Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 1 of 73 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND
POLLUTI ON PREVENTION

MEMORANDUM

Date: November 3, 2010

SUBJECT: Imazosulfuron: Human Health Risk Asse ssment for Proposed Uses on Rice, Peppers

and Tomatoes.

PC Code: 118602 DP Barcode: 362653, 348001
Decision No.: 406200 Registration No.: 59639-RLU, 59639-RLL,

59639-RAA
Petition No.: 9F7535, 9F7573 Regulatory Action: Section 3 Registration Risk Assessment Type: Single Chemical/Aggregate Case No.: None

TXR No.: None CAS No.: 122548-33-8

MRID No.: None 40 CFR: Pending

FROM: Sheila Healy, Toxicologist

Risk Assessment Branch III Health Effects Division (7509P)

AND Steve Funk, Chemist Cassi Walls, Ph.D., Biologist Nancy Tsaur, Chemist

THROUGH: Paula Deschamp, Chief

Risk Assessment Branch III Health Effects Division (7509P)

AND Jack Arthur, Designated Reviewer Charles Smith, Designated Reviewer

Risk Assessment Review Committee

TO: James Tompkins/Bethany Benbow , Risk Management Team 25

Herbicide Branch Registration Division (7505P) Risk Management DivisionImazosulfuron Human Health Risk Assessment DP No. 362653

Page 2 of 73 The Health Effects Division (HED ) of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides. The Regist ration Division (RD) of OPP has requested that HED evaluate hazard and exposure data and conduc t dietary, occupational, residential and aggregate exposure assessments, as n eeded, to estimate the risk to human health that will result from the proposed food use of imazosu lfuron on tomatoes, peppers and rice. Risk was previously assessed for non-food use on turf and or namentals, and has been incorporated into the aggregate risk assessment pr esented in this document.

HED has evaluated the toxicity and exposure databases for the active ingredient (ai), imazosulfuron,

and has conducted a human health risk assessment in support of the Section 3 Registration Action

for this first food use of imazosulf uron. HED has determined that potential exposure could occur via the dietary (food and drinking water), residential and occupational pathways. HED determined that there is reasonable certainty that no harm will result to the gene ral population or to infants and children from aggregate exposure resulting from the proposed uses.

A summary of the findings and an assessment of human health risk resulting from the proposed uses for imazosulfuron are provided in this document. The HED team members contributing to this risk assessment include Nancy Tsaur (occupational/resi dential assessments), Cassi Walls (dietary assessment), Steve Funk (residue chemistry data re view) and Sheila Healy (hazard evaluation and risk assessment). Faruque Khan, Senior Scie ntist, Environmental Risk Branch I (ERB1),

Environmental Fate and Effects Division (EFED), provided the drin king water exposure assessment.Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 3 of 73 1.0 Executive S ummary ................................................................................................................ 5
2.0 HED Recommendatio ns ......................................................................................................... 7
2.1 Data Deficiencies/Conditions of R egistration ................................................................... 8

2.2 Tolerance Considerations ................................................................................................... 9

2.2.1 Enforcement Analytical Method ................................................................................... 9

2.2.2 Internation al Harmonization ....................................................................................... 10

2.2.3 Recommen ded Tolerances ............................................................................................ 10

2.2.4 Revisions to Petitioned -For Tolerances ...................................................................... 10

2.3 Label Recommendations .................................................................................................. 10

2.3.1 Recommen dations from Residue Reviews .................................................................. 10

2.3.2 Recommen dations from Occupational Assessment ................................................... 11

2.3.3 Recommen dations from Residential Assessment ....................................................... 11

3.0 Ingredient Profile .................................................................................................................. 11

3.1 Structure a nd Nomenclature ........................................................................................... 11

3.2 Physical/Ch emical Characteristics .................................................................................. 12

3.3 Summary of Existing/Proposed Uses .............................................................................. 13

4.0 Haz ard Characterization and Dose-Response Assessment ............................................... 16

4.1 Toxicology Studies Available for A nalysis ...................................................................... 16

4.2 Absorption, Distributio n, Metab olism, & Elimination (ADME) .................................. 16

4.2.1 Dermal Absorption ....................................................................................................... 17

4.3 Toxicological Effects ......................................................................................................... 18

4.4 Safety Factor for Infan ts and Children (FQPA Safety Factor) .................................... 18

4.4.1 Completeness of the Toxicology Database .................................................................. 19

4.4.2 Evidence of Neurotoxicity ............................................................................................ 19

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ............ 19

4.4.4 Residual Uncertainty in the Exposure Database ........................................................ 20
4.5 Toxicity Endpoint and Point of Departure Selections ................................................... 21

4.5.1 Dose-Response Assessment .......................................................................................... 21

4.5.2 Recommen dation for Combining Routes of Exposures for Risk Assessment ......... 22

4.5.3 Cancer Classification and Risk Assessment Recommendation ................................ 22

4.5.4 Summary of Points of Departure and T oxicity Endpoints Used in Human Risk

Assessment

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

4.6 Endocrine Disruption ....................................................................................................... 24

5.0 Dietary Exposure and Risk Assessment .............................................................................. 25

5.1 Metabolite/Degradate Residue Profile ............................................................................ 25

5.1.1 Summary of Plant and Animal Metabolism Studies ................................................. 25

5.1.2 Summary of Environmental Degradation .................................................................. 26

5.1.3 Comparison of Metab olic Pathways ............................................................................ 26

5.1.4 Residues of Concern Summary and Rationale ........................................................... 27

5.2 Food Residue Profile ......................................................................................................... 28

5.3 Water Residue Profile ....................................................................................................... 31

5.4 Dietary Risk Assessment .................................................................................................. 32

5.4.1 Description of Residue Data Used in Dietary Assessment ........................................ 32

5.4.2 Percent Crop Treated Used in Dietary Assess ment ................................................... 32

5.4.3 Acute Dietary Risk Assessment ................................................................................... 32

5.4.4 Chronic Dietary Ris k Assessment ............................................................................... 33Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 4 of 73 5.4.5 Cancer Dietary Ris k Assessment ................................................................................. 33

5.4.6 Summary Table ............................................................................................................. 33

6.0 Residential (Non-Occu pational) Exposure/Risk Characterization .................................. 35

6.1 Residential Handler Exposure ......................................................................................... 35

6.2 Post-Application Exposure ............................................................................................... 36

6. 3 Spray Drift ......................................................................................................................... 39

7.0 Aggregate Exposure/Risk Characteriz ation ....................................................................... 39

7.1 Acute Aggregate Ris k ....................................................................................................... 39

7.2 Short- and Intermed iate-Term Aggregate Risk ............................................................. 39

7.3 Chronic Aggregate Ris k ................................................................................................... 40

7.4 Cancer Aggregate Ris k ..................................................................................................... 40

8.0 Cumulative Exposure/Risk Characterization .................................................................... 40

9.0 Occupation al Exposure/Risk Characterization ................................................................. 40

9.1 Short-/Intermediate-/Long-Term Handler Risk ............................................................ 40

9.2 Short- and Intermediate-T erm Pos t-Application Risk .................................................. 43

10.0 Incidents

............................................................................................................................... .. 43

11.0 Environmental Justice Considerations ............................................................................... 43

12.0 References .............................................................................................................................. 44 Appendix A. Toxicology Prof ile and Executive Summaries ........................................................ 45
A.1 Toxicology Data Requirements ........................................................................................ 45
A.2 Toxicity Profiles ................................................................................................................ 46
A.3 Haz ard Identification and Endpoint Selection ............................................................... 50
A.4 Executive S ummaries ........................................................................................................ 52
A.5 Toxicology Data Required as a Condition of R egistration ............................................ 65 Appendix B. Metabolism Summary Table .................................................................................... 65 Appendix C. Review of Human Research ...................................................................................... 72Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 5 of 73 1.0 Executive Summary

Use Profile : Imazosulfuron, a sulfonylurea herbicide (2-chloro- N -[[4,6-dimethoxy-2-pyrimidinyl)- amino]carbonyl]imidazo[1,2- a ]pyridine-3-sulfonamide), is a new active ingredient (ai) proposed for use on tomatoes, peppers and rice in conjunc tion with a pending regi stration on turf grass (residential, commercial, golf cour ses and sod farms), ornamentals and bare-ground non-crop areas. Imazosulfuron (V-10142) is to be formulated as a 75% ai water-dispersib le granule (WG). This granular formulation is to be a dded to water, resulting in a disper sion of finely divided herbicide particles suspended in water to be applied for weed control.

