Rimsulfuron D 391083

Page 2 of 35 Table of Contents

1.0 Executive Summary

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

2.0 Regulatory Conclusions and Recommendations

................................ ............................ 6

2.2.1 Enforcement Analytical Method

................................ ................................ ......... 7

2.2.2 International Harmonization

................................ ................................ ............... 7

2.2.3 Recommended Tolerances

................................ ................................ .................... 7

2.2.4 Revisions to Petitioned

- For Tolerances

................................ .............................. 8

2.3 Label Recommendations

................................ ................................ ...................... 8

2.3.1 Recommendations from Residue Reviews

................................ .......................... 8

2.3.2 Recommendations for Worker Safety

................................ ................................ . 8

2.3.3 Recommendations for Residential Safety

................................ ........................... 8

3.0 Ingredient Profile

................................ ................................ ................................ .............. 8

3.1 Structure and Nomenclature

................................ ................................ ............... 8

3.2 Physical and Chemical Properties

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

3.3 Summary of Existing/Proposed Uses

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

4.0 Hazard Characterization and Dose

- Response Assessment

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

4.1 Toxicology Studies Available for Analysis

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

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

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

4.2.1 Dermal Absorption

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

4.3 Toxicological Effects

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

4.4 Safety factor for Infants and Children (FQPA Safety Factor)

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

4.4.1 Completeness of the Toxicology Database

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

4.4.2 Evidence of Neurotoxicity

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

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

.. 12

4.4.4 Residual Uncertainty in the Exposure Database

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

4.5 Toxicity Endpoint and Point of Departure Selections

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

4.5.1 Dose

- Response Assessment

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

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment 14

4.5.3 Cancer Classification and Risk Assessment Recommendation

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

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human

Risk Assessment

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

5.0 Dietary Exposure/Risk Characterization

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

5.1 Pesticide Metabolism and Environmental Degradation

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

5.1.1 Metabolism in Primary Crops and Livestock

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

5.1.2 Metabolism in Rotational Crops

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

5.1.3 Analytical Methodology

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

5.1.4 Magnitude of the Residue in Plants

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

5.1.5 Environmental Degradation

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

5.1.6 Comparative Metabolic Profile

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

5.1.7 Residues of Concern Summary

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

5.1.8 Drinking Water Residue Profile

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

5.1.9 Food Residue Profile

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

5.2 Dietary Exposure and Risk

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

5. 2.1 Acute Dietary Exposure/Risk

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

5.2.2 Chronic Dietary Exposure/Risk

................................ ............................. 19Rimsulfuron D 391083

Page 3 of 35 5.2.3 Cancer Dietary Risk

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

6.0 Re sidential (Non

- Occupational) Exposure/Risk Characterization

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

6.1.1 Spray Drift

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

7.0 Aggregate Risk Assessments and Risk Characterization

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

8.0 Cumulative Risk Characterization/Assessment

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

9.0 Occupational Exposure/Risk Pathway

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

9.1 Short

- Term Handler Risk

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

9.2 Post

- application Exposure and Risk

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

9.3 Restricted Entry Interval (REI)

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

10.0 Data Needs and Label Recommendations

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

10.1 Toxicology

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

10.2 Residue Chemistry

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

10.3 Occupational and Residential Exposure

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

11.0 References:

................................ ................................ ................................ ....................... 26 Appendix A: Physical and Chemical Properties

................................ ................................ ...... 27 Appendix B: Toxicology Assessment

................................ ................................ ........................ 28 B.1 Toxicity Profiles

................................ ................................ ................................ ....... 28 Appendix C: Chemical Name and Structures of Rimsulfuron and Metabolites

.................. 32 Appendix D: Review of Human Research

................................ ................................ ................ 34 Appendix E. International Residue Limit Status Sheet

................................ ......................... 35Rimsulfuron D 391083

Page 4 of 35 1.0 Executive Summary

Use Profile:

Rimsulfuron is a sulfonylurea herbicide (Group 2) that works via inhibition of acetolactate synthase (ALS). It is currently regis tered to E. I. du Pont de Nemours and Co. (DuPont) for use

on bushberries, caneberries

, soybeans, potatoes, field corn, tomatoes, grapes, various tree fruits, and tree nuts for pre

- and post

- emergence control of annual grasses, broadle af weeds, and yellow nutsedge. Rimsulfuron is a low hazard, low exposure and low risk chemical. The previous risk assessment for rimsulfuron was conducted November 4, 2011 ( D384623, E. Holman 11/4/11 )

Interregional Research Project No. 4 (IR

- 4) has submitted a petition supporting the use of

rimsulfuron on chicory (roots and tops) (PP# 1E7883 ) . The proposed formulation is a water dispersible granule (WG/WDG) multiple active ingredient (MAI) product ( Basis ® Herbicide; EPA Reg. No. 352

- 571) , conta ining 5 0 % rimsulfuron and 25% thifensulfuron

- methyl. B asis

Herbicide ® is to be applied only to “Chrysolite” variety of sulfonylurea tolerant chicory from Florimond Desperez seed company. This assessment addresses the potential exposure and risk

of rimsul furon only

.

