30 days between applications. † Max Single Application Rate = (4 oz prod/A) (1 lb/16 fl oz)(25% ai) = 0.06 25 lb ai/A

.

Rimsulfuron may be applied for the control of grass and broadleaf weeds once at 0.063 lb ai/A/year or as two split applications with a 30 day interval. However, no more than 0.063 lb ai/A may be applied per year.

Personal Protective Equipment (PPE) : The PPE for Matrix ® SG Herbicide is long

- sleeved shirt, and long pants, shoes pl us socks, and chemical resistant gloves (Category A,such as butyl rubber, natural rubber, neoprene rubber, or nitrile rubber, all >14 mils). The restricted entry interval (REI) for rimsulfuron is 4 hours

.

Conclusions . The label directions are adequate t o allow evaluation of the residue data relative to

the labeled uses. Th e available caneberry and blueberry data support the proposed 21

- day PHI

for all berry commodities. It is noted that while all blueberry field trials were conducted with anRimsulfuron Risk Assessment Document D384623, D386178

Page 10 of 37 adjuvant (non

- ionic surfactant or crop oil concentrate), none of the caneberry trials included an adjuvant. The label directions include no discussion of the use of adjuvant for the proposed commodities. However, HED finds the blueberry data adequate for representation of the impact of adjuvants and therefore no prohibition of the use of adjuvant on caneberry is required. See

Section 5.1.4 for further discussion.

2.2 Structure and Nomenclature

Table 2.2. 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 regis try number 122931

- 48

- 0

End

- use product (EP) 25% WDG (Resolve TM SG Herbicide; EPA Reg. No. 352

- 748 )

2.3 Physical and Chemical Properties

Table 2.3. Physicochemical Properties of Rimsulfuron

Parameter Value Reference
Melting point 176

- 17 8 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 Dissociation constant, pK

a 4 Octanol/water partition coefficient, Log(K OW ) pH 5: 1.94 pH 7: 0.0342 pH 9: not attemptedRimsulfuron Risk Assessment Document D384623, D386178

Page 11 of 37 Table 2.3. Physicochemical Properties of Rimsulfuron

Parameter Value Reference
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)

2.4 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.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on pa tterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intak e by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated r isks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of spec ialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

3.0 Hazard Characterization/Assessment

3.1 Hazard and Dose

- Response Characterization

3.1.1 Database Summary

3.1.1.1 Studies available and considered (animal, human, general literature)

Studies available for hazard characterization include three 90

- day oral toxicity feeding studies (rats, mice, dog); two prenatal developmental toxicity studies (rat, rabbit); a reproduction and fertility effects study in rats; a chronic dog feeding study; two gene mutation assays (bacterial or mammalian cells in culture); an in vivo m ammalian c ytogenetics study in m ouse ; an in vitro mammalian cytogenetics study in human lymphocytes; an unscheduled DNA synthesis ( UDS)

assay in primary rat hepatocyte cultures ; a metabolism study; a combined chronic toxicity/carcinogenicity study in rats and a carcinogenicity study in mice.Rimsulfuron Risk Assessment Document D384623, D386178

Page 12 of 37 3.1.1.2 Sufficiency of studies/data

For the proposed new uses, the toxicological database for rimsulfuron is adequate for risk

assessment purpose s. However, in accordance with the new part 158 guidelines, acute and subchronic neurotoxicity, immunotoxicity and 21/28 day dermal toxicity studies are required. In the available toxicity studies, there was no evidence of neurotoxicity or treatment

- rel ated effects on the immune system. Additionally, there is no concern for increased susceptibility of the young and a developmental neurotoxicity study in not required at this time.

An inhalation toxicity study is not available for rimsulfuron. As a resu lt, an oral toxicity study in dogs was used to assess inhalation exposure. To better characterize the potential hazard and portal of entry effects from inhalation exposure, an inhalation toxicity study would be needed. However, since potential inhalatio n exposure is low, and the Margins of Exposure (MOEs) calculated using the NOAEL from the oral study are high, an inhalation toxicity study is not required at this time. The need for an inhalation toxicity study may be revisited during registration revie w.

Based on the weight of the evidence, HED does not believe that the submission of the required studies will result in lower points of departure (POD) than those currently used for overall risk assessment. Therefore, the available studies are consider ed adequ ate for the purposes of

dose/ endpoint selection and hazard characterization and additional safety factors are not needed.

3.1.2 Toxicological Effects

The database indicates that target organs for rimsulfuron are the liver and kidney. In subchronic toxicity studies in rats, decreased body weight, body weight gain, increased relative liver and absolute kidney weights, and diuresis were observed at doses ≥ 375 mg/kg bw/day. At 500 mg/kg bw/day, decreased liver enzymes and bilirubin , fatty change, and hepatocellular hypertrophy were observed in dogs. In chronic rat studies, decreased body weight gain, and increased liver weights were observed at ≥ 121/568 mg/kg bw/day (M/F). Increased mortality

was observed at 414 mg/kg bw/day in m ales . In a subchronic study in mice, increased red blood cell (RBC) and hemoglobin, and decreased body weight gain and food efficiency were observed

at ≥ 225 mg/kg bw/day. After chronic exposure, decreased body weight, increased incidences of

dilation a n d cysts in the glandular stomach, and degeneration of the testicular artery and tunica albuginea were observed at 1127/1505 mg/kg bw/day (M/F). In dogs, diuresis indicated by increased urinary volume, platelet concentration and kidney weights accompanied by decreased urinary osmolality was observed at ≥ 125 mg/kg bw/day after 90 days. Chronic exposure led to

increased absolute liver and kidney weights and increased incidence of seminiferous tubule degeneration and increased numbers of spermatid giant cell s present in epididymides in males at

≥ 81.8 mg/kg bw/day in males . At 342.4/358.5 mg/kg bw/day (M/F) decreased mean body weight and body weight gain, increased serum cholesterol levels and alkaline phosphatase activity, increased absolute liver weight, a nd increased relative liver and kidney weights were observed

.Rimsulfuron Risk Assessment Document D384623, D386178

Page 13 of 37 In the developmental toxicity study in rats, no developmental toxicity was seen at the highest dose tested. In the developmental toxicity study in rabbits, and in the two generation study in

r ats, developmental and offspring toxicity w ere 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.

HED classified rimsulfuron as “Not Likely to be Carcinogenic to Humans ” 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 mut a gen. It has low acute oral, dermal and inhalation toxicity, but is a moderate eye irritant. It is not a dermal sensitizer.

3.1. 3 FQPA

The database is considered adequate to characterize any potential for prenatal or postnatal susceptibility for infants and children.

3.2 Absorption, Distribution, Metabolism, Excretion (ADME)

The metabolism of 14 C

- labeled rimsulfuron was studied in male and female rats. The low dose groups were treated once by oral gavage with 25 mg/kg 14 C

- pyridi ne

- labeled compound and the high dose groups with 250 mg/kg of either 14 C

- pyridine

- or 14 C

- pyrimidine

- labeled compound. The repeat dose groups were gavaged orally with unlabeled test compound (25 mg/kg) for 14 consecutive days, followed on the 15th day b y 25 mg/kg of 14 C

- pyridine

- test compound. Excretion accounted for 93 to 96% of the administered radioactivity, with 58 to 67% appearing

in the urine and 20 to 33% in the feces. Tissue distribution of labeled residues was low. Males showed slightly high er hepatic accumulation than females within each test group. Animals in the repeat dose groups also showed a slight accumulation in the spleen. The metabolic profiles were

determined using 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. The parent compound is metabolized by cleavage or contraction of the sulfonylurea bridge, leading to

the formation of 3

- (ethylsulfonyl)

- 2

- pyridinesulf onamide (IN

- E9260) or N

- (4, 6

- dimethoxy

- 2

- pyrimidinyl)

- N

- ((3

- ethylsulfonyl)

- 2

- pyridinyl) urea (IN

- 70941). IN

- 70941 is deamidated to

form IN

- 70942, which is sequentially demethylated and hydroxylated.