V-10142 may be applied to tomatoes and rice prio r to crop planting (pre-emergent) and shortly following new crop plantings (post-emergent). App lications to peppers may only be made to well established peppers (at least 10 in ches tall). Application timing may also vary depending on the target weed (pre-emergence or post-emergence w eeds). However, only one application may be made per season for all three crops: tomatoes, peppe rs, and rice. The applic ation rates range from 0.2 lb ai/A to 0.3 lb ai/A for tomatoes, peppers, a nd rice. Soil-directed ground application is to be used for all three crops; aerial application is permitted for rice only. Foliar application may be

allowed for tomato and rice.

Hazard Assessment : Chronic studies in the rat and dog indi cate that liver is the primary target organ for chronic oral exposure. Mild to moderate thyroid effects were apparent only in the chronic toxicity study in dogs and advers e eye effects were observed in ra ts fed > 1000 mg/kg beginning at 3

months in the chronic to xicity/carcinogenicity study. Decreased body weight and body weight gain compared to control was a frequent finding throughout the toxicology database for imazosulfuron.

Metabolism studies in the rat indicate that imazo sulfuron is extensively absorbed, metabolized and excreted (urine, ~66% of the administered dose; feces, ~33%). The parent and 5 metabolites were identified and quantified in these studies. The parent was detect ed only in feces and amounted to 0.9% of the administered dose (AD). HMS, the predominant metabolite, was found in the urine (31% AD) and feces (6.5% AD). Lesser metabolites (< 5% AD) were also identified in urine and feces. Proposed mammalian metabolic pathways for imazosulfuron are: 1) demethylation, 2) hydroxylation of the pyrimidine ring, 3) methylat ion of the hydroxyl group, 4) opening of the pyrimidine ring and formation of guanidine a nd 5.) hydrolysis of the sulfonylurea bridge.

In a 21-day dermal toxicity study in rats, no localized dermal or syst emic effects were seen at the limit dose of 1000 mg/kg/day, the derm al and systemic NOAEL. There was no evidence of increased susceptibility in the submitted toxicology database. There is no concern for increased susceptibility to offspring following pre- and postnatal exposure to rats or in

utero exposure in rabbits. Neither the rat nor rabb it developmental studies identified developmental

effects.

The genotoxic potential of imazosulfuron has been assessed as negative by several in vitro and in

vivo mutagenicity studies. The two-year combin ed chronic toxicity a nd carcinogenicity study in rats, as well as the 18-month carci nogenicity study in m ice, showed no evidence of carcinogenicity. Imazosulfuron is classified as “not likely to be carcinogenic to humans,” based on the absence of significant tumor increases attributed to treatment.Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 6 of 73 The oral LD 50 of imazosulfuron is greater than 5000 mg/ kg; the acute inhalation LD 50 is greater than 2 mg/L; and the acute dermal LD 50 is greater than 2000 mg/kg. All acute studies are in Toxicity Category III or IV. Imazosulfuron is not irritati ng to the skin or eyes and is not a sensitizer.

Dietary Exposure (food/water) : The residue chemistry data and environmental fate data are adequate to assess human exposure. The chronic dietary food exposure assessm ent is conservative.

The assessment is based on reliable data and will not underestimate exposure/risk.

Acute: An unrefined acute dietary risk anal ysis was conducted with the DEEM-FCIDTM model, assuming 100% crop treated (CT) an d tolerance level residues, to fo rm a conservative evaluation of exposure for imazosulfuron. At the 95 th percentile of exposure, all acute analyses yielded risk
estimates well below 100% of the aPAD threshold level of concern for each population subgroup. For food and drinking water, acute aggregate dietary risk was calcula ted at <1% of the aPAD for the general population. For the subgroup with the highest calculated exposur e, all infants (< 1 year old), acute aggregate dietary risk occupied 1.4% of the aPAD.

Chronic: An unrefined chronic dietary risk analysis was conduc ted with the DEEM-FCIDTM model, assuming 100% CT and tolerance-le vel residues, to form a conserva tive evaluation of exposure for imazosulfuron. All chronic analys es yielded risk estimates well below 100% of the cPAD threshold level of concern for each population subgroup. For food and drinking water, the chronic aggregate dietary risk was calculated at <1% of the cPAD for the general U.S. population. For the subgroup with the highest calculated exposur e, all infants, chronic aggregate dietary risk occupied 2.7% of the

cPAD.

Residential Exposure : No new residential uses and no occupati onal uses at residential sites are being requested in this petition; theref ore, a new residential risk assess ment was not conducted. Residential exposure risk was assessed for a pending registrati on for turf grass, orname ntals and bare-ground non-crop areas (DP#349707, Kelly O’Rourke, 02/17/ 2009) and is incorporated in th is assessment. The MOEs for

residential handlers are well above LOC of 100 and are not of concern.

Aggregate Risk: Acute: Aggregate acute risk is equivalent to acute di etary risk via food and drinking water exposure pathways and comprises 1.4% of the aPAD for the most highly exposed population, infants < 1 year

old.

Chronic: Aggregate chronic risk is equivalent to chronic dietar y risk via food and drinking water exposure pathways and comprises2.7% of the cPAD for the most highly exposed population, infants < 1 year old.

Short- and Intermediate Term: There is poten tial short- and intermediate-term exposure to imazosulfuron via the dietary pathway (which is considered background exposure) and the residential pathway (which is considered the pr imary pathway). Since no dermal hazard was identified, the exposure pathways for adults incl ude only the dietary and inhalation (residential handler) routes. For children, th e exposure pathway incl udes the dietary exposure and the incidental oral post-application residential pathway.Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 7 of 73 All aggregate MOEs are gr eater than 100; therefore, aggregat e exposure is not of risk concern.

Occupational Exposure/Risk: Agricultural Handlers: Occupati onal short- (1 - 30 days) and in termediate-term (1 – 6 months) dermal and inhalation exposures ar e expected from imazosulfuron handler activities associated with the proposed agricultural uses. Since no hazard was identified for the dermal route of exposure,

dermal risks were not assessed.

All baseline inhalation scenarios (i .e., no respiratory protection) for handlers resulted in MOEs greater than the level of concern LOC (i.e., MOEs ≥ 100) and are therefore not of concern. The maximum exposure (MOE = 59,000) occurred from mixing/loading dry flowables for aerial applications to rice at the maximu m application rate (0.3 lb ai/A). There is no occupational cancer

risk associated with imazosulfuron since it is cla ssified as “Not Likely to be Carcinogenic to

Humans.”

Agricultural Postapplication: Since no hazard was identified for the dermal route of exposure, occupational short- and intermediate-term non-can cer dermal risks were not assessed for postapplication activities. Based on the Agency's current practices, a quant itative post-application inhalation exposure non-can cer assessment was not pe rformed for imazosulfuron at this time.

Environmental Justice Considerations : Potential areas of environmen tal 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 pa rt on data from studies in which adult human subjects were intent ionally exposed to a pesticide or other chemical. These studies (listed in Appendix C) have been determined to re quire a review of their et hical conduct, and one of these studies is also subject to review by the Human Studies Review Board. All of the listed studies have received the appropriate review.