Human Health Risk Assessment:

For the proposed new use, t he toxicological database for rimsulfuron is sufficient for risk

assessment purposes

. All the requirements of the new Part 158 guidelines have now been

submitted or waived. The recently submitted immunotoxicity, acute neurotoxicity and subchronic neurotoxicity studied are currently under review.

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

Effects seen in the subchronic and/or chronic toxicity studies in one or more sp ecies included decreased body weight and body weight gain, increased relative and/or absolute liver and kidney weights, diuresis (increased urine volume), decreased liver enzymes and bilirubin and increased serum cholesterol, fatty change, hepatocellular h ypertrophy, increased red blood cell (RBC), hemoglobin and platelet concentration, increased incidences of dilation and cysts in the glandular stomach, degeneration of the testicular artery and tunica albuginea, increased incidence of

seminiferous tubule d egeneration and increased numbers of spermatid giant cells present in epididymides in males.

Rimsulfuron has low acute toxicity by the oral, dermal and inhalation rout e s, but is a moderate eye irritant. It is not a dermal sensitizer. Rimsulfuron is not mutagenic and has been classified as “Not Likely to be Carcinogenic to Humans ,” based on the lack of evidence for carcinogenicity

in studies conducted in rats and mice.Rimsulfuron D 391083

Page 5 of 35 In the developmental toxicity study in rats, no developmental toxicity was seen at t he highest

dose tested. In the developmental toxicity study in rabbits, and in the two generation study in rats, developmental/offspring toxicity was seen in the presence of maternal/systemic toxicity of comparable severity, and at similar dose levels. C onsequently, there is no quantitative or qualitative evidence of increased susceptibility following pre

- and/or postnatal exposures, and

there are no concerns or residual uncertainties. There was no evidence of neurotoxicity or immunotoxicity in the recen tly submitted studies which have undergone preliminary evaluation and are currently under detailed review. Therefore, HED has concluded that the FQPA Safety

Factor should be reduced to 1X.

An endpoint for acute dietary risk was not selected because no ad verse effects were observed which could be attributed to a single do s e exposure

. The endpoint for chronic dietary risk assessment was chosen from the rat chronic/carcinogenicity study, and was based on liver and body weight effects. Incidental oral endpo ints were not selected because residential exposures are not anticipated. The endpoint for dermal and inhalation risk assessments for occupational

workers was chosen from the 90

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

Dietary Exposure (food/ drinking water ) :

The residue chemistry data and environmental fate data are adequate to assess human exposure. The chronic dietary food exposure assessments are conservative. The assessments are based on

reliable data and will not underestimate exposure/risk.

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

.

Chronic: HED conducted an unrefined chronic dietary assessment, bas ed 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 % of the cPAD, and are therefore below the level of concern for the general US population and all population subgroups

.

Cancer: R imsulfur on is classified as “not likely to be carcinogenic to humans” ; therefore, there is no cancer risk associated with exposure to rimsulfuron

.

Residential Exposure :

There are no proposed residential uses for rimsulfuron

, therefore a non

- occupational exposure

assessment was not conducted

.

Aggregate Ri sk :

Acute: Acute exposures were not considered because an adverse effect attributable to a single

dose was not identified.Rimsulfuron D 391083

Page 6 of 35 Chronic: Aggregate chronic risk is equivalent to chronic dietary risk. There is potential chronic

exposure via the diet (food and d rinking water) and estimated chronic risk is <1% of the cPAD

as determined in Section 5.4.

Occupational Exposure/Risk :

Agricultural Handlers: Occupational short

- term (1

- 30 days) and intermediate

- term (1

- 6 months) dermal and inhalation exposures are expected from rimsulfuron handler activities associated with the proposed agricultural use.

HED used data from the Pesticide Handlers Exposure Database (PHED) Version 1.1 as presented “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (http://www.epa.gov/pesticides/science/handler

- exposure

- table.pdf) , dated March 2012 ). The

estimated short

- and intermediate

- term combined dermal and inhalation margins o f exposure (MOE s ) ranged from 8

, 8 00 to 11 ,000. HED's level of concern (LOC) is an MOE less than 100, and therefore the estimated risks for handlers applying rimsulfuron to chicory are not of concern.

Agricultural Post

- application: A post

- application dermal exposure assessment was condu cted using surrogate data and default assumptions. The estimated short

- and intermediate

- term combined dermal and inhalation margins of exposure (MOE s ) ranged from 1

, 3 00 to 12 ,000.

HED's LOC is an MOE less than 100, and therefore the estima ted risks for post

- application

activities in chicory fields are not of concern.

Based on the Agency's current practices, a quantitative post

- application inhalation exposure non

cancer assessment was not performed for rimsulfuron at this time.

Environmental Justice Considerations : Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment . Dietary and non

dietary exposures were considered.

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. The se studies (listed in Appendix D ) have been determined to require a review of their ethical conduct, and one

of these studies is als o subject to review by the Human Studies Review Board. All of the listed studies have received the appropriate review.

2.0 Regulatory Conclusions and Recommendations

Provided that a revised Section B (OPPTS 860.1200) is submitted, HED can recommend for a n

un conditional registration and permanent tolerances for the proposed uses of rimsulfuron on chicory tops and roots. No a dditional data are needed as conditions of registration as outlined in Section 2.1 below. The specific tolerance recommendations ar e discussed in Section 2.2, and

label modifications are discussed in Section 2.3.