3.3 FQPA Considerations

3.3.1 Adequacy of the Toxicity Database

The toxicology database for rimsulfuron is adequate to characterize potential pre

- and/or post

natal susceptibility for infants and children. Acceptable/guideline studies for developmental toxicity in rats and rabbits and a 2

- generation reproduc tion study in rats were available for FQPA

assessment. As part of the new part 158 guidelines, acute and subchronic neurotoxicity studies, an immunotoxicity study, and a 21/28 day dermal toxicity study are required. However, based on the toxicology data, additional safety factors are not needed to account for the lack of these

studiesRimsulfuron Risk Assessment Document D384623, D386178

Page 14 of 37 3.3.2 Evidence of Neurotoxicity

No evidence of neurotoxicity was observed in the available developmental, reproduction,

subchronic or chronic studies. A cute and subchroni c neurotoxicit y studies are required based on the latest guideline requirements.

3.3.3 Developmental Toxicity

In a n acceptable prenatal developmental s tudy in rats, pregnant females were given r imsulfuron by gavage at dose levels of 0, 200, 700, 2000 or 6000 mg/kg bw/day during gestation days 7 through 16. A NOAEL was not established for either maternal or developmental toxicity, as no maternal or offspring effects were observed at the highest dose tested of 6000 m g/kg bw/day

.

In a n acceptable prenatal developmental toxicity study in rabbits , pregnant New Zealand White

rabbits received r imsulfuron by gavage at dose levels of 0, 25, 170, 500, or 1500 mg/kg bw /day during gestation days 7 through 19. In the rabbit st udy, maternal toxicity was observed at a lower dose than that which caused developmental toxicity. The NOAEL for maternal toxicity

was 170 mg/kg bw /day and the LOAEL was 500 mg/kg bw /day based on mortality, abortion a nd decreased body weight. For develop mental toxicity, the NOAEL was 500 mg/kg bw /day and the LOAEL was 1500 mg/kg bw /day as there were only 2 viable pups at 1500 mg/kg bw /day. The pup mortality was a result of increased mortality in dams at 1500 mg/kg bw /day

3.3.4 Reproductive Toxicity

In a n acceptable two

- generation reproduction study, rats were fed diets containing r imsulfuron at dose levels equivalent to 0, 2.8, 165 or 830 mg/kg bw /day for F 0 males; 0; 3.4, 204 or 1021 mg/kg bw /day for F 0 females; 0, 3.7, 217 or 1316 mg/kg bw /day for F 1 males; and 0, 4.3, 264 or 1316 mg/kg bw /day for F 1 females, respectively.

For parental systemic toxicity, the NOAEL was 165 /204 mg/kg bw /day in males /females and the

LOAEL was 830 /1021 mg/kg bw /day in males /females based on decreased body weight gain.

S imilar effects were observed in offspring at similar or slightly higher doses. For offspring toxicity, the NOAEL was 217 /264 mg/kg bw/ day in males / females and the LOAEL was 1316 mg/kg bw /day based on decreased mean body weight in F 1 males, decreased body weight gain in

F 1 females, decreased mean pup weight of the F 2 females , decreased daily food consumption in

F 1 males, and decreased mean number of male F 1 pups

. Decreased weight was also the key finding for systemic effects. Thus, the toxic effect s in of fspring occurred at the same dose level as the systemic parental effects.

3.3. 5 Pre

- and/or Postnatal Toxicity

3.3.5.1 Determination of SusceptibilityRimsulfuron Risk Assessment Document D384623, D386178

Page 15 of 37 In the developmental toxicity study in rats, no developmental toxicity was seen at the highest dose tested. In the developmental toxicity study in rabbits, and in the two generati on study in rats, developmental and offspring toxicity were seen in the presence of maternal/systemic toxicity. Consequently, there is no evidenc e of quantitative or qualitative increased susceptibility following pre

- and/or postnatal exposures.

3.3.5.2 Degree of Concern Analysis and Residual Uncertainties for Pre and/or Post

- natal Susceptibility

There are no concerns, nor residual uncertainties for pre

- and/or postnatal toxicity since there was no indication of increased susceptibility of rats or rabbits to in utero and/or postnatal

exposure to r imsulfuron in the data provided.

3.3.6 Recommendation for a Developmental Neurotoxicity Study

Ther e is no e vidence to support requiring a d evelopmental n eurotoxicity study. Neither the subchronic or chronic toxicity studies in rats and dogs

, the developmental toxicity studies in rats

and rabbits , nor the 2

- generation reproduction study indicated that the nervous system was specifically affected by treatment with r imsulfuron. Acute and subchronic neurotoxicity studies are required by the most recent guidelines and are considered to be data gaps.

3.3.7 FQPA Safety Factor for Infants and Children

Based on the hazard and exposure data, HED determined that the FQPA S F can be reduced to 1x

because :
T here is no evidence of increased susceptibility following in utero and/or postnatal exposure in the developmental toxicity studies in rats or rabbits, and in the 2

- generation rat reproduction study ; and t here are no residual uncertainties concerning pre

- and postnatal toxicity

. Although the ACN and SCN are considered to be required under the current guidelines,

t here are no concerns for neurotoxicity based on the available data and a DNT is not required. The chronic dietary food exposure assessment utilize s tolerance level residues from field trial data and 100 percen t crop treated data for all commodities. Conservative surface water modeling estimates were used. The assessments are based on reliable data and will not underestimate exposure/risk for

rimsulfuron

. There is no potential for residential exposure

. Despit e the requirement for immunotoxicity and neurotoxicity studies, there is no evidence that rimsulfuron either causes neurotoxic effects or directly targets the immune system, and therefore an additional uncertainty factor is not needed to account for the

la ck of these studies.

3.4 Hazard Identification and Toxicity Endpoint Selection

3. 4 .1 Acute Reference Dose (aRfD)

– Females Ages 13

- 49 and General PopulationRimsulfuron Risk Assessment Document D384623, D386178

Page 16 of 37 There were no toxicological effects attributable to a single dose observed in oral toxicity stu dies including the developmental toxicity studies in rats and rabbits. Therefore, a dose and endpoint

w ere not selected for this risk assessment.

3 .4.2 Chronic Reference Dose (cRfD)

Study Selected: Combined Chronic/Carcinogenicity

– Rat ( 870.4100 )

MRID No. 42047101 Dose/Endpoint for establishing the RfD: The dose selected for risk assessment is the NOAEL of 11.8 mg/kg bw/day based on decreased body weight gains and liver effects at the LOAEL of 121 mg/kg bw/day.