2.0 HED Recommendations

HED has examined the toxicology and residue ch emistry database for imazosulfuron. Pending

submission of a revised Section B (see requirements under Directions for Use), there are no residue chemistry issues that would preclude granting a conditional registration for the requested uses of

imazosulfuron or establishment of tolerances for residues of imazosulfuron as follows:

Tolerances are established for residues of imazosulfuron, including its metabolites and degradates, in or on the commodities in the ta ble below. Compliance with the tolerance levels specified below is to be determined by measuring only imazosulfuron, or 2-chloro- N

- [[(4,6-dimethoxy-2-pyrimidinyl)amino]carbonyl]imidazo-[1,2- α ]pyridine-3-sulfonamide, in or on the following commodities.

Pepper, Bell.................................................................0.02 ppm Pepper, non-Bell .........................................................0.02 ppmImazosulfuron Human Health Risk Assessment DP No. 362653

Page 8 of 73 Rice, grain...................................................................0.02 ppm Tomato ........................................................................0.02 ppm

2.1 Data Deficiencies/Condi tions of Registration

The following must be provided prior to a tolera nce being established or registration allowed:

RESIDUE CHEMISTRY

860.1200 Directions for Use

The label must be amended to add the following restriction for applicat ion to rice: Do not apply to rice fields if fields are used for the aq uaculture of edible fish and/or crustaceans.

• A 12-month plant back interval (PBI) must be proposed for soybeans and for cereal grain crops, and the 8-month rotational interval for field corn planted following rice must be removed. In addition, the petiti oner will need to remove the st atement concerning the use of

shorter rotational intervals “where local experience has shown crop safety.”

The following data are required as a condition of registration:

TOXICOLOGY

870.7800 Immunotoxicity The immunotoxicity study in rats and/or mice is required to fulfill current Section 158 data requirements. The registrant has stated th at an immunotoxicity study is underway, scheduled to be completed in August 2010.

RESIDUE CHEMISTRY

860.1360 Multiresidue Methods

The following additional information must be provided concerning the multiresidue methods testing for imazosulfuron: the petitioner must explain why testing for imazosulfuron under Protocol D through the complete method wit hout cleanup was not conduc ted or provide the

results of testi ng without cleanup.

860.1380 Storage Stability

The final report(s) of the storage stability studies must be submitted, reflecting storage intervals of up to 11.8 months for peppers, up to 34.5 months for rice grain, and up to 17.3 months for tomatoes. Details concerning the preparation of samples and fortification solutions should be provided with the final report(s).Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 9 of 73 860.1850 Confined Accumulati on in Rotational Crops

The HPLC profile for the pyrimidinyl (Py)-label grain storage stabilit y analysis must be submitted to confirm that the metabolite profile was stable in Py-label grain. There is no information in the residue chemistry database to indicate that this is an unstable label.

860.1900 Field Accumulation in Rotational Crops

The petitioner previously indicated that a wh eat rotational crop study was being conducted. This study has not been submitted and is required.

The following data should be submitted with future uses:

RESIDUE CHEMISTRY

In consideration of the low anticipated diet ary burdens of imazosulfuron to livestock, HED recommends that the requirements for rumina nt and poultry feeding studies be waived for this petition. No feeding studies need to be submitted to support the proposed uses of imazosulfuron on pepper, rice, and tomato. HED notes that if additional uses of imazosulfuron with livestock feed items are pr oposed in the future, feeding studies may be required.

TOXICOLOGY

Based on the available toxicity database and the Agency's cu rrent practices, the inhalation risk for imazosulfuron was assessed using an or al toxicity study. Th e Agency sought expert advice and input on issues related to this route to route extrapol ation approach (i.e. the use of oral toxicity studies for inhala tion risk assessment) from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency

received the SAP’s fina l report on March 2, 2010 ( http://www.epa.gov/scipoly/SA P/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, re-examine and develop new policies and procedures for conducting i nhalation risk assessments, including route to route extrapolation of toxicity data. If any new policie s or procedures are developed, the Agency may revisit the need fo r an inhalation toxicity study for imazosulfuron and/or a reexamination of the inhalation toxicity risk assessment.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

The petitioner has proposed a high performance liquid chromatography method with tandem mass spectroscopy detection (LC/MS/MS) , Method RM-42C-3, for enforcement of tolerances for residues of imazosulfuron in/on crop commodities. The me thod has been adequately validated and has undergone a successful independent laboratory validation (ILV) with rice grain. HED has evaluated the method against the criteria (SOP AOB-019, 09 /15/08) for a tolerance method validation (TMV)Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 10 of 73 and has concluded that the method is acceptable for tolerance enforcement. The method adequately

determines residues of imazosulfuron as well as the metabolite UDPM in pepper, rice, and tomato commodities. The validated limit of quant itation (LOQ) is 0.02 ppm for each analyte (imazosulfuron, UDPM) in/on pepper, rice, and tomato commodities.

The submitted multiresidue methods test data for imazosulfuron and UDPM are considered to be tentatively adequate pending submission of the fo llowing additional information: 1) the petitioner must explain why testing for imazosulfuron under Protocol D through the co mplete method without cleanup was not conducted or provide the results of testing withoutcleanup and 2) the petitioner must explain why imazosulfuron was tested through only one of the two Protocol D Florisil elution procedures. The data indicate that the multiresidue methods are not suitable for determination of

imazosulfuron.

2.2.2 International Harmonization

There are currently no maximum residue limits (M RLs) established by Codex, Canada, and Mexico

for imazosulfuron.

2.2.3 Recommended Tolerances

HED recommends for the following tolerances and commodity definition:

Tolerances are established for residues of imazosulfuron, including is metabolites and degradates, in or on the commodities in the ta ble below. Compliance with the tolerance levels specified below is to be determined by measuring only imazosulfuron, or 2-chloro- N

- [[(4,6-dimethoxy-2-pyrimidinyl)amino]carbonyl]imidazo-[1,2- α ]pyridine-3-sulfonamide, in or on the commodity.

Table 2.2.3. Tolerance Summary for Imazosulfuron

Commodity Proposed Tolerance (ppm) Recommended Tolerance (ppm) Pepper, Bell 0.02 ppm 0.02 ppm
Pepper, non-Bell 0.02 ppm 0.02 ppm
Rice, grain 0.02 ppm 0.02 ppm

Tomato 0.02 ppm 0.02 ppm

2.2.4 Revisions to Petitioned-For Tolerances

There are no revisions the to lerance petition (Table 2.2.3).

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

The label must be amended to add the following rest riction for application to rice: Do not apply to rice fields if fields are used for the aquacu lture of edible fish and/or crustaceans.Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 11 of 73 Pending submission of field rotati onal crop data a 12-month PBI must be proposed for soybean and cereal grain crops, and the 8-month rotational interval for field corn planted following rice must be removed. In addition, the petitioner will need to revise the statement conc erning the use of shorter intervals “where local experience has shown crop safe ty” to specify a minimum rotational interval of 12 months for cereal grain crops. The remaining ro tational crop restri ctions appear to be supported by the available data from the confined rotational crop study.

2.3.2 Recommendations from Occupational Assessment

The imazosulfuron technical material has been classi fied in Toxicity Category III for acute dermal and Toxicity Category IV for prim ary eye irritation and primary skin irritation. Per the WPS, a 12- hr restricted entry interval (RE I) is required for chemicals classifi ed under Toxicity Category III or IV. The proposed label indicates a 12- hour REI, which complies with the WPS

2.3.3 Recommendations from Residential Assessment

No modifications to the propos ed turf grass, ornamental a nd bare ground uses of the WDg formulation (EPA File symbol 59639- RLL) are recommended. No residential uses or occupational

uses at residential sites are be ing requested in this petition.

3.0 Ingredient Profile

Imazosulfuron is a sulfonylurea herb icide being developed by Valent U.S.A. Corporation for control of broad-leaf weeds and sedges in pepper, rice, and tomato. Imazosulfuron acts by inhibiting the enzyme acetolactate synthase. This petition (PP#9F7535) is the first food/feed use request for imazosulfuron. Valent has proposed uses for im azosulfuron on peppers, rice and tomatoes in addition to the previously requested registration for use on turf, orname ntals, and bare ground.