2.1 Data Deficiencies/Conditions of RegistrationRimsulfuron D 391083

Page 7 of 35 The following must be provided prior to a tolerance being established or registration

allowed:

860.1200 Directions for Use

The Section B and the supplemental label for use on chicory should be revised to specify

a minimum preharvest interval ( PHI ) of 1 1 0 days, based on field trial data.

The following d ata are required as a condition of registration :

None

2.2 Tolerance Con siderations

2.2.1 Enforcement Analytical Method

Currently, a high performance liquid chromatography/ultraviolet detection ( 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 i s 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 limit of quantitation ( LOQ ) is 0.05 ppm.

DuPont also proposed two additional methods using liquid chromatog raphy with tandem mass

spectrometry (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.

2.2.2 International Harmonization

There are no Codex or Canadian maximum residue limits (MRLs) for residues of rim s u lfu ron on chicory

. An International Residue Limit Status sheet is attached (Appendix E ).

2.2.3 Recommended Tolerances

HED concurs with the proposed tolerances and recommends for the following residue definition:

Note to PM: The Tolerance Expressions for rimsulfuron should be revised as follows:

Tolerances are established for residues of the herbicide rimsulfuron, including i ts 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 onlyRimsulfuron D 391083

Page 8 of 35 rimsulfuron ( N

- [[(4,6

- dimethoxy

- 2

- pyrimidinyl)amino]carbonyl]

- 3

- (ethylsulfonyl)

- 2

- pyridi nesulfonamide ).

Chicory

, tops

................................ ................................ ................. 0.01 ppm Chicory

, roots

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

2.2.4 Revisions to Petitioned

- For Tolerances

None

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

T he supplemental label for use on chicory should be revised to specify a minimum PHI of 1 1 0 days, based on field trial data.

2.3.2 Recommendations for Worker Safety

The personal protective equipment (PPE) and Restricted Entry Interval (REI) recommended on

the label are considered a ppropriate

.

2.3.3 Recommendations for Re sidential Safety

There are no proposed residential uses for rimsulfuron

, therefore there are no residential safety

recommendations noted.

3.0 Ingredient Profile

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

3.1 Structure and Nomenclature

Table 3.1. Rimsulfuron Nomenclature.

CompoundRimsulfuron D 391083

Page 9 of 35 Table 3.1. Rimsulfuron Nomenclature.

Common name Rimsulfuron

Company experimental name DPX

- E9636

IUPAC name 1

- (4,6

- dimethoxypyrimidin

- 2

- yl)

- 3

- (3

- ethylsulfonyl

- 2

- pyridylsulfonyl)urea

CAS name N

- [[(4,6

- dimethoxy

- 2

- pyrimidinyl)amino]carbonyl]

- 3

- (ethylsulfonyl)

- 2

- pyridinesulfonamide

CAS registry number 122931

- 48

- 0

3.2 Physical and Chemical Properties

The physical and chemical properties of rimsulfuron are provided in Appendix A.

3.3 Summary of Existing/Proposed Uses

Rimsulfuron is currently regis tered to E. I. du Pont de Nemours and Co. (DuPont) for use on bushberries, caneberries, soybeans, potatoes, field corn, tomatoes, grapes, various tree fruits, and tree nuts for pre

- and post

- emergence control of annual grasses, broadleaf weeds, and yellow nutsedge.

DuPont’s BASIS ® Herbicide (EPA Reg. No. 352

- 571) is a water dispersible granule formulation containing 50 % active ingredient . It is applied as postemergence broadcast spray using ground equipment to chicory . A single b roadcast spray application of rimsulfuron to chicory may be

made at a maximum application rate of 0.009 lb ai/A (0.3 oz/A) or two sequential applications at 0.0047 lb ai/A (0.15 oz/A) may be made

. The total application rate cannot exceed 0.009 lb

a i/A/growing season (0.3 oz/A/growing season)

. BASIS® can be applied only to “Chrysolite” variety of sulfonylurea tolerant chicory . Application of BASIS® prior to the 2

- true leaf stage, or

after the 4

- true leaf stage of Chrysolite chicory could result in crop injury. The proposed use pattern is summarized in Table 3 .1.Rimsulfuron D 391083

Page 10 of 35 Table 3.1 Summary of Directions for Use of Rimsulfuron.

Applic. Timing, Type, and Equipment Formulation

[EPA Reg. No.] Applic.

Rate

lb ai/A Max. No.

Applic.

per Season RTI 1

(days) Max.

Seasonal Applic.