Executive Summary : In a combined chronic/ carcinogenicity study in rat, rimsulfuron (purity: 98.8%; batch # 58246

- 69

- 1 thru 6) was given to Cr1:CD BR rats for two years at dietary

concentrations of 25, 300, 3000, and 10000 ppm (1.00, 11.8, 121, a nd 414 mg/kg /day (males); 1.38, 17.1, 16 3, and 569 mg/kg /day (females), respectively). The LOAEL for males and females is based on decreased body weight gain and liver effects . The LOAEL for males is 121 mg/kg/day (NOAEL=11.8 mg/kg/day). The LOAEL for females is 568 mg/kg/day (NOAEL =163 mg/kg/d ay).

Comments about Study and Endpoint: The NOAEL selected for risk assessment represents the lowest available NOAEL for effects of rimsulfuron following long

- term dietary administration ; therefore, it is protective of potential toxic effects. The stu dy 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 chronic rat study provided the most sensitive endpoint s for chronic dietary risk assessment.

Uncertainty Factor (UF): 100X (10X for inter

- species extrapolation and 10X for intra

- species variation). Because the FQPA Safety Factor has been reduced to 1X, the reference dose and the chronic population adjusted dose (cPAD) are the same.

Chronic Reference Dose (cRfD) = 1 1.8 mg/kg bw /day (NOAEL) = 0. 1 18 mg/kg bw /day 100 (UF)

3. 4 .3 Dermal Absorption

The dermal risk assessment was based on an oral study since a route

- specific dermal toxicity study was not submitted for rimsulfuron. In addition, a dermal absorption stud y is not available. Therefore, a conservative default dermal absorption factor of 100% was used for dermal risk

assessment.

3 .4.4 Dermal Exposure (Short

- , Intermediate

- Term)

Study Selected: 90 Day Toxicity

- DogRimsulfuron Risk Assessment Document D384623, D386178

Page 1 7 of 37 MRID No. 41356322

Dose and Endpoint for Risk Assessment: The dose selected for risk assessment is the NOAEL of 6.25 mg/kg bw/day based on increased urinary volume, kidney weights, and osmola l ity at the LOAEL of 125 mg/kg bw/day.

Executive Summary: In a 90 day toxicity study in dogs, rimsu lfuron (purity: 98.8%; batch # 17, 463) was given to beagle dogs in the diet at 0, 250, 5000, 20000 ppm ( 0, 6.25, 125, or 500 mg/kg bw/day). Diuresis was the most notable effect observed and was indicated by increased urinary volume, platelet concentratio n and kidney weights accompanied by decreased urinary osmolality in mid and high dose dogs of both sexes. Adaptive change in the liver was evident in mid and high dose dogs of both sexes as indicated by increased relative and absolute liver weights,

alkal ine phosphatase activity and cholesterol content. On the basis of body weight decrement, the MTD for this compound is between 5,000 and 20,000 ppm in diet in male and female dogs. The LOAEL is 125 mg/kg/day, based on increased urinary vol ume, kidney weig hts, and osmolarity. The NOAEL is 6.25 mg/kg/day.

Comments about Study and Endpoint: No dermal studies are available for rimsulfuron, therefore, the oral toxicity study in dogs was used for dermal risk assessment. The selected endpoint provides the m ost 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 risk assessment

.

3. 4 .5 Inhalation Exposure ( Short

- , Intermediate

- Term)

Study Selected: 90 Day Toxicity

- Dog

MRID No. 41356322

Dose and Endpoint for Risk Assessment: See above, under Dermal Exposure

Executive Summary: See above, under Dermal Exposure)

Comments about Study and Endpoint:

In the absence of a route

- specific inhalation toxicity stud y for rimsulfuron, HED relied on the oral toxicity study in dogs for inhalation risk assessment. The selected endpoint provides the

most sensitive NOAEL availa ble from a n oral study of appropriate duration for short

- and

intermediate

- term exposures

. Since the endpoint was selected from an oral study , HED assumed equivalent toxicity via the inhalation and oral routes for the purpose of route

- to

- route extrapolation

.

3. 4 .6 Level of Concern for Margin of Exposure

The Level of Concern for M argins of Exposure (MOEs) is 100 , based on the combined uncertainty factors of 10X for interspecies extrapolation and 10X for intraspecies variability

.Rimsulfuron Risk Assessment Document D384623, D386178

Page 18 of 37 The FQPA Sa fety Factor has been reduced to 1x and no additional safety factors have been

retained

.

3.4.7 Recommendation for Aggregate Exposure Risk Assessments

When there are potential occupational and residential exposures to a pesticide, the risk

assessment must address exposures from three major sources: oral, dermal and inhalation exposures, and determine whether the individual exposures can be combined if they have the same toxicological effects. For rimsulfuron, short

- / intermediate

- term dermal and inhalation

exposure and risk are being assessed based on the same endpoint and dose from the oral study in the dog . Therefore, these routes of exposure can be combined

.

3.4.8 Classification of Carcinogenic Potential

The doses used in the two

- year rat and 18

- month mouse studies were adequate. N o ev i dence of carcinogenicity was observed. Therefore, HED determined that rimsulfuron should be classified

as “ Not Likely to be Carcinogenic to Humans. ” As such, there is no cancer risk associated with registered or proposed uses of rimsulfuron.

3. 4 .9 Summary of Toxicological Doses and Endpoints for Rimsulfuron for Use in Human

Risk Assessments

A summary of the toxicological endpoints and doses chosen for the relevant exposure scenarios

for human risk assessment is found in Table 3. 4 .9.

Table 3.4.9. Toxicological Doses and Endpoints for Rimsulfuron for Use in Human Health Risk Assessments.

Exposure

Scenario Point of

Departure Uncertainty/F

QPA Safety

Factors RfD, PAD, Level of Concern for

Risk Assessment Study and Toxicological

Effects

Acute Dietary (females 13

- 49)

Acute Dietary (general population) No appropriate endpoint attributable to a single dose identified

.

Chronic Dietary (all populations) NOAEL= 11.8

mg/kg bw/day UF A =10x

UF H =10x FQPA SF=1x Chronic RfD = chronic NOAEL Safety Factors = 0.118 mg/kg bw/day

cPAD = Chronic RfD

FQPA SF

= 0.118 mg/kg bw/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 Use pattern does not indicate a need for this risk assessment.Rimsulfuron Risk Assessment Document D384623, D386178

Page 19 of 37 Table 3.4.9. Toxicological Doses and Endpoints for Rimsulfuron for Use in Human Health Risk Assessments.

Exposure

Scenario Point of

Departure Uncertainty/F

QPA Safety

Factors RfD, PAD, Level of Concern for

Risk Assessment Study and Toxicological

Effects

Dermal Short

Term (1

- 30 days);

intermediate

Term (1

- 6 months) NOAEL= 6

. 25

mg/kg /day UF A =1 0 x

UF H =10x

DAF=10 0% Occupational LOC for MOE = 100 90 Day Toxicity

- Dog LOAEL=125 mg/kg/day,

based on increased urinary volume, kidney weights, and decreased

osmola l ity.