In conjunction with this petition, Valent has submitte d an application for Section 3 registration of a new end-use product, a 75% water-dispersible gr anule (WG) formulation (V-10142 Ag Herbicide; EPA File Symbol 59639-RAA) for use on pepper, ri ce and tomato. The 75% WG formulation is proposed for preemergence and/or postemergence applications to peppers, rice, and tomato at maximum seasonal application rates up to 0.3 lb ai/A. Use on peppers is restricted to soil-directed application with a 21-day preharvest interval (PHI). Soil and/or fo liar applications are proposed for rice and tomato, with a 21-day PHI for tomato; applications to rice may be made until the 2-inch internode growth stage.

3.1 Structure and Nomenclature

Table 3.1. Test Compound NomenclatureImazosulfuron Human Health Risk Assessment DP No. 362653

Page 12 of 73 Table 3.1. Test Compound Nomenclature

Chemical Structure

N N

N N

N H N H S O

O Cl

O CH 3 O CH 3

O

Common Name Imazosulfuron

Company experimental name V-10142; TH-913

IUPAC name 1-(2-chloroimidazo[1,2- α ]pyridin-3-ylsulfonyl)-3-(4,6-dimethoxypyrimidin-2- yl)urea

CAS Name 2-chloro- N -[[(4,6-dimethoxy-2-p yrimidinyl)amino] carbonyl]imidazo- [1,2- α ]pyridine-3-sulfonamide
CAS Registry Number 122548-33-8
End-use product/EP 75% WG (V-10142 Ag Herbicide; EPA File Symbol 59639-RAA)

Chemical Class Sulfonylurea herbicide

Known Impurities of Concern No impurities of toxicological significance were identified as quantifiable. Three impurities were present around or below the limit of detection of the analyses and must be included on a revised CSF, along with their upper certified limit (MRID 47350101)

3.2 Physical/Chemical Characteristics

Table 3.2. Physical and Chemical Properties

Parameter Value Reference 1

Molecular Weight 412.81 47305101
Melting point/range 198.0 oC 47305112

pH 4.61 at 25 oC (1% suspension in water) 47305105
Density 1.652 at 20 oC 47305105
Water solubility (20°C) 429 mg/L at pH 7; 3936 mg/L at pH 9 47305115

Solvent solubility (20°C to 25°C) 0.820 mg/L in hexane 174.6 mg/L in n -octanol 597.2 mg/L in toluene 4478.5 mg/L in acetone 144.8 mg/L in methanol 12,744.7 mg/L in dichloromethane 2,220.3 mg/L in ethyl acetate 47305105

Vapor pressure (25°C) below LOD (<3.5 x 10 -6 Pa) 47305116

Dissociation constant, pKa 3.94 in methanol/0.01 M citrate buffer at 252 nm

0.30 in methanol/HCl at 268 nm 47305113

Octanol/water partition coefficient, log K OW (25°C) 2.43 at n -octanol/pH 4 buffer

-0.07 at n -octanol/pH 7 buffer

-1.56 at n -octanol/pH 9 buffer 47305114

UV/visible absorption spectrum pH Wavelength (nm) A ε , x10 4

acidic 238.5 0.8877 3.55

201.0 1.1653 4.66
neutral 238.0 0.8293 3.32 47305111Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 13 of 73 Table 3.2. Physical and Chemical Properties

Parameter Value Reference 1

232.0 0.8278 3.31

200.5 1.1497 4.60
basic 244.0 0.7607 3.04

231.0 0.8500 3.40

1 Referenced in the petition summary document (Report No. 200900084) for PP#9F7573.

3.3 Summary of Existing/Proposed Uses

Valent USA Corporation has previously requested registration for use on turf, ornamentals and bare ground with uses summarized in the memo, IMAZOSULFURON: Human Health Risk Assessment for Proposed Uses on Turf and Ornamentals in Non-Crop Areas, DP#348001, S. Healy, March 13,

2009

.

Valent has submitted a draft label dated 2/16/09 for a new end-use product, V-10142 Ag Herbicide, a 75% WG formulation (EPA File Symbol 59639-RAA), for use on pepper, rice, and tomato. The proposed use directions are summarized in Table 3.3.Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 14 of 73 Table 3.3. Summary of Direct ions for Use of Imazosulfuron
Applic. Timing, Type, and Equip. Formulation Applic.

Rate (lb ai/A) Max. No. Applic. per

Season Max.
Seasonal Applic. Rate

(lb ai/A) PHI (days) Use Directions and

Limitations

Peppers (Bell and Non-bell): Use is restricted to field-grown peppers.

Postemergence, Directed to soil,

Ground 75% WG 0.2-0.3 1 0.3 21 Apply to established pepper plants ≥ 10 inches tall; apply to row middles, avoiding contact with the crop, or under the rows toward the pepper stem

≤ 2 inches above the soil
surface.

Rice
Preemergence/

Delayed Preemergence, Broadcast to soil,
Ground or aerial 0.2-0.3 1 0.3 Drill seeded : Apply to prepared moist seedbed.

Postemergence, Broadcast foliar,

Ground or aerial 0.15-0.2 1 0.2 Dry or water seeded : Apply to moist soil or

flooded fields.
Drill seeded : Apply to

rice in at least the 2-leaf growth stage (second leaf fully expanded),

Preemergence +

Postemergence, Broadcast,
Ground or aerial 75% WG

0.15 2 0.3 Not specified; application may be made

until 2-inch

internode stage of rice

Drill seeded : Apply preemergence to moist seedbed, then postemergence to moist

soil or flooded fields with a minimum 21-day
retreatment intervalImazosulfuron Human Health Risk Assessment DP No. 362653

Page 15 of 73 Table 3.3. Summary of Direct ions for Use of Imazosulfuron
Applic. Timing, Type, and Equip. Formulation Applic.

Rate (lb ai/A) Max. No. Applic. per

Season Max.
Seasonal Applic. Rate

(lb ai/A) PHI (days) Use Directions and

Limitations

Tomato: Use is restricted to field-grown tomatoes
Pre-transplant, Broadcast to soil,

Ground Apply to prepared bed prior to transplant or installation of plastic mulch; transplanting may begin 1 day after application.

Postemergence, Broadcast foliar,

Ground Direct seeded : Apply “over the top” to

established tomatoes at the 4- to 5-leaf stage through early bloom.

Postemergence, Broadcast foliar,

Ground Transplanted : Apply “over the top” 3-5 days after transplanting through early bloom stage only if a pre-transplant application was not made.

Postemergence, Directed to soil,
Ground 75% WG 0.2-0.3 1 0.3 21

Direct seeded or transplanted : Apply to
established tomatoes at the 4- to 5-leaf stage only if a pre-transplant application was not made. Apply to soil surface from crop row to row
middle.

Established Turf (residential, commercial, golf course and sod farms) a

Groundboom, Low-pressure
Handheld Equipment 1, 2 V-10142
Herbicid e [EPA Reg. No.

59639- RLL] 3 0.5-0.75 2 Not specified N/A N/A

Around Outdoor Ornamentals (field grown conifers, deciduous t rees, non-bearing fruit and nut trees and landscape plants) a

Groundboom, Low-pressure
Handheld Equipment 1 V-10142
Herbicid e [EPA Reg. No.

59639- RLL] 3 0.5-1.0(preemergence)

0.5-0.75(postemergence) Not specified Not specified N/A N/A

Bare Ground Non-Crop aImazosulfuron Human Health Risk Assessment DP No. 362653

Page 16 of 73 Table 3.3. Summary of Direct ions for Use of Imazosulfuron
Applic. Timing, Type, and Equip. Formulation Applic.

Rate (lb ai/A) Max. No. Applic. per

Season Max.
Seasonal Applic. Rate

(lb ai/A) PHI (days) Use Directions and

Limitations

Aerial or

Handheld Equipment V-10142
Herbicid e [EPA Reg. No.