Rate

lb ai/A PHI

(days) Use Directions and

Limitations

Sulfonyl

- Tolerant Varieties of Chicory “Chrysolite”

Postemergence,

2

- true leaf stage

to 8

- true leaf stage; Broadcast, foliar; Ground equipment only. Basis

Herbicide

50 % WDG [352

- 571] 0.009

(0. 3

ounce/ A) 1

-- 0.009 (0.3 ounce/A) 90 Apply in 19

- 30

gallons/acre (GPA). Can

be used with both a nonionic surfactant at min of 0.25% v/v (1qt/100 gal spray solution) and an

ammonium nitrogen/sulf

ate fertilizer (rate of 2 qt/A). 0.0 05 (0. 15

ounce/ A) 2

1 RTI = Retreatment interval

4.0 Hazard Characterization and Dose

- Response Assessment

4.1 Toxicology Studies Available for Analysis

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; a metabolism study; genotoxicity studies; a combined chronic toxicity/carcinogenicity study in rats and a carcinogenicity study in mice. Additional studies, currently under HED review, include acute and subchronic neurotoxicity studies and an immunotoxicity study.

T h is toxicological database for rimsulfuron is adequate for risk assessment purposes. I n accordance with the new P art 158 guidelines, a 21/28 day dermal toxicity stud y is required.
However, this dermal toxicity study has been waived and is no longer required because, due to expected low toxicity by the dermal route and demonstrated low dermal exposure, dermal risks

are below HED’s level of concern. Regarding the other required Part 158 studies currently under review, preliminary evaluation of the data show an absence of neurotoxicity and immunotoxicity at any of the dose levels, and these studies are not expected to change points of departure or endpoints selected in this risk assessmen t.

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

The metabolism of 14 C

- labeled rimsulfuron was st udied in male and female rats . Single dose exposure rats were treated once by oral 14 C

- pyridine

- labeled or 14 C

- pyrimidine

- labeled compound. The repeat dose groups were gavaged orally with unlabeled test compound for 14 consecutive days, followed on the 15th day by 14 C

- pyridine

- test compound. Tissue distribution of labeled residues was low. Males showed slightly higher hepatic accumulation than females within each test group. Animals in the repeat dose groups also showed a slight accumulation inRimsulfuron D 391083

Page 11 of 35 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

- pyridinesulfonamide (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. 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.

4.2.1 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, no in vivo dermal abso rption stud ies are

available. Therefore, a conservative default dermal absorption factor of 100% was used for

dermal risk assessment.

4.3 Toxicological Effects

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

In subchronic toxicity studies in rats, decreased body weight, body weight gain, increased relative liver and absolute kidney weights, and diuresis were observed; in the dog subchronic study decreased liver enzymes and bilirubin, fatty change, and hepatocellular hypertrophy were observed. In chronic rat studies, decreased body weight gain, and increased liver weights were observed in both sexes, with increased mortality at higher dose levels in males. In a subchronic study in mice, increased red blood cell (RBC) and hemoglobin, and decreased body weight gain and food efficiency were observed. After mouse chronic exposure, decreased body weight, increased incidences of dilation and cysts in the glandular stomach, and degeneration of the testicular artery and tunica albuginea were observed. In dogs, diuresis indicated by increased urinary volume, platelet concentration and kidney weights accompanied by decreased urinary osmolality was observed after 90 da ys. 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 in males, while in both

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

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

- generation study in rats (in which decreases in body weight gain were observe d in both parents and offspring, developmental and offspring effects w ere seen in the presence of maternal/systemic toxicity at the same dose levels . Consequently, there is noRimsulfuron D 391083

Page 12 of 35 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 st udies. Rimsulfuron is not considered to be a mutagen or clastogen. It has low acute oral, dermal and

inhalation toxicity, but is a moderate eye irritant. It is not a dermal sensitizer.

4.4 Safety factor for Infants and Children (FQPA Safety Factor)

Ba sed on the hazard and exposure data, HED determined that the FQPA S F can be reduced to

1x.

4.4.1 Completeness o f the Toxicology Database

The toxicology database is complete for risk assessment. The existing data bas e for FQPA

assessment includes developmental and reproductive toxicity studies

. Also, acute and subchronic neurotoxicity battery studies and an immunotoxicity study have been recently submitted and are undergoing detailed review. Detailed review of the developmental and reproductive s tudies, and i nitial screening of the neurotoxicity and immunotoxicity, suggest s there is no concern for neurotoxicity or immunotoxicity.

4.4.2 Evidence of N eurotoxicity

No clinical signs of neurotoxicity w ere observed in the available developmental, repr oduction, immunotoxicity, subchronic or chronic studies . Acute and subchronic neurotoxicity studies are currently under review, and the preliminary evaluations reveal no indication of neurotoxicity.

4.4.3 Evidence o f Sensitivity/Su sceptibility in the De veloping o r Young Animal

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 toxi city (see Section 4.3) were seen in the presence of maternal/systemic toxicity. Consequently, there is no evidence of quantitative or qualitative increased susceptibility following pre

- and/or postnatal exposures.

4.4.4 Residual Uncertainty in the Exposure Datab ase

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

- dietary exposure estimates were based on several conservative assumptions, HED does not believe that the exposure estimates are underestimated. The chro n ic dietary assessment conducted with

DEEM

- FCID utilized tolerance residues for all crops. In addition, default processing factors

were assumed for all commodities

. 100% crop treated was assumed for all commodities. The DEEM analysis also assumed th at all drinking water will contain rimsulfuron at the highest

EDWC le vels modeled by EFED for ground water or surface water. For these reasons it can beRimsulfuron D 391083

Page 13 of 35 concluded that the DEEM

- FCID analysis does not underestimate risk from chronic exposure to

rimsulfuron

.