Inhalation Term (1

- 30 days);

intermediate

Term (1

- 6 months) NOAEL= 6

. 25

mg/kg /day UF A =1 0 x

UF H =10x

IAF=10 0% Occupational LOC for MOE = 100 90 Day Toxicity

- Dog LOAEL=125 mg/kg/day,

based on increased urinary volume, kidney weights, and decreased

osmola l ity.
Cancer (oral, dermal, inhalation) Rimsulfuron is considered “not likely to be carcinogenic to humans” due to the absence of tumors in rat

and mouse 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 ob served 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 human population (interspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. DAF=Dermal absorption factor. IAF=inhalation absorption factor (i.e., inhalation toxicity considered to be equivalent to toxicity via the oral r oute)

.

4.0 Public Health and Pesticide Epidemiology Data

There are no new public health data or pesticide epidemiology data to report at this time.

5.0 Dietary Exposure/Risk Characterization

5.1 Pesticide Metabolism and Environmental Degradation

5.1.1 Metabolism in Primary Crops and Livestock
MARC Decision Memo, L. Cheng, G. Herndon, 11//FEB/1998; and DP # 200158, M. Nelson, 29/MAR/1994 MARC Briefing Memo, L. Cheng, 04/FEB/1998; and DP # 200157, M. Nelson, 17/MAR/1994

The nature of the residue in plant s and livestock is sufficiently understood based on adequate metabolism studies conducted with rimsulfuron, labeled in the pyridine or pyrimidine ring, in field corn, potatoes, tomatoes, lactating goat, and laying hen.

The metabolic pathways were found to be similar in plants and livestock. The major route of rimsulfuron metabolism/degradation involves sulfonylurea bridge contraction, with sulfonylurea bridge cleavage as a minor metabolic route. The metabolites detected were IN

- 70941, IN

- 70942,

IN

- E9260, IN

- J290, IN

- 69190 (goat), IN

- H1043 (goat), IN

- T5831 (potato), IN

- JF999 (hen, tomato), and unresolved polar/nonpolar products. Based on the results of the studies, HEDRimsulfuron Risk Assessment Document D384623, D386178

Page 20 of 37 concluded that the residue of concern in plant and livestock commodities is the parent compound, rimsulfuron.

5.1.2 Metabolism in Rotational Crops

DP# 200157, M. Nelson, 17/MAR/1994

The nature of rimusulfuron residues in rotational crops is adequately understood based on the previously submitted confined accumulation study in wheat. Rimsulfuron is extensively metabolized in rotational crops. Metabolites 1N

- 70941, IN

- E9260, and IN

- Hl043 were identified in the straw of wheat planted into aged (30 days and 120days), 14 C

- E9636 treated soil and grown to maturity. No undegraded rimsulfuro n was detected in the straw of wheat at maturity.

5.1.3 Analytical Methodology

DP# 330813, S. Hummel, 08/AUG/2006 DP# 326655, D. Rate, 15/MAY/2007

Enforcement methods : Currently, an HPLC/UV method exists for the enforcement of tolerances

for residues of rimsulfuron in/on corn, potato, and tomato commodities. The method, AMR

1241

- 88, involves extraction of samples with pH 7 potassium phosphate buffer and methanol (75:25, v:v). The extract is acidified to pH 2.5

- 3.5 (using concentrated phosphoric acid) and filtered for analysis by HPLC/UV with column switching, using a phenyl column for clean

- up chromatography followed by an R

x column for analytical chromatography. The LOQ is 0.05

ppm.

DuPont also proposed two additional methods using liquid chromatography with tandem mass spectroscopy (LC/MS/MS) for tolerance enforcement: Method DuPont

- 15033 for watery and dry crop matrices, and Method DuPont

- 15027 for oily crop matrices. These methods were also adequate for data collection, as shown in the submitted studies. The validated LOQ is 0.01 0 ppm in each matrix. Based on feedback from the ILV for each method, revised methods DuPont

15033 and DuPont

- 15027 have been submitted and address all recommended changes from the ILV. These changes included the addition of refrigeration/homogenization periods, in order to reduce the degradation of rimsulfuron residues, and fixing noted typographical errors. Thus, the conditional data requirement from D326655 (D. Rate, 5/13/2007) has been met.

Data

- Collection methods: Samples were analyzed for rimsulfuron usin g the LC/MS/MS method, DuPont

- 15033 (Revision 1), as described above and in D326 6 55.

The submitted LS/MS/MS method s (Method 15033 and 15027, Revision 1) are adequate for enforcing toler ances. No new DER was written for the submitted revised method s (MRID s 4 833 2001 and 48332002), as they have been reviewed in a previously submitted petition ( DP# 326655, D. Rate, 5/13/2007 ). The current submission incorporates the ILV comments as previou sly requested by HED and fulfills the conditional data requirement set in D326655 . The

method s do not require a PMV trial, and can be forwarded to FDA.

5.1. 4 Magnitude in PlantsRimsulfuron Risk Assessment Document D384623, D386178

Page 21 of 37 DP# 3 86512

, E. Holman

, September 2011

The available caneberry and blueberry field trial data are acceptable and support the proposed use patterns for rimsulfuron ( WDG ) on these proposed commodities . An adequate number of tests were conducted on each crop in the appropriate geographical regions. All samples were analyzed for the residue of concern using an adequate method, and sample storage conditions and intervals were supported by the available storage stability data.

It is noted that while all the blueberry trials included an adjuvant in the spray mixture (NIS or COC), none of the caneberry trials included adjuvants. Given that the blueberry trials, including adjuvant, yielded residues <0.01 ppm (LOQ), identical to the result of the caneberry trials without adjuvant, the impact of adjuvants is believed to be minimal. Theref ore, while the proposed label does not include discussion of the use of adjuvants on the proposed commodities, HED does not believe that prohibition of the use of adjuvants on caneberry is necessary. The proposed use pattern and label is adequate and revi sions are not required.

5.1. 5 Environmental Degradation

DP#s 358869 and 358875, J. Mel é ndez, 23/JAN/2009

Rimsulfuron is expected to transform/degrade into a number of transformation/degradation products under different environmental conditions. The th ree major degradates of rimsulfuron result from contraction or cleavage of the sulfonurea

- bridge (IN

- 70941 and IN

- 70942 from

contraction while IN

- J9260 from cleavage). In contrast, the minor degradates are cleavage degradates (IN

- J9260 is a minor degradate in systems other than aerobic soil, IN

- J290 and IN

T5831). A summary of the degradation profiles in various laboratory systems is included in

Table 5.1. 5

.

Table 5.1. 5

. Transformation/degradation profiles of rimsulfuron in various systems.

Degradate

Name Max Degradate Concentration in % of applied and (Time in Days to Max Concentration; Does it

Decline Y/N)
Hydrolysis @ pH7 Aerobic Soil Anaerobic Soil Other Studies

IN

- 70941 17%

(3 days; Y to 1%) 55%

(10 days; Y to 30%) 32%

(10 days; Y to 6%) H 2 OPhotolysis: Similar to

hydrolysis with reduction in

transformation of IN

- 70941 into IN

70942 and/or increase in the degradation of IN

- 70942. Plus

enhanced formation of IN

- J920 and

IN

- E9260 Aerobic Aquatic Data: May not represent the natural environment as the system was exposed to light TFD (Terrestrial Field Dissipation) Data: None Identified possibly due to inappropriate LOD/LOQ (limits of detection/quantification) IN

- 70942 84%

(30 days; N) 30%

(360 days; N) 56%

(360 days; N)

IN

- E9290 10%

(30 days; N) 19%

(30 days; Y to 16%) 23% (360 days; N)

IN

- J290 7%

(14 days; Y to 6%) 3%

(30 days; Y to 1%) 8%

(28 days; Y to 6%)Rimsulfuron Risk Assessment Document D384623, D386178

Page 22 of 37 5.1. 6 Comparative Metabolic Profile
In rats, r imsulfuron is excreted within the first 72 hours following dosing in the urine (~64%) and the feces (~30%). 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 highest percentage of the urinary (42 to 55%) and fecal (5 to 16%) r adioactivity was attributed to unmetabolized parent compound. Metabolism involves either the contraction or cleavage of the sulfonylurea bridge. While the cleavage of the bridge to form the pyridinesulfonamide metabolite is expected, the contraction reac tion is not.