59639- RLL] 3 0.5-1.0(preemergenc e)

0.5-0.75(postemergenc e) Not specified Not specified N/A N/A

a DP#348001, S. Healy, March 13, 2009.

1 For turf, aerial applications are prohibited, and product is not to be applied through any type of irrigation system.

2 A second application is permitted for turf (application interval = 21 days), however, the number of applications and interval are not specified for the ornament al and bare ground non-crop use sites.

3 The formulation is a water dispersible granule (75% ai).

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis

Data from the following studies were used to evaluate the hazard pot ential of imazosulfuron:

• Acute: Acute oral t oxicity of imazosulfuron, technical and its 5 metabolites/degradates, IHOA, UDPM, IPSN, M-1 (N-(2-chloroimidazo [1,2-a] pyridin-3-ylsulfonyl)-N’-(4-hydroxy6-methoxy-2-pyrimidinyl)urea) and ADPM (Table B.1) in rats; acute dermal, rat; acute inhalation, rat; acute eye irritati on, rabbit; acute dermal irritati on, rabbit; dermal sensitization, guinea pig and acute neurotoxicity, rat.

• Subchronic: 13-week oral, ra t; 13-week oral, mouse; 21-day dermal, rat; and subchronic neurotoxicity, rat.

• Chronic: 52-week oral, dog; 108-week carcinogenicity, mouse; 2-year oral/c arcinogenicity,

rat.

• Reproduction/developmental: Developmental to xicity, rabbit; devel opmental toxicity/onegeneration reproduction, rat; and two-generation reproduction, rat.

• Other: 9 genotoxicity screens (including 5 metabolites) and 2 metabolism/pharmacokinetic
studies in rats.

4.2 Absorption, Distribution, Metab olism, & Elimination (ADME)

No differences in the excretion profile based on ge nder or radiolabel positi on were observed in a rat metabolism study. The majority of the dose was r ecovered in the urine (~ 66%) and a substantial amount was isolated in the feces (~33%). Almost al l radioactivity isolated in the feces was absorbed and excreted in the bile. Thus, the test compound was nearly comple tely absorbed and near total excretion (96% administered dose) was achieved by 48 hours post-dose. At 72 hours post-dose, only
0.25% of the administered dose was detected in th e gastrointestinal contents, organs, tissues and

residual carcass. Of this resi dual radioactivity, label was dete cted only in the kidney (0.045 μg equiv/g), plasma (0.044 μg equiv/g), and liver (0.036 μg equiv/g); levels in other organs and tissuesImazosulfuron Human Health Risk Assessment DP No. 362653

Page 17 of 73 were less than 0.020 μg equiv/g. These data indicat e that imazosulfuron does not bioaccumulate at this low dose level of 5 mg/kg.

Five metabolites were identified and accounted for approximately 75 % of the administered dose. HMS (1-(2-chloroimidazo[1,2-a]pyridin-3-ylsul fonyl)-3-(4-hydroxy-6-met hoxypyrimidin-2-yl)urea) was the major metabolite detected in urine (55.7 % administered dose) and feces (6.5%). Other
metabolites accounted for < 5% of the administered dose and parent was isolated in negligible amounts (< 1%) in the feces. Metabolic reactions included de methylation, hydroxylation of the pyrimidine ring, methylation or glucuronida tion of the hydroxyl group, and opening of the pyrimidine ring and formation of guanidine (Figure 4.2).

Figure 4.2

4.2.1 Dermal Absorption

Data from a dermal penetration study are not available. However, in a 21-day dermal toxicity study in rats, no dermal or systemic effects were seen at the limit dose of 1000 mg/kg/day, the dermal and systemic NOAEL; a dermal endpoint was not identif ied. Furthermore, there are no concerns forImazosulfuron Human Health Risk Assessment DP No. 362653

Page 18 of 73 developmental or neurological toxi cities. The lack of dermal and systemic toxicity may be attributable to poor dermal absorption.

4.3 Toxicological Effects

Imazosulfuron is a selectiv e herbicide which inhibits the plant en zyme acetolactate synthase (ALS). ALS is required to synthesize the essential, br anched-chain amino acids, valine, leucine and

isoleucine. ALS inhibito rs exhibit low mammalian toxicity, likely due to the fact that mammals lack acetolactate synthase.

The toxicity database for imazosulfuron suggests that this herbicide possesses re latively low toxicity. Many of the effects of single or repeated dosi ng are observed near or beyond the respective limit doses. The primary target organ of imazosulfuron toxi city was the liver in all species tested. Mild to moderate thyroid effects were a pparent only in the ch ronic toxicity study in dogs. Dramatic eye effects (retinal degeneration, lens vascularization, cataracts and corn eal scarring) we re observed in rats fed > 1000 mg/kg beginning at 3 months in th e chronic toxicity/carcin ogenicity study. Ocular effects, increased incidence of eye opacity, corneal edema, infl ammation and neovascularization, were also observed in the high-dose males (4577 mg /kg/day) of the 90-day f eeding toxicity study in rats. Decreased body weight and body weight gain compared to control was a frequent finding throughout the toxicology database for imazosulfuron.

Clinical signs observed in males at the limit dose of the acute ne urotoxicity study, decreased motor activity, abnormal gait, upward curvature of the spine and piloerection at the limit dose can be attributed to generalized toxicity and were resolved by Day 2 of th e study. No neurotoxic effects were observed during the subchronic sc reening battery or noted as clin ical signs in any other repeatdose study.

While ≥ 60% mortality was observed at 500 mg/kg/day and abortion (1/5, not treatment-related) at 250 mg/kg/day in a dose range-finding study in rabb its, no developmental effects were observed at 125 mg/kg/day (highest dose test ed) in the guideline study. No developmental or reproductive toxicity was observed in the one -generation rat study. Decreased pup viability was observed in the rat two-generation reproducti on study at a dose approach ing the limit dose (LOAEL = 892 mg/kg/day) in both the F1 and F2 offspring generations. Mortality wa s also observed in the parental generation at this dose. No qualitative or quantitativ e offspring susceptibility was apparent in any of

the submitted studies for imazosulfuron.

Review of acceptable carcinogenicity and mutage nicity studies provides no indication that imazosulfuron is a carcinogen, mutagen or clastogen.

Study summaries of the acute, subc hronic and chronic toxi city and genotoxicity for imazosulfuron are provided in Appendix A at the end of the document.

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

There is an adequate toxicity database for imazosulfuron and exposure data are complete or are estimated based on data that reasonably account for potential exposures. Th ere is no evidence ofImazosulfuron Human Health Risk Assessment DP No. 362653

Page 19 of 73 susceptibility following in utero and/or postnatal exposure in the developmental toxi city studies in rats or rabbits, or in the 2-generation rat re production study. There are no residual uncertainties concerning pre- and postnatal toxicity and no neurotoxicity concerns . The chronic dietary (food and drinking water) exposure assessments are conservative. The dietary and residential assessments are

based on reliable data and will not underestim ate exposure/risk. Based on these data and conclusions, the FQPA Safety F actor can be reduced to 1X.

4.4.1 Completeness of the Toxicology Database

The toxicology database is co mplete with the exception of an immunotoxicity study (OPPTS 870.7800) which is a new data requirement under 40 CFR Part 158.500 for registration of a pesticide (food and non-food uses). EPA has evaluated the available toxicity data for imazosulfuron and determined that an additional database uncertainty factor is not needed to account for potential immunotoxicity. The reasons follow:

• HED does not believe that conducting a speci al series 870.7800 immunotoxicity study will result in a NOAEL less than 75 mg/kg/day, whic h is presently used as the cRfD point of departure.

• The most sensitive endpoint in the database is moderate thyroid hypertrophy. Liver toxicity accompanied by body weight and food consum ption effects are seen throughout the toxicology database. No treatment-related ch anges were seen in hematology parameters, organ weights (thymus, spleen), gross necr opsy (enlarged lymph node s)or histopathology (spleen, thymus, lymph nodes ) when tested up to the limit dose in mice and rats.