4.5 Toxicity Endpoint and Point of D eparture Selections

4.5.1 Dose

- Response Assessment

Endpoint selection and points of departure have been presented in the previous risk assessment (E. Holman, D384623, 11/04/11), and are summarized in Tables 4.5.4.1 and 4.5.4.2 below.

For acute dietary exposure, t here were no toxicological effects attributable to a single dose observed in oral toxicity studies including the acute neurotoxicity study in rats (currently under review) and developmental toxicity studies in rats and rabbits. Therefore, a dose and endpoint

w ere not selected for this risk assessment.

For chronic dietary exposure, the rat chronic/carcinogenicity study was selected for risk

assessment because t he NOAEL from th at study represents the lowest available NOAEL for effects of rimsulfuron following long

- term dietary administration , and is protective of all other

toxic effects seen in the existing database . The study is appropriate for chronic dietary exposure

due to the route (oral) and long

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

No residential e xposures are anticipated for the projected use patterns, so residential risk

assessments were not conducted.

For Short

- and Intermediate

- Term Dermal and Inhalation exposures, in the absence of route

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

- to

- route extrapolation in the risk assessment, and equivalent toxicity via the inhalation and oral routes was assumed for the purpose of route

- to

- route extrapolation. In the subchronic dog study, the effects seen at the

LOAEL

, increased urinary volume, kidney weights, and decreased osmolality, are not considered to be severe. However, the kidney is a target organ in rats and dogs (increased kidney weights, diueresis) following rimsulfuron exposure; also, other sufonylurea compounds in the HED Integrated Structure, Toxicity, Endpoints and Propertie s (iSTEP) database produce kidney effects such as nephropathy, kidney weight changes and atrophy in subchronic, chronic and multi

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

- and

intermediate

- term dermal and inhalatio n exposures are considered appropriate for risk

assessment.

The dog subchronic study used for Short

- and Intermediate

- Term Dermal and Inhalation

exposures provides a lower NOAEL than the rat chronic rat study used for the Chronic RfD. However, the LOAELs for both studies, 120 mg/kg/day for the rat study versus 125 mg/kg/dayRimsulfuron D 391083

Page 14 of 35 are very similar, suggesting that the difference in NOAELs may just be a matter of dose selection, and thus not toxicologically significant.

4.5.2 Recommendation for Combining Routes o f Exposures for Risk Assessment

Since the toxicological endpoints for the dermal and inhalation route of exposure are based on the same study and the toxicological effect are the same, the dermal and inhalation routes are combined together.

4.5.3 Cancer Classification and Risk Assessment Recommendation

HED determined that rimsulfuron should be classified as “ Not Likely to be Carcinogenic to

Humans. ” (Jessica Kidwell, Dec 16, 2008. TXR 0052726) As such, there is no cancer risk associated with registered or proposed uses of rimsulfuron.

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk

Assessment

Table 4 .5. 4. 1 Summary of Toxicological Doses and Endpoints for Rimsulfuron for Use in Dietary, Non

Occupational , and Occupational Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD,

Level of

Concern for

Risk

Assessment Study and Toxicological Effects

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

.

Chronic Dietary (All Populations) NOAEL=

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

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

= 0.118 mg/kg/day

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

- Rat

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

Incidental Oral

Short

- Term (1

- 30 days);

intermediate

Term (1

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

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 osmolality.Rimsulfuron D 391083

Page 15 of 35 Table 4 .5. 4. 1 Summary of Toxicological Doses and Endpoints for Rimsulfuron for Use in Dietary, Non

Occupational , and Occupational Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD,

Level of

Concern for

Risk

Assessment Study and Toxicological Effects

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 osmolality.

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 observed adver se effect level.

LOAEL = lowest observed a dverse 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 adjust ed 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 route).

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, la ctating goat s , and laying hen s

.

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 (see Appendix C for structures) . Based on the

result s of the studies, HED 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

- Hl 043 were identified in the straw of wheat planted into aged (30 days and 120days), 14 C

- E9636 treated soilRimsulfuron D 391083

Page 16 of 35 and grown to maturity (Structures are provided in Appendix C)

. No undegraded rimsulfuron was detected in the straw of wheat at maturity.

5.1.3 Ana lytical Methodology

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

DP# 3 91764

, M. Negussie

, 10/JAN/2012

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 analysi s 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 validate d 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/ho mogenization 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 : Chicory s amples w ere analyzed for residues of rimsulfuron usin g the LC/MS/MS method, from DuPont Method 13412

, Revision Number 1

, modified to improve performance.

Samples of chicory from the submitted crop field trials were analyzed using acceptable data

collection method. The submitted LC/MS/MS method (Method 13412, Revision 1) has been previously reviewed in conjunction with a petition for thifensulfuron

- methyl ( DP# 330813, S. Hummel, 08/AUG/2006) for oily crop matrices. RAB3/HED has evaluated the method for chicory according to our SOP Number ACB

- 019 and found the method to be adequate for enforcing tolerances . The method does not require a laboratory tolerance method validation (TMV) trial, and can be forwarded to FDA.