Metabolism of rimsulfuron in plants and other animals (poultry and ruminants) appears to be

similar to its metabolism in rats. Metabolism involves either the contraction or cleavage of the sulfonylurea bridge. While the cleavage of the br idge to form the pyridinesulfonamide metabolite is expected, the contraction reaction is not. The major residue found in plants is the

parent compound, rimsulfuron

.

5.1. 7 Pesticide Metabolites and Degradates of Concern

Table 5.1. 7

. Summary of Metabolites and Degradates to be I ncluded in th e Risk Assessment and Tolerance Expression

.

Matrix Residues included in Risk

Assessment Residues included in Tolerance Expression

Plants Primary Crop rimsulfuron rimsulfuron

Rotational Crop rimsulfuron Not Applicable

Livestock Ruminant rimsulfuron Not Applicable

Poultry rimsulfuron Not Applicable

Drinking Water rimsulfuron Not Applicable

5.1. 8 Drinking Water Residue Profile

DP#s 358869 and 358875, J. Mel é ndez, 23/JAN/2009; DP 384624, M. Barrett, 10/27/11

EFED previously assessed the drinking water residue profile for rimsulfuron (DP 358869 and 358875). The maximum use rate of 0.0625 lb ai/A/season for citrus, pome and stone fruit that was previously assessed is equivalent to the proposed use rate on caneberry and blueberry. Therefore, the recommended values for estimated drinking water concentrations remain unchanged (DP 384624). The residue of concern in drinking water is parent rimsulfuron only (HED MARC decision memo; 29/MAR/1994). EFED estimated the residues of rimsulfuron in surface water and groundwater using the FQPA Index Reservoir Screening Tool ( FIRST ) and Screening Concentrations in Groundwater ( SCIGROW ) models, respectively. The models and their descriptions are available at the EPA internet site:Rimsulfuron Risk Assessment Document D384623, D386178

Page 23 of 37 http://www.epa.gov/oppefed1/models/water/ . The maximum EDWCs are presented below in

Table 5.1. 8

.

Table 5.1. 8 . Summary of Estimated Surface Water and Groundwater Concentrations of Rimsulfuron 1

.

Maximum Surface Water EDWC (ppb) Maximum Ground w ater Acute/Chronic EDWC (ppb) Acute Value Chronic/Cancer Value

5.596 0.120 0.016

1 Degradates are not included as recommended by HED Metabolism Committee. The EDWCs were calculated based on the maximum application rate of 0.0625 lb ai /A/season (for citrus, pome and stone fruits, ground broadcast application, wetted in).

The chronic surface water EDWC was higher than the groundwater EDWC; therefore, the surface water value of 0.120 ppb was used in the chronic dietary assessment. The acute surface water value is not relevant to this dietary assessment, as a toxic effect attributable to a single

do se has not been identified for rimsulfuron.

5.1. 9 Food Residue Profile

D385612, E. Holman, October 28, 2011

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, and pistachios; 0.05 ppm in/on tomatoes, 0.09 ppm in/on almond hulls, and 0.1 ppm in/on field corn grain, forage, and stover. The recommended tolerances associated with the new uses of

rimsulfuron on caneberry and b ushberry is 0.01 ppm on all associated commodities. In addition, the dietary exposure assessment includes chicory (roots and tops), which also has a proposed tolerance of 0.01 ppm. The proposed use on chicory will be assessed separately under the

forthco ming memo D391764.

The unrefined chronic dietary assessment is based on the assumption that rimsulfuron residues are present at tolerance levels (established or recommended) in all commodities for which

tolerances have been established and that 100% o f those crops are treated. DEEMTM Version 7.81 default processing factors were applied to all processed commodities for which they were

available. There are no processed commodities associated with the proposed uses currently

under review.

5.1. 1 0 International Residue Limits There are no established or proposed Codex maximum residue limits (MRLs) for residues of

rim s u lfu ron. However, there is a Canadian MRL of 0.05 ppm for rimsulfuron residues on blueberry, based on their method LOQ of 0.05 ppm an d no residues above LOQ being observed in their reviewed field trials. Given the availability of a more sensitive analytical method with an LOQ of 0.01 ppm, HED recommends proceeding with setting a tolerance for the bushberry crop

group of 0.01 ppm , which includes the blueberry commodity

. With PMRA having only a tolerance on blueberry of 0.05 ppm, if USEPA were to harmonize tolerance s on this commodity, this would result in an inconsistency with the remaining commodities in the bushberry crop

group.Rimsulfuron Risk Assessment Document D384623, D386178

Page 24 of 37 5.2 Dietary Exposure and Risk

5.2.1 Acute Dietary Exposure/Risk An acute dietary assessment was not performed, since a toxicological endpoint attributable to a single dose has not been identified for rimsulfuron.

5.2.2 Chronic Dietary Exposure/Risk

D3 94389 , E. Holman, October 28, 2011

Rimsulfuron chronic dietary (food + water) exposure estimates using the DEEM

- FCI DTM

software are well below HED’s level of concern for the U.S. population and each of the population subgroups. Dietary exposure was estimated to be 0.000428 mg/kg bw /day for the U.S. population (<1% of the cPAD) and 0.001063 mg/kg bw /day (<1% of the cPAD) for the most highly exposed population subgroup (children, 1

- 2 years old). The estimated exposures

and risks from residues of rimsu lfuron in food and water are summarized in Table 5.2. This assessment is a conservative estimate of the dietary exposure to rimsulfuron, with the assumptions of 100% crop treated and tolerance

- level residues for all commodities.

Table 5.2. Chronic Agg regate Dietary (Food + Drinking Water) Exposure and Risk for Rimsulfuron.

Population Subgroup Chronic Dietary Cancer

Dietary Exposure (mg/kg bw /day) % cPAD Dietary Exposure (mg/kg bw /day) Risk

General U.S. Population 0.000428 <1

N/A N/A All Infants (< 1 year old) 0.000544 <1

Children 1

- 2 years old 0.001063 <1

Children 3

- 5 years old 0.001003 <1

Children 6

- 12 years old 0.000686 <1

Youth 13

- 19 years old 0.000504 <1

Adults 20

- 49 years old 0.000342 <1

Adults 50+ years old 0.000254 <1

Females 13

- 49 years old 0.000337 <1

The values for the highest exposed population for each type of risk assessment are in bold text.

5.2 .3 Cancer Dietary Risk

HED classified rimsulfuron as “not likely to be carcinogenic.” Therefore, there is no cancer risk associated with existing or proposed uses

.