• An immunotoxicity study in rats and/or mice (OPPTS 870.7800) is required as part of the new 40 CFR §158 Guidelines and HED recommends that it be a condition of registration.

4.4.2 Evidence of Neurotoxicity

There is no indication that imazosulf uron is a neurotoxic chemical ba sed on clinical observations of neurotoxicity during the conduct of developmental or chronic studies. No adverse neurobehavioral signs were observed at doses approaching the limit dose in any of the short-term studies (subchronic oral, 21-day dermal). No neur otoxic effects were observed du ring the subchronic neurotoxicity

screen in which adverse effects of decreased body weight, body we ight gain and food efficiency were observed at 575 mg/kg/day (LOAEL). The acute neurotoxic ity screen (ACN) yielded a LOAEL at the limit dose for clinical signs, abnormal gait, decreased activity, piloerection and upward curvature of the spine and decreased motor act ivity in males, all of which were resolved by Day 2. No treatment-related effects were observed in FOB parameters, gross and neurohistopathology, motor activity or brain morphometrics of the AC N. The weight of evidence

demonstrates that imazosulfuron is not a neurooxic compound because the clinical findings in the ACN study occurred only at the limit dose and may be attributed to generalized toxicity.

A developmental neurotoxicity study is not required at this time.

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

There was no evidence of increased susceptibility in the submitted toxicology database. There is no concern for increased susceptibility to offspring following pre- and postnatal exposure to rats or inImazosulfuron Human Health Risk Assessment DP No. 362653

Page 20 of 73 utero exposure in rabbits. Neither the rat nor rabb it developmental studies identified developmental effects. The parental NOAEL is clearly defined, less than or equal to the offspring NOAEL and based on general systemic toxicity. At near- limit dose, 20% - 30% decreases in numbers of implants/dam, total pups/dam and live pups/dam on PND 0, and viability i ndex were observed.in F 1 pups of the 2-generation reproduc tive study in rats. Similarly, decreased live pups/dam and live births and viability and lacta tion indices were noted for F 2 pups. The points of departure are protective of these effects

4.4.4 Residual Uncertainty in the Exposure Database

Although data have been requested to confirm the stability of imazosulfuron during frozen storage, the metabolic profile of pyrimidine-labeled imazos ulfuron in rice grain in the confined rotational crop trial and characterize field accumulation, there are no residua l uncertainties in the exposure

database because:

Storage stability ; The interim study showed stability in rice grai n for about 100 days and stability in tomato and pepper for about 200 days . However, field trial samples were stored for considerably longer intervals prior to analys is and the stability of imazosulfron in those commodities for the longer intervals must be de monstrated. Major inst ability would lead to

an underestimation of the residues in the field trial commodity samples at the time of harvest

and therefore to an understatement of the di etary intake risk. Ev idence suggests that

imazosulfuron is stable in/on frozen commoditie s for extensive intervals. The lack of degradation of the residue over a 100 to 200 day period suggests stability for longer intervals. Typically, with many unstable pestic ides the degree of degradation decreases with time, i.e., degradation should be detected in the first months of storage. Sulfonylurea pesticides are known to be stable in soil. Also, storage stab ility studies from other sulfonylurea pesticidesindicate a significant stability in various types of commodities. For example, halosulfuronmethyl shows no degradation for frozen storag e intervals of 800 – 1000 days on corn grain, soybean seed, wheat grain, lettuce, and sugar beet roots, and rimsulfur on is stable in frozen cotton seed oil, orange, and sugarcan e for at least 300 – 400 days.

Metabolic profile : Grain samples from the confined rotational crop study were stored for a relatively long interval (9 months) prior to comp letion of the analyses. Analysis of an Imlabel sample after the 9 month period yielded a metabolic profile similar to that on a sample analyzed at the start of the period. A similar comparison must be made for the Py-label sample of grain. This is of no practical consequence for risk assessment because total residue levels (TRR) on grai n were small (<0.01 ppm at a 365 day plantback interval), imazosulfuron was not present, and no me tabolites/degradates were considered toxicologically significant.

Field accumulation : The grain (wheat ) rotational crop study is need ed to identify maximum levels of residues in grain and livestock feed items (forage, straw) as a function of the plantback interval. On an interim basis, a pl antback interval of 12 m onths is being imposed for grains and soybeans. The results of the rotational crop study may allow a shorter plantback interval. The confined rotationa l crop study showed that imazosulfuron andImazosulfuron Human Health Risk Assessment DP No. 362653

Page 21 of 73 metabolites will be negligible (<0.01 ppm) on fo rage, hay, straw, stover, and grain at a 365 day plantback interval and will therefore make no contribution to the dietary intake.

The chronic dietary assessment conducted with DEEM-FCIDTM was an unrefined analysis. The

assessment utilized tolerance level residues for all crops. In addition, default processing factors were assumed for all commodities. One hundred percent crop treated was assumed for all commodities. The dietary analysis also assumed that all drinking water will cont ain imazosulfuron at the highest chronic estimated drinking water concentration (EDWC) levels modeled by EFED for ground water

or surface water. For these reasons it can be concluded that the DEEM-FCIDTM analysis does not

underestimate risk from chroni c exposure to imazosulfuron.

4.5 Toxicity Endpoint and Point of Departure Selections

The details for selecting toxicity endpoints and points of departure for various exposure scenarios are presented in the Appendix A2. An acute referenc e dose for the general po pulation was established based on decreased motor activity observed at the limit dose in the acute neurotoxicity screen. A separate endpoint for the Females age 13-49 popul ation subgroup was not id entified; there was no pre- and/or postnatal toxicity observed in deve lopmental or reproductive animal studies following a single oral dose. The chronic reference dose was based on adverse thyroid effects observed in the chronic toxicity study in dogs. No dermal hazar d was identified. Intermediate- and short-term

inhalation and incidental oral endpoints were based on two co-cri tical subchronic rat studies in which decreased body weight, body weight ga in and food consumption were observed.

4.5.1 Dose-Response Assessment

Imazosulfuron exhibits no mortality following a single oral dose as high as 5000 mg/kg; imazosulfuron is classified as Toxicity Category IV according to all acute hazard indicators save acute dermal (LD 50 > 2000 mg/kg, HDT) where the Toxicity Category is III.

For acute dietary exposure, an acu te dose (aRfD) of 4 mg/kg/day wa s selected for assessment of all populations based on a NOAEL of 400 mg/kg/day in the rat acute ne urotoxicity study. The LOAEL of 2000 mg/kg/day was based on decreased motor act ivity, piloerection and upward curvature of the spine observed in both sexes and decreased moto r activity observed in males only. This is a conservative endpoint since effects were seen only at the limit dose and there is a substantial dose spread between the NOAEL and LOAEL.

For chronic dietary exposure, a chronic reference dose (cRfD) of 0.75 mg/kg/day was selected for assessment of all populations based on a NOAEL of 75 mg/kg/day with moderate thyroid hypertrophy observed in the chroni c dietary study in dogs. This study provides the most sensitive endpoints point of departure for risk assessm ent; the mouse carcinogenicity study yielded an equivalent NOAEL but with a larger dose spread. The selected NOAEL is protective of liver effects.

For short- and intermediate-term residential and occupational exposures i nvolving incidental oral and inhalation exposure, the NOAEL of 235 mg/kg/day was selected from the rat subchronic toxicityImazosulfuron Human Health Risk Assessment DP No. 362653

Page 22 of 73 study. This study was co-critical with the 2-ge neration reproductive toxicity study in rats and provided the best estimate of the NOAEL. Simila r effects on body weight were seen at the LOAEL of 892 mg/kg/day in the 2-ge neration reproductive toxicity study and 956 mg/kg/day in the subchronic toxicity study. Combined, both studies are appropriate for the duration of exposure and populations exposed.