5.1. 4 Magnitude of the Residue in Plants

DP# 3 91764

, M. Negussie

, 10/JAN/ 2012

The available chicory field trial data are acceptable and reflect the proposed use patterns provided the directions for use are revised as specified in OPPTS 860.1200. 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. The proposed tolerancesRimsulfuron D 391083

Page 17 of 35 (0.01 ppm) in/on chicory roots and leaves are adequate. Provided the label is revised as requested, the proposed use pattern an d label will be adequate.

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 three 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 aerob ic soil, IN

- J290 and IN

T5831) ( structures are provided in Appendix C )

.

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,

lun g, 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%) radioactivity was attributed to unmetabolized parent compound. Metabolism involves either the contraction or cleavage of the sulfonylurea bridge.

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. The major residue found in plants is the parent compou nd, rimsulfuron

.

5.1. 7 Residues of Concern Summary

Table 5.1. 7

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

.

Matrix Residues included in Risk

Assessment Residues included in Tolerance Expression

Plants Primary Crop R imsulfuron Ri msulfuron

Rotational Crop Rimsulfuron Rimsulfuron

Livestock Ruminant Rimsulfuron Rimsulfuron

Poultry Rimsulfuron Rimsulfuron

Drinking Water Rimsulfuron 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 ; DP 391086, M. Barrett,

3/15/12Rimsulfuron D 391083

Page 18 of 35 EFED previously assessed the drinking water residue profile for rimsulfuron (DP 358869

, 358875

, 384624 ) ) for other uses which drive exposure according to the Tier 1 modeling; the

new chicory use is at a much lower rate (i.e., maximum annual application of 0.00938 lb ai/acre versus 0.06250 lb ai/acre). EFED updated the previous estimates based upon a revisio n of the aerobic soil degradation rate for rimsulfuron. T here is no difference in the use pattern for the new use on chicory that would modify the inputs for the Tier 1 modeling to the extent that the highest previously calculated estimated drinking water concentrations would change . The

maximum use rate of 0.0625 lb ai/A/season for citrus, pome, stone fruit , canberry and bushberry that was previously assessed is more conservative that the proposed use on chicory

. Therefore, the recommended values for est imated 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 usi ng 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: 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 val ue is not relevant to this dietary assessment, as a toxic effect attributable to a single

dose 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, pistachios caneberry and bushberries ; 0.05 ppm in/on tomatoes, 0.09 ppm in/on almond hulls, 0.1 ppm in/on field corn grain, forage, and stover. The proposed tolerance associated with the new uses of rimsulfuron on chicory (roots and tops) is 0.01 ppm.

The unrefined chronic dietary assess ment 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% of those crops are treated. DEEMTM Version 7.81 default proce ssing 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.Rimsulfuron D 391083

Page 19 of 35 5.2 Dietary Exposure and Risk

5.2.1 Acute Dietary Exposure/Risk

An acu te 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 + drinking 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 rimsulfuron in food and water are summarized in Table 5.2. This

assessmen t 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 Aggregate Dietary (Food + Drinking Water) Exposure and Risk for Rimsulfu ron.

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 to humans .” Therefore, there is no

cancer risk associated with existing or proposed uses

.Rimsulfuron D 391083

Page 20 of 35 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

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

- occupational exposure

assessment was not conducted

.

6.1.1 Spray Drift

S pray 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. However, to a lesser extent, spray drift resulting from the ground application o f rimsulfuron could also be a potential source of exposure. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be p laced on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the Ag DRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off

- target dri ft with specific products with significant

risks associated with drift.

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 drinking water). Becau se 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 drinking water. Section 5.2.2 describes the chronic aggregate

ris k , 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 any other substances, and rimsulfuron does not appear to produce a toxic metabolite produced by other substances. For the purposes of this action, therefore, EPA has

assumed that rimsulfuron does not have a common mechanism of toxicity wi th other substances. For information regarding EPA’s efforts to determine which chemicals have a commonRimsulfuron D 391083

Page 21 of 35 mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Program s concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common

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

.

9.0 Occupational Exposure/Risk Pathway

9.1 Short

- and Intermediate

- 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 BASIC ® SG Herbicide for ground boom applications

- Applying the spray mixture by a ground bo om sprayer

Application equipment : Ground broadcast applications may be made with tractor drawn ground boom 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 a vailable 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 p rotection provisions of FIFRA. The HED 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/

han dler

- exposure

- table.pdf ).

Exposure durations : According to the proposed label, one application on chicory is allowed per

y ear at the maximum rate of 0.009 lb ai/A

, resulting in short

- term handler exposures. Two sequential applications may be made a t a maximum seasonal rate of 0.009 lb ai/A/growing season. Since, HED typically assumes commercial applicators use rimsulfuron for longer

dura tions (> 1 month), intermediate

- term exposures were also assessed. Long

- term exposures are not expected ; therefo re, 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 syst ems) , formulationRimsulfuron D 391083

Page 22 of 35 changes, etc. are considered. The proposed PPE includes long

- sleeved shirt and long pants, shoes plus socks and chemical resistant gloves.

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 rimsulfuron are considered upper

- bound.