6.0 Residential (Non

- Occupational) Exposure/Risk CharacterizationRimsulfuron Risk Assessment Document D384623, D386178

Page 25 of 37 There are currently no residential uses for rimsulfuron, therefore no non

- occupational exposure is expected t o result from the proposed and labeled uses.

6.1 Other (Spray Drift, etc.)

Spray drift is a potential source of exposure for residents living in close proximity to spraying operations. This situation is particularly the case with aerial application. Howeve r, to a lesser extent, spray drift resulting from the ground application of rimsulfuron could also be a potential source of exposure. The Agency has been working with the Spray Drift Task Force (a membership of US pesticide registrants), EPA Regional Offi ces, State Lead Agencies for pesticide regulation, and other parties to develop the best spray drift management practices. The Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchar d airblast, and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off

- target drift, and risks associated with pesticide application.

7.0 Aggregate Risk Assessments and Risk Characterization

In accordance with the FQPA, HED must consider and aggregate rimsulfuron 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 ha s considered both the route and duration of exposure. The only exposure identified for rimsulfuron is chronic (food and water). Because there are currently no registered residential uses for rimsulfuron and chronic exposures due to residential use are not expected, chronic risk is solely due to dietary risk from food and water. Section 5.2.2 describes the chronic aggregate risk , which is not of

concern

.

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 an y 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

assumed that rimsulfuron does not have a common mechanism of toxicity with other substances

. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common

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

.

9.0 Occupational Exposure/Risk PathwayRimsulfuron Risk Assessment Document D384623, D386178

Page 26 of 37 D394390 , S. Oonnithan, November 9 , 2011

9.1 Short

- Term Handler Risk

The scenarios, inputs, and assumptions used for estimating exposures resulting from the proposed uses of rimsulfuron are summarized below:

Exposure scenarios assessed :

- M ix ing and loading Matrix ® SG Herbicide for ground boom applications

- Applying the spray mixture by a ground boom sprayer

- Mixing, loading and applying by a low

- pressure handwand

- Mixing, loading and applying by a back

- pack sprayer

Application equipment : Ground broadcast applications may be made with tractor drawn ground boom or band sprayers. Spot applications may be made with backpack and low pressure hand wand sprayers.

Unit exposures : No chemical

- specific handler exposure data were submitted in support of this

action To assess handler exposures for regulatory actions when chemical

- specific data are not available, HED relies on the most scientifically reliable surrogate data currently available from

various sources such as the Office of Pesticide Handler Exposure Database ( O PHED) and the Agricultural Handler Exposure Task Force (AHETF)

. Some of this data, such as the industry task force data, is compensatory and is subject to the data protection provisions of FIFRA. The

HE D policy on use of surrogate data is described in more detail on the Agency's website ( http://www.epa.gov/ pesticides/science/ handler

- exposure

- data.html ). The s cenario

- specific surrogate exposure data, including their sources are presented in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table ” ( http://www.epa.gov/pesticides/science/

handler

- exposure

- table.pdf ).

Exposure d urations : According to the proposed label, only one application on berries is allowed per year at the maximum rate of 0.063 lb ai/A

, resulting in short

- term handler exposures. However, HED typically assumes commercial applicators use rimsulfuron for lon ger durations (> 1 month), and therefore intermediate

- term exposures were assessed. Long

- term exposures are not expected ; therefore, a long

- term assessment was not conducted.

Personal Protective Equipment (PPE): Typically, HED uses a tiered approach to PPE starting

with baseline attire (e.g., long

- sleeve shirt, long pants, shoes and socks) . If the estimated MOE is less than the LOC of 100, mitigation is applied ( e.g., gloves, respirator , apron, etc.) to attain an

MOE above the LOC. If the estimated risks continue to be of concern with maximum PPE, then engineering controls (e.g., enclosed cockpits and closed mixing/ loading systems) , formulation changes, etc. are considered. The proposed PPE includes long

- sleeved shirt and long pants, shoes plus so cks and chemical resistant gloves.Rimsulfuron Risk Assessment Document D384623, D386178

Page 27 of 37 Dermal absorption : In the absence of a dermal absorption study, HED assumed 100 % absorption of residues from skin; this assumption is considered to be conservative, and therefore

dermal risks associated with rimsulfur on are considered upper

- bound.

Table 9.1 summarizes the risks associated with handler’s exposure to rimsulfuron when used in accordance with the proposed use pattern for weed control in bush

- and caneberries. The

estimated risks for short

- and intermediate

- term are the same since the same endpoint and dose

were used to estimate risks for both durations. The estimated short

- term combined risks for occupational handlers are MOE ≥ 370 with an LOC of 100, and therefore the dermal and

inhalation ris ks are not of concern.Table 9.1. Rimsulfuron

- Short

- and Intermediate

- Term Occupational Exposure and Risk for Handlers Treating Bush

- and Caneberr ies.

Scenario and (Source of unit exposures) PPE 1 Appl.

rate
lb ai/A Acres

treated /day Dermal unit exp., μg/lb ai Inhal.

unit exp., μg/lb ai Derm. dose

mg/kg/day 2 Inhal. dose

mg/kg/day 3 Total dose

mg/kg/day 4 Sh. & Interm.

term Total

MOE 5

Mixing/loading sol. granules (surrogate DF) for gr. boom appl. (AHETF) SL

0.063 80 227 8.96 0.01634 0.00065 0.01699 370

Applying with a ground boom sprayer (AHETF) SL, Open cab 78.6 0.34 0.00566 0.00002 0.00568 1,100

Mixing/loading/applying with a back

pack sprayer (OPHED) SL,

Gloves 5 2,500 30 0.01125 0.00014 0.01139 550

Mixing/loading/applying with a low

pressure handwand sprayer (OPHED) 430 30 0.00194 0.00014 0.00207 3,000

Abbreviations used: A= acres, AHETF = agricultural handler exposure task force, MOE = margin of exposure, OPHED = pesticide h andler exposure database and PPE = personal protective equipment, SL=single layer.

1. SL = Single layer PPE= long

- sleeved shirt, l ong pants and shoes with socks.

2. Dermal exposure (mg/kg/day) = [ A ppl. rate (lb ai/A) * acres treated/day * dermal unit exposure ( μg/ lb ai handled/day /1000) ] / body wt ( 7 0 kg).

3. Inhalation exposure (mg/kg/day) = [ A ppl. rate (lb ai/A) * acres treated /day * i nhalation unit exposure ( μg/ lb ai handled/day /1000)] / body wt ( 7 0 kg). 4. Total dose (mg/kg/day) is the total exposure from dermal and inhalation routes for the day.

5. Short

- term Total MOE = Short

- term NOAEL ( dermal or inhalation NOAEL 6.25 mg/k g/day) / total dose (mg/kg/day)

.9.2 Postapplication Exposure and Risk

Rimsulfuron is applied as a ground

- directed pre

- and postemergence spray to control weeds in

bush

- and cane berries. Common postapplication activities performed on commercially grown bush berries are pruning and hedging of vines, irrigation and scouting which have the potential for dermal exposure to workers performing such activities. But, the proposed label recommends

use of a directed sp ray application adjusted to provide complete coverage of the weeds while minimizing the amount of spray contact ing berry plant foliage

. In addition, the label advises

growers to time rimsulfuron application(s) to take advantage of normal rainfall patterns in order

to optimizing herbicide performance. Both these application methods are expected to result in little or no dermal exposure to workers doing bushberry

- related cultural practices following

treatment , and therefore a postapplication exposure assess ment was not conducted. In addition,

dermal e xposure for handlers applying Matrix ® SG Herbicide on bush

- and caneberries result s in significantly higher exposure s; thus, handler exposures would be protective of all potential postapplication exposure scena rios

.