No dermal hazard was identified in the 21-day dermal toxicity study in rats wherein hepatotoxicity and neurotoxicity were assessed. Therefore, no dermal endpoint was selected for quantitative risk

assessment for imazosulfuron

Neither dermal nor inhalation long-term exposure is not expected; theref ore, no endpoints were

selected

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

Residential exposures (dermal, oral , and inhalation) should be combin ed if the toxicological effects

are the same. Effects of decr eased body weight, body weight ga in and food consumption were

observed in the co-critical subchron ic rat studies selected for short- term/intermediate-term incidental

oral and short-term/intermediate-term inhalation e xposure for risk assessment; therefore, these routes of exposure can be combined to estimate aggregat e risk. Since no hazard was identified in the dermal toxicity study and there are no concerns fo r developmental neurotoxici ty, the dermal route of exposure need not be included in aggregate risk estimates.

4.5.3 Cancer Classification and Ri sk Assessment Recommendation

Two adequate rodent carcinogenicity studies we re submitted and evaluated for imazosulfuron. There was no evidence of carcinogenicity in rats and mice up to the limit dose at 24- and 18-months, respectively. Imazosulfuron was de termined to be non-mutagenic in bacteria and negative in an in

vivo mammalian cytogenetics assay. Overall, there was no evidence that imazosulfuron was either mutagenic or clastogenic in either in vivo or in vitro assays. The cancer classi fication is “not likely to be carcinogenic to humans,” based on the abse nce of significant tumor increases and therefore,

there is no concern for ca ncer risk to humans.

4.5.4 Summary of Points of Departure and T oxicity Endpoints Used in Human Risk

Assessment

Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Imazosulfuron for Use in Dietary and NonOccupational Human Health Risk Assessments

Exposure/
Scenario Point of Departure Uncertainty/ Safety Factors RfD, Level of
Concern for

Risk

Assessment Study and Toxicological EffectsImazosulfuron Human Health Risk Assessment DP No. 362653

Page 23 of 73Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Imazosulfuron for Use in Dietary and NonOccupational Human Health Risk Assessments

Exposure/
Scenario Point of Departure Uncertainty/ Safety Factors RfD, Level of
Concern for

Risk

Assessment Study and Toxicological Effects

Acute Dietary (General Population, including
Infants and Children) NOAEL=

400 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X Acute RfD = 4 mg/kg/day

aPAD = 4 mg/kg/day Acute neurotoxicity screening battery (rat; MRID 47305319). LOAEL = 2000 mg/kg/day based on the following clinical signs: abnormal gait, decreased activity, piloerection and upward curvature of the spin e; and incidents of irregular breathing, reduced righting reflex, tremors, decreased visual placement response in males and increased response to
sound in one female. Acute Dietary (Females 13-49 years of age) An acute reference dose was not identified for fema les age 13-49 because ther e was no prenatal or fetal toxicity observed in developmental or reproductive animal studies following a single oral dose.

Chronic Dietary (All Populations) NOAEL= 75 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X Chronic RfD = 0.75 mg/kg/day

cPAD =0.75 mg/kg/day Chronic toxicity (dog; MRID 47305305) LOAEL = 150 mg/kg/day based onmoderate thyroid hypertrophy (males at midand high-dose; mild hypertrophy in females at high-dose).

Incidental Oral Short-Term (1- 30 days) and

IntermediateTerm (1-6 months) NOAEL=

235 mg/kg/day (MRID 47305232) UF A = 10X

UF H = 10X FQPA SF = 1X Residential
LOC for MOE

= 100 Reproduction, 2 generation (rat; MRID 47305304) and 90-day oral toxicity (rat; 47305232). LOAEL = 892 mg/kg/day based on mortality, clinical signs, decreased body weights, body weight gains and food consumption in parents (MRID 47305304). LOAEL = 956 mg/kg/day based on decreased body weight gains and food efficiency (MRID 47305232).

Dermal ShortTerm (1-30 days) and

IntermediateTerm (1-6 months) No systemic toxicity occu rred at the limit dose and the primary toxic effects of c oncern (liver, eye) were adequately assessed in a 21-day dermal toxicity study (MRID 47305236). It is concluded that this compound is not or poorly absorbed through the skin and, therefore, a quantitative risk assessment for this route and duration is not necessary.

Inhalation Short- Term (1- 30 days) and
IntermediateTerm (1-6 months) NOAEL=

235 mg/kg/day (MRID 47305232;
inhalation toxicity equivalent to oral toxicity) UF A = 10X

UF H = 10X FQPA SF = 1X Residential

LOC for MOE

= 100 Reproduction, 2 generation (rat; MRID 47305304) and 90-day oral toxicity (rat; 47305232). LOAEL = 892 mg/kg/day based on mortality, clinical signs, decreased body weights, body weight gains and food consumption in parents (MRID 47305304). LOAEL = 956 mg/kg/day based on decreased body weight gains and food efficiency (MRID 47305232).

Cancer (oral, dermal, inhalation) Classification: “ Not likely to be Carcinogenic to Humans ” based on the absence of significant tumor increases in two adequate rodent carcinogenicity studies (MRID 47305307, mouse; 47305306, rat).Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 24 of 73 Point of Departure (POD) = A data point or an estimated poin t that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower en vironmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern.

Table 4.5.4.2. Summary of Toxicological Doses and Endpoints for Imazosulfuron for Use in Occupational Human

Health Risk Assessments

Exposure/
Scenario Point of Departure Uncertainty

Factors Level of Concern

for Risk

Assessment Study and Toxicological Effects

Dermal ShortTerm (1-30 days) and

IntermediateTerm (1-6 months) No systemic toxicity occu rred at the limit dose and the primary toxic effects of c oncern (liver, eye) were adequately assessed in a 21-day dermal toxicity study (MRID 47305236). It is concluded that this compound is not or poorly absorbed through the skin and, therefore, a quantitative risk assessment for this route and duration is not necessary.

Inhalation Short-Term (1- 30 days) and
IntermediateTerm (1-6 months) NOAEL=

235 mg/kg/day (MRID 47305232;
inhalation toxicity equivalent to oral toxicity) UF A =10X

UF H =10X Occupational LOC

for MOE = 100 Reproduction, 2 generation (rat; MRID 47305304) and 90-day oral toxicity (rat; 47305232). LOAEL = 892 mg/kg/day based on mortality, clinical signs, decreased body weights, body weight gains and food consumption in parents (MRID 47305304). LOAEL = 956 mg/kg/day based on decreased body weight gains and food efficiency (MRID 47305232). Cancer (oral, dermal, inhalation) Classification: “ Not likely to be Carcinogenic to Humans ” based on the absence of significant tumor increases in two adequate rodent carcinogenicity studies (MRID 47305307, mouse; 47305306, rat). Point of Departure (POD) = A data point or an estimated poin t that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower en vironmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern.

4.6 Endocrine Disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain su bstances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effect s as the Administrator may designate.” The EDSP employs a two-tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if a ny, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine related effects caused by the substanc e, and establish a dos e-response relationship between the dose and the E, A, or T effect.Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 25 of 73 Between October 2009 and February 2010, EPA is issui ng test orders/data call- ins for the first group of 67 chemicals, which contains 58 pe sticide active ingredients and 9 in ert ingredients. This list of chemicals was selected based on the potential fo r human exposure through pathways such as food and water, residential activity, and certain post-application agricultural scenarios. This list should

not be construed as a list of know n or likely endocrine disruptors.

Imazosulfuron is not among the group of 58 pesticide active ingredients on th e initial list to be
screened under the EDSP. Unde r FFDCA Sec. 408(p), the Agency must screen all pesticide chemicals. Accordingly, EPA anticipates issuin g future EDSP test orders/data call-ins for all pesticide active ingredients.

For further information on the status of the ED SP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, pleas e visit our website: http://www.epa.gov/endo/.