Table 9.1 summarizes the risks associated with handler’s exposure to rimsulfuron when used in

accord ance with the proposed use pattern for weed control in chicory . 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 ≥ 11,00 0 with an LOC of 100, and therefore the dermal and inhalation risks

are not of concern.Table 9.1. Rimsulfuron

- Short

- and Intermediate

- Term Occupational Exposure and Risk for Handlers Treating Chicory

.

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 gloves 0.0 09 8 0 51.6 8.96 0.00046 0.000 081 0.00054 11,000

Applying with a ground boom sprayer (AHETF) SL, Open cab 78.6 0.34 0.00071 0.0000031 0.0007 1 8,8 00

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, long 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 ( 8 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 ( 8 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/kg/day) / total dose (mg/kg/day)

.9.2 Post

- application Exposure and Risk

Rimsulfuron is applied as postemerg ence spray to control weeds in chicory

. Common post

application activities performed on commercially grown chicory fields are irrigation and scouting which have the potential for dermal exposure to workers performing such activities.

Chemical

- specific data relevant to post

- application exposure (i.e., disl odgeable foliar residue (DFR) data) for the rimsulfuron proposed use were not submitted. Therefore, post

- application exposure estimates were calculated using the standard HED ExpoSAC assumptions (i.e ., default DFR input parameters and exposure duration) a nd HED transfer coefficients (SOP No. 3.1).

HED uses a concept known as the transfer coefficient (TC) to numerically represent the post

application exposures one would receive (generally presented as cm 2 /hour). A TC is a measure

of the residue transfer red from a treated surface to a person who is doing a task or activity in a treated area. These values are the ratio of an exposure for a given task or activity to the amount of pesticide residue on treated surfaces available for transfer. HED has develop ed a series of standard TCs that are unique for a variety of job tasks or activities that are used in lieu of

chemical

- and scenario

- specific data. HED used Policy 3.1 Science Advisory Council for Exposure Policy Regarding Agricultural Transfer Coefficien ts to estimate TCs for the various tasks that post

- application workers might perform on each crop grouping.

In the absence of chemical

- specific DFR data, HED assumes that 20% of the initial application is available for transfer on day 0 (i.e., 12 hours after application) and that the residue dissipates at a rate of 10% per day. Furthermore, HED also assumes an 8 hour workday for post

- application

workers. Exposures were calculated on each day after application. Exposures and risks were

calculated for e ach post

- application activity.

Table 9.2 presents the results of the occupational post

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

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

Table 9.2. Post

- application Exposure and Risk use of Rimsulfuron on Chicory.

Crop App

Rate (lb ai/A) Work

Activity Transfer

Coefficients a (cm 2 /hr) Post

application Day b DFR c

(μg/cm

2 ) Daily Dose d
(mg/kg/day) MOE e

Chicory
(vegetable root and leafy vegetable 0.00 9 scouting 210 0 0.0 25 0.000 53 12 ,000

irrigation 1900 0 0.00 48 1 ,300

a Transfer coefficient from Science Advisory Council for Exposure: Policy Memo #003 "Agricultural Transfer Coefficients,"

06/03/2011.

b Day after treatment represents approximately 12 hours following application when sprays have dried.

c DFR = Application Rate (lb ai/acre) x Fraction of active ingredient that remains on the foliage when sprays have dried x 4.54E8 μg/lb

x 24 .7E

- 9 acre/cm 2

. d Daily dose = DFR (μg/cm 2 ) x TC (cm 2 /hr) x conversion factor (1 mg/1,000 μg) x exposure time (8 hrs/day) x dermal absorption

(100%) / body weight (80 kg).

e MOE = NOAEL (6.25 mg/kg/day) / daily dose (mg/kg/day)

.Rimsulfuron D 391083

Page 25 of 35 Based on the Agency's current practices, a quantitative post

- application inhalation exposure assessment was not performed for rimsulfuron at this time. However, volatilization of pesticides may be a potential source of post

- application inhalation exposure to individuals nearby to pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ) and is in the process of evaluating the SAP report. The Agency may, as app ropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative post

- application inhalation 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 th e following acute toxicity studies: acute dermal toxicity, acute inhalation toxicity, primary skin irritation, and primary eye

irritation. 2) Based on the required sensitization or hypersensitivity studies, the end use product is not a sensitizer, and the re have been no reports 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

NoneRimsulfuron D 391083

Page 26 of 35 10.2 Residue Chemistry

None

10.3 Occupational and Residential Exposure

None

11.0 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/206 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 DP# 391764, M. Negussie, 10/JAN/2012

D 399026 , C. Walls

, April 2012Rimsulfuron D 391083

Page 27 of 35 Append ix A: Physical and Chemical Properties

Table A.1 . Physicochemical Properties of Rimsulfuron

Parameter Value Reference
Melting point 176

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

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

- 4.5: 0.024 ± 0.001 g/L (20 C)

Solvent solubility (25°C) N,N

- dimethylformamide 241 ± 1 g/L Dimethyl sulfoxide 113 ± 3 g/L Methylene chloride 35.5 ± 0.4 g/L