Based on the Agency's current practices, a quantitative postapplication inhalation exposure assessment was not performed for use of rimsulfuron on bush

- and caneberries, prima rily

because of the low vapor pressure ( 1.1 X 10 - 8 torr at 25 °C ), low ap plication rate ( 0.063 lb ai/A) and ground

- directed method of application . However, there are multiple potential sources of postapplication inhalation exposure to individuals performing postapplication activities in previously treated fields. These potenti al sources include volatilization of pesticides and re

suspension 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,

an d Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/ scipoly/SAP/ meetings/ 2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as available postapplication inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational postapplication 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 postapplication in halation exposure assessment

for rimsulfuron

.

9.3 Restricted Entry Interval (REI)

The currently registered product label lists a REI of 4 hours. PR Notice 95

- 03 on the Reduced REI policy (3

- May

- 1995) does not list rimsulfuron as an active ingredient approved for a 4

- hour REI. However, PR 95

- 03 allows a 4

- hour REI provided that end

- use products meet the following reduced risk criteria:

1) The end

- use product is in Toxicity Category III or IV for all of the following acute to xicity studies: acute dermal toxicity, acute inhalation toxicity, primary skin irritation, and primary eye

irritation.Rimsulfuron Risk Assessment Document D384623, D386178

Page 30 of 37 2) Based on the required sensitization or hypersensitivity studies, the end use product is not a sensitizer, and there have been no repo rts of hypersensitivity. 3) The registrant has no data indicating, and is not aware of, adverse health effects associated with the end use product, e.g., carcinogenicity, neurotoxicity, developmental effects or reproductive effects. 4) The registrant is not aware and has not been informed of incident information (illness or injury reports) that are “definitely” or “probably” (as defined by the California Incident Reporting System) related to post application exposures to the product.

The label REI is typically based on the acute toxicity of technical chemical. Under the worker protection standard ( WPS ) , active ingredients classified as Toxicity Category IV for Acute Dermal and Primary Skin Irritation are assigned a 4

- hour REI ; therefore, t he 4

- hour REI on the proposed label is acceptable.

10.0 Data Needs and Label Recommendations

10.1 Toxicology As part of the new part 158 guidelines, the following studies are still needed to complete the toxicity database: acute and subchronic neurotoxicity, immunotoxicity and a 21/28 day dermal toxicity study

. These data requirements were previously noted in the 2009 risk assessment (DP360852, D. Rate, 13/AUG/2009). Progress towards meeting these requirements is being made, including EPA receipt of the prop osal for the rimsulfuron immunotoxicity testing regarding species and dose selection to fulfill the 870.7800 guideline study. This proposal has been reviewed by HED (D 384959, J. Kidwell, 5/Jan/2011) and the registrant should incorporate these recommendations into their forthcoming immunotoxicity data submission.

10.2 Residue Chemistry

None

10.3 Occupational and Residential Exposure

None.

References:

DP# 36 5798, D. Dotson, 13/AUG/2009 DP# 360852, D. Rate, 13/AUG/2009 MARC Decision Memo, L. Cheng, G. Herndon, 11//FEB/1998; and DP # 200158, M. Nelson,

29/MAR/1994 MARC Briefing Memo, L. Cheng, 04/FEB/1998; and DP # 200157, M. Nelson, 17/MAR/1994 DP# 200157, M. Nelson, 17/MAR/1994 DP# 330813, S. Hummel, 08/AUG/2006 DP# 326655, D. Rate, 15/MAY/2007 DP#s 358869 and 358875, J. Mel é ndez, 23/JAN/2009

DP# 3 85612, E. Holman, Oct 2011

DP# 394389 , E. Holman, Oct . 2011

D394390 , S. Oonnithan, Nov. 2011Rimsulfuron Risk Assessment Document D384623, D386178

Page 31 of 37 Appendix A: Toxicology Assessment

A. 1 Toxicity Profiles

Table A .1 .1 Acute Toxicity Profile

– Rimsulfuron

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

870.1100 Acute oral Rat

Acute oral Mouse 41356311, 41356310,41

931634

41931623 LD 50 = > 5000

mg/kg

LD 50 = > 5000 mg/kg IV

IV

870.1200 Acute dermal Rabbit 41356312, 41356313, 41931624,41

931635 LD 50 = > 2000

mg/kg IV

870.1300 Acute inhalation Rat 41356314; 41931625;4 1931637;41 931636; 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

, 41356318,41 931639,

41356317 No irritation IV

870.2600 Skin sensitization Guinea Pig 41931628, 41356320, 41931641, 41931640,41

356319 Not a sensitizer IV

Table A. 1 .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)/ ACCEPTABLE

GUIDELINE 0, 50, 1500, 7500, 2000 ppm (0, 2.5, 75, 375, 1000 mg/kg bw/day ) NOAEL = 75 mg/kg bw/day

LOAEL = 375 mg/kg bw/day based on reduced body wt. gains.Rimsulfuron Risk Assessment Document D384623, D386178

Page 32 of 37 Table A. 1 .2 Subchronic, Chronic and Other Toxicity Profile

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

870.3100

90

- Day oral toxicity (mouse) 41356323 ((1989)/ ACCEPTABLE

NONGUIDELINE (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) NOAEL = M: 56.25 ; F: >1125 mg/kg bw/day

LOAEL = M: 225 m g/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)/ ACCEPTABLE

GUIDELINE 0, 250, 5000, 20000 ppm (0, 6.25, 125, or 500 mg/kg bw /day). NOAEL = 6.25 mg/kg bw/day

LOAEL = 125 mg/kg/day based on urinary volume and osmolarity

870.3700a

Prenatal developmental in (Rat) 41356324 (1989)/ ACCEPTABLE

GUIDELINE 0, 200, 700, 2000, 6000 mg/kg bw /day 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)/ ACCEPTABLE

GUIDELINE 0, 25, 170, 500, 1500 mg/kg bw /day 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 e ffects (rat) 41931644 (1990)/ ACCEPTABLE

GUIDELINE 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); and 0, 4.29, 264, 1316 mg/kg

bw /day (F 1 females) respectively). Parental/Systemic NOAEL = 165 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 male s.

870.4100b Chronic toxicity (dog) 41931643(1991)/ ACCEPTABLE

GUIDELINE 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) respectively) 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 onRimsulfuron Risk Assessment Document D384623, D386178

Page 33 of 37 Table A. 1 .2 Subchronic, Chronic and Other Toxicity Profile

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

increased absolute liver and kidney weights and increased incidence of seminiferous tubule degeneration and increased numbers of spermatid gi ant cells present in epididymides in males.

The LOAEL in females 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 incre ased relative liver and kidney weights.

870.4200 Carcinogenicity (rat) 42047701(1991)/ ACCEPTABLE

GUIDELINE 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)] 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)/ A CCEPTABLE

GUIDELINE 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)] NOAEL = 351 mg/kg bw/day ( males ) ; 488 mg/kg bw/day (f

emales )

. 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 evidence of carcinogenicity.