Acetonitrile 17.2 ± 0.5 g/L

Acetone 14.8 ± 0.5 g/L Ethyl acetate 2.85 ± 0.17 g/L

Methanol 1.55 ± 0.11 g/L

Toluene 0.363 ± 0.022 g/L Xylenes 0.093 ± 0.008 g/L

n

- Hexane <0.01 g/L Vapor pressure (25°C) <10
- 5 Pa Dissociation constant, pK

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

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

pH 5.03 at 240 nm, ε = 2.24 x 10 4 (log ε = 4.35) and at 290 nm, ε = 4.81 x 10 2 (log ε = 2.68)Rimsulfuron D 391083

Page 28 of 35 Appendix B : Toxicology Asses sment

B

. 1 Toxicity Profiles

Table B .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 B

. 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 D 391083

Page 29 of 35 Table B

. 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 effects (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

.Rimsulfuron D 391083

Page 30 of 35 Table B

. 1 .2 Subchronic, Chronic and Other Toxicity Profile

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

LOAEL = 342.4 mg/kg/day) based on increased absolute liver and kidney weights and increased incidence of seminiferous tubule degeneration and increased numbers of spermatid 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) / ACCEPTABLE

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, 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 [nuclearRimsulfuron D 391083

Page 31 of 35 Table B

. 1 .2 Subchronic, Chronic and Other Toxicity Profile

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

or 1.1 mg /mL silver grain counts] was induced.

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

NOT YET CLASSIFIED

– study under

review NOAEL = 2000 mg/kg LOAEL > 2000 mg/kg. No clinical signs, changes in body weight and/or food consumption, gross or microscopic pathology, or

neurobehavioral effects were observed

870.6200b

Subchron ic Neurotoxicity (rat) 48710303 (2011) 0, 1000. 3000, 7500 ppm (M/F) 0, 55. 170, 438 mg/kg/day (M) 0, 69, 193, 507 mg/kg/day (F)

NOT YET CLASSIFIED

– study under

review NOAEL = 438/507 mg/kg/day (M/F)

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

fore/hind

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

observed.

870.7800

28

- day Immuno

toxicity (mouse) 4871 0305 (2011) 0, 300, 600, 1800, 6500 ppm 0, 45, 93, 288, 1006 mg/kg/day

NOT YET CLASSIFIED

– study under

review NOAEL = 1006 mg/kg/day LOAEL > 1006 mg/kg/day No clinical signs, gross or microscopic pathology, or changes in body weight and/or food consumpti on, brain, spleen or thymus weights, or in humoral immune response were observed.Rimsulfuron D 391083

Page 32 of 35 Appendix C: Chemical Name and Structures of Rimsulfuron and Metabolites

Company code; Chemical name Chemical structure

IN

— 70941

N

- (4 ,6

- Dimetho x y
- 2

- pyrimidinyl)

- N

- ((3

- ethylsulfonyl)

- 2

- pyridinyl)

urea

IN

- 70942

N

- ((3

- ethylsulfonyl)

- 2

- pyridinyl)

- 4,6

- dimethoxy

- 2

- pyrimidinamine

IN

- E9260

3

- (Ethylsulfonyl )

- 2

- pyridinesulfonamide.

IN

- T5831

N

- (4,6

- dimethoxy

- 2

- pyrimidinyl)urea

IN

- 69190

2

- amino

- 4,6

- dimethoxy

- 5

- pyrimidinol

IN

- J290

2

- Amino

- 4,6

- dimethoxypyrimidineRimsulfuron D 391083

Page 33 of 35 Company code; Chemical name Chemical structure

IN

- H1043

2

- Amino

- 4,6

- dihydroxypyrimidine

IN

- JF999

N

- [((3

- Ethylsulfonyl)

- 2

- pyridinyl)]

- 4

- hydroxy

- 6

- methoxy

- 2

- pyrimidineamineRimsulfuron D 391083

Page 34 of 35 Appendix D : 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 to determine their dermal and inhalation exposure. Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as PHED and the Outdoor Residential Exposure Task Force (ORETF). EPA has reviewed all the studies supporting these multi

- pesticide generic exposure databases, and has found no clear and convincing evidenc e that the conduct of any of them was either fundamentally unethical or significantly deficient relative to the ethical standards prevailing at the time the research was conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subj ects of Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued reliance on these studies.Rimsulfuron D 391083

Page 35 of 35 Appendix E . International Residue Limit Status Sheet

Rimsulfuron (PC Code 129009; 12/05/ 2011) Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : Rimsulfuron

US Canada Mexico 2 Codex 3

40 CFR 180.478:

Plant/Livestock: rimsulfuron, N

- ((4,6

- dimethoxypyrimidin

- 2

- yl)aminocarbonyl)

- 3

- (ethylsulfonyl)

- 2

- pyridinesulfonamide) N

- [[(4,6

- dimethoxy

- 2

- pyrimidinyl)amino]carbo nyl]

- 3

- (ethylsulfonyl)

- 2

- pyridinesulfonamide None

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 2 Codex 3
Chicory, roots 0.01 Chicory, tops 0.01

Completed: M. Negussie; 12/05/2011

1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

3 * = absent at the limit of quan titation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have n ot been finalized by the CCPR and the CAC.