870.5100

In vitro Bacterial Gene Mutation Assay 42471310 (1992)/ ACCEPTABLE

GUIDELINE 5000, 1000, 750, 500, 100, 75, 50, 25, 10, 0 μg/plate and (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. There was no evidence of induced mutant colonies over background.

870.5300

In Vitro Mammalian

Cells in Culture Gene Mutation assay in

CHO 4135632 8 (1989)/ ACCEPTABLE

GUIDELINE 0, 10, 100, 250, 750, 1300 μg/mL in the presence and absence of mammalian

metabolic activation with S/9.

41356327 (1989)/ ACCEPTABLE

GUIDELINE 0, 0. 0008, 0.004, 0.008, 0.04, 0.08, 0.4, 0.8, or 1.1 mg /mL There was no evidenc e 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 Risk Assessment Document D384623, D386178

Page 34 of 37 A. 2 Rationale for Toxicology Data Requirements.

Table A

. 2.1. Guideline Number: 870.6200 Study Title: Acute & Subchronic Neurotoxicity Rationale for Requiring the Data

The acute and subchronic neurotoxicity studies are a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide (food and non

- food uses).

The Neurotoxicity Test Guideline (OPPTS 870.6200) prescribes functional and structural

ne urotoxicity testing and is designed to evaluate the potential of a repeated chemical exposure to produce adverse effects on the nervous system. Although some information on neurotoxicity may be obtained from standard guideline toxicity study data, studies not specifically conducted to assess neurotoxic endpoints may be inadequate to characterize a pesticide’s potential neurotoxicity. While data on clinical signs of toxicity or histopathology in routine chronic or subchronic toxicity studies may offer usef ul information on potential neurotoxic effects, these endpoints alone may be insufficient to detect more subtle neurological effects. Practical Utility of the Data

How will the data be used? Neurotoxicity studies provide critical scientific information needed to characterize potential hazard to the human population on the nervous system from pesticide exposure. Since epidemiologic data on the effects of chemical exposures on neurologic parameters are limited and may be inadequate to characterize a pest icide’s potential neurotoxicity in humans, animal studies are used as the most sensitive endpoint for risk assessment. These animal studies can be used to select endpoints and doses for use in risk assessment of all exposure scenarios and are considered

a primary data source for reliable reference dose calculation.

How could the data impact the Agency's future decision

- making? If the neurotoxicity studies show that the test material poses either a greater or a diminished risk than that given in the inter im decision’s conclusion, the risk assessments for the test material may need to be revised to reflect the magnitude of potential risk derived from the new data.

If the Agency does not have these data, a 10X database uncertainty factor may be applied for conducting a risk assessment from the available studies.

Table A .2 .2. Guideline Number: 870.7800 Study Title: Immunotoxicity Rationale for Requiring the Data The immunotoxicity study is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide (food and non

- food uses).

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional immunotoxicity testing and is des igned to evaluate the potential of a repeated chemical exposure to produce adverse effects (i.e., suppression) on the immune system. Immunosuppression is a deficit in the ability of the immune system to respond to a challenge of bacterial or viral infectio ns such as tuberculosis (TB), Severe Acquired Respiratory Syndrome (SARS), or neoplasia. Because the immune system is highly complex, studies not specifically conducted to assess immunotoxic endpoints are inadequate to characterize a pesticide’s potential immunotoxicity. While data fromRimsulfuron Risk Assessment Document D384623, D386178

Page 35 of 37 hematology, lymphoid organ weights, and histopathology in routine chronic or subchronic toxicity studies may offer useful information on potential immunotoxic effects, these endpoints alone are insufficient to predict immu notoxicity. Practical Utility of the Data

How will the data be used? Immunotoxicity studies provide critical scientific information needed to characterize potential hazard to the human population on the immune system from pesticide exposure. Since epidemiologic data on the effects of chemical exposures on immune parameters are limited an d are inadequate to characterize a pesticide’s potential immunotoxicity in humans, animal studies are used as the most sensitive endpoint for risk assessment. These animal studies can be used to select endpoints and doses for use in risk assessment of all exposure scenarios and are considered a primary data source for reliable reference dose calculation. For example, animal studies have demonstrated that immunotoxicity in rodents is one of the more sensitive manifestations of TCDD (2,3,7,8

- tetrachlorodiben zo

- p

- dioxin) among developmental, reproductive, and endocrinologic toxicities. Additionally, the EPA has established an oral reference dose (RfD) for tributyltin oxide (TBTO) based on observed immunotoxicity in animal studies (IRIS, 1997).

How could the data impact the Agency's future decision

- making? If the immunotoxicity study shows that the test material poses either a greater or a diminished risk than that given in the interim decision’s conclusion, the risk assessments for the test material may

need to be revised to reflect the magnitude of potential risk derived from the new data.

If the Agency does not have these data, a 10X database uncertainty factor may be applied for conducting a risk assessment from the available studies.

Guideline Number: 870.3250 Study Title: 21/28

- Day Dermal Toxicity Rationale for Requiring the Data

The subchronic ( 21/28

- day) dermal toxicity study is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide for food use.

The dermal toxicity Test Guidelines (OPPTS.870.3250) is intended to evaluate the toxic effects associated with continuous or repeated exposures to a test substance for a period of 21/28

- days.

The Agency needs a 21/28

- day dermal toxicity study for food use pesticides because a

route

- specific study eliminates the uncertainties associated with use of an oral study and dermal absorption factors for dermal risk assessments

Practical Utility of the Data

How will the data be used?

A route specific (i.e., dermal) study will provide critical scientific information needed to characterize potential hazard to the human population exposed to the pesticide by the dermal route. This study will provide a dose and a toxicological endpoint of concern for quantification of risks for dermal exposures. This study would eliminate the uncertainties associated with the use of an oral study with a default (100% oral equivalent) dermal absorption factor.

In many cases, toxicity observed via the der mal route will be different than toxicity observedRimsulfuron Risk Assessment Document D384623, D386178

Page 36 of 37 via oral exposure, due to absorption and distribution of the toxic agent after exposure or differences in metabolism (i.e., systemic versus local). This means that the route

- to

- route extrapolation (i.e., use of an oral dose/endpoint) in risk assessment could result in under or over

estimation of risks from the dermal route.

How could the data impact the Agency’s future decision

- making?

If the dermal toxicity study indicates that the test material po ses either a greater or lesser risk than that calculated using an oral dose, (as used in the interim decision), the risk assessment would be revised to reflect the magnitude of potential risk derived from the new data. Also, the requested data would allow the Agency to determine if the risks were over

- estimated or under

estimated. If the risks were under

- estimated, additional risk mitigation measures could be required. If the risks were over

- estimated, risk mitigation measures could be reduced.Rimsulfuron Risk Assessment Document D384623, D386178

Page 37 of 37 Appendix B: Tolerance Setting

Table B.1. Tolerance Summary for Rimsulfuron

. Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity

Definition

Caneberry, subgroup 13

- 07A 0.01 0.01

Bushberry

, subgroup 13

- 07B 0.01 0.01 Set at 0.0 1 ppm , a value that is not

harmonized with the MRL in Canada of 0.05 ppm (set on blueberry)

.

Appendix C : Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies, which comprise the Occupational Pesticide Handlers Exposure Database (OPHED) (http://www.epa .gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html) have been determined to require a review of their ethical conduct, have received that review, and have been determined to

be ethically conducted.