5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

The nature of the residue in plants is adequately understood for purposes of this petition based on acceptable metabolism studies with potato, rice, a nd tomato. The data demonstrate that the

metabolism of imazosulfuron is similar in three dissimilar crops, and that hydrolysis of the sulfonylurea linkage is the major metabolic process. Hydrolytic degradation of the sulfonamide moiety yields metabolites IPSN, or 2-chloro-imid azo[1,2-a]pyridine-3-sulfoni c acid amide, UDPM, or (4,6-dimethoxy-pyrimidin-2-yl)-urea, and ADP M, or 4,6-dimethoxy-pyrimidin-2-ylamine. In addition, O-demethylation of the pyrimidine ring yields the only identif ied double-ring metabolite, HMS. See Appendix B, Table B.1 for chemical na mes and structures of metabolites. Imazosulfuron and UDPM were the major residues in rice grain, rice straw, and toma to, but were minor residues in potato tuber, where total radioa ctive residues (TRR) were signif icantly lower overall. UDPM was generally only a fraction of the imazosulfuron concentrati on, with the exception of tomato fruit.

HED has determined that the residue of concer n in crop commodities for tolerance enforcement

assessment is imazosulfuron. The residue of concern for risk assessment is the sum of imazosulfuron and UDPM, expressed as equivalents of imazosulfuron.

The nature of the residue in livestock is adequately understood based on acceptable metabolism studies with goats and hens. The data demonstrat e that metabolism of imazosulfuron is similar in ruminants and poultry, and that hydrolysis of th e sulfonylurea linkage is the major metabolic process. Imazosulfuron was a majo r residue in ruminant milk and tissues, except fat, and in poultry eggs and tissues. An imidazolyl-ring metabol ite, IPSN, or 2-chloro-imidazo[1,2-a]pyridine-3- sulfonic acid amide, was also a major metabolite in ruminant and poultry tissues, and was present in milk and eggs at up to 10% TRR. UDPM was iden tified as a minor metabolit e in eggs only, and the double-ring metabolite HMS was identified in rumina nt milk and kidney and in poultry liver at
<10% TRR. HED has determined that the residue of concern in livestock commodities for toleranceImazosulfuron Human Health Risk Assessment DP No. 362653

Page 26 of 73 enforcement is imazosulfuron. The residue of concern for risk assessment is the sum of imazosulfuron and IPSN, expressed as stoc hiometric equivalents of imazosulfuron.

A tentatively acceptable confined rotational cr op study has been submitted; supporting storage stability data are required for the Py-label grain. The study results indicate that the metabolism of imazosulfuron proceeds in rotational crops via rout es similar to metabolism in primary crops, and suggest, based on the presence of higher levels of HMS and metabolites derived from IPSN, that soil

metabolites may contribute significantly to residues in rotated crops. Imazosulfuron was not identified in any rotational crop commodity; how ever, HMS and UDPM were identified as major metabolites in rotational sorghum and wheat matrices (except grain) at PBIs of 30 – 120 days. In addition, three major metabolites we re identified in rotational sor ghum and wheat matrices (except grain) that were not id entified in primary crops: the IPSA conjugate metabolites IPSA-isoserine, IPSA-acetylisoserine, and IPSA-caffeoylisoserine.

No field rotational crop data were submitted in support of this petition.

5.1.2 Summary of Environmental Degradation

Imazosulfuron biodegrades within weeks in aerobic terrestrial and aquatic e nvironments (half-lives of 36.5 days and 17 days, respectively). It also de grades in anaerobic environments (half-life of 28 days). Considering abiotic degradation, imazosulfuron is photolyzed at pH 7 in water (half-life of 3.5 days). It can be hydrolyzed under acidic environmen t (pH 4.0) but is stable at neutral and alkaline conditions (pH 7-9). Under the fi eld conditions in the soil, the calculated half- life values of imazosulfuron are 9.5 days for first applica tion and 15.2 to 75.3 days following the second application.

The environmental degradates of imazosulfuron that are of possible exposure concern for drinking water include the parent co mpound’s major degradates, HMS, IPSN, IHOA, ADPM, UDPM and SDPM (Appendix B). HMS is the only degradate that retains both imidazolyl (Im) and pyrimidinyl (Py) ring structures. HMS has be en detected using both Im and Py radio-label rings in aquatic photolysis, aerobic soil metabolism and anaerobic aquatic metabolism studies. IPSN and ADPM are included for maximum formation at lower pH. IPSN (14.2%) and ADPM (35.3 %) were also major degradates formed in aerobic soil metabolism and a quatic photolysis studies, respectively. Carbon dioxide is a major degradate in the aerobic soil metabolism study of imazosulfuron, in which it was up to 53.3% of the app lied radioactivity.

5.1.3 Comparison of Metabolic Pathways

Based on identified metabolites, the proposed ma mmalian metabolic pathways for imazosulfuron are: 1) demethylation, 2) hydroxylation of the pyr imidine ring, 3) methylation of the hydroxyl group, 4) opening of the pyrimidine ring and formation of guanidine and 5) hydrolysis of the sulfonylurea bridge (Figure 4.2).

IPSN and HMS were the predominant environm ental degradates, products of aerobic soil metabolism. The pyrimidines, ADPM, UDPM and SDPM are products of hydrolysis (ADPM only) and aqueous photolysis.Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 27 of 73 Hydrolysis of the sulfonylurea linka ge is the major metabolic proce ss in plants (potato, rice and tomato) and ruminants and poultry.

5.1.4 Residues of Concern Summary and Rationale

Table 5.1.4 Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression

Matrix Residues included in Risk

Assessment Residues included in Tolerance Expression

Primary Crop Imazosulfuron, UDPM Imazosulfuron Plants Rotational Crop Not Applicable Not Applicable

Ruminant Imazosulfuron, IPSN Imazosulfuron Livestock Poultry Imazosulfuron, IPSN Imazosulfuron

Drinking Water Imazosulfuron, HMS, IPSN, ADPM, UDPM, SDPM Not Applicable

Rationale:

Plants: In primary crops, imazosulfuron (28, 64, a nd 17% TRR) and UDPM (18, 13, and 30% TRR) were detected in rice grain, rice straw, and toma to, respectively, during plant metabolism studies. UDPM concentration was usually su bstantially less than the imazosulfuron concentration, and was absent (< 1%) in the potato t uber. The petitioner suggested imazosulfuron as the residue for
tolerance enforcement. Imazosulfuron and UDPM were not detected in field tr ials except for one of two replicates at one location where each was detected at 0.02 ppm (LOQ). Likewise, no residues were found in the processed commodities of rice and tomato. Therefore, imazosulfuron is an adequate marker for tolerance enforcement a nd imazosulfuron plus UDPM should be included for

risk assessment. The inclusion of imazosulfuron only in the tolerance expression will provide an adequate tool for enforcement purposes and is in accord with the internati onal practice (Codex) of establishing as simple a residue definition as practical. The latter is particularly pertinent in situations where no quantifia ble residues are anticipated.

In confined rotational studies c onducted at 3x the maximum proposed seasonal application rate, the following metabolites were identified: UDPM, ADPM, HMS, IPSA-isoserine, IPSA-acetylisoserine, and IPSA-caffeoylisoserine. The TRR was < 0.01 pp m in rotational kale a nd radish root at a 144 day PBI, but significant TRRs were found in rotati onal grain crops even at a 365 day PBI. For the latter, none of the metabolites exceeded 0.01 ppm at a 365 day PBI when the application rate is extrapolated to 1X. At 120-day PBI, IPSA c onjugates were present at significant amounts (0.03- 0.12 ppm extrapolated to 1X) in small grain hay and st raw and matrices (but not in grain). However, the Residues of Concern Knowledgebase Subcomm ittee (ROCKS) did not consider the conjugated

metabolites to be residues of concern due to the low level of exposure and likely decreased hazard (e.g. increased molecular size and in creased solubility). Therefore, rotational crop tolerances and residues of concern are not applicable, but the is sue may be revisited upon review of the wheat rotational crop field trials currently being conducted.Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 28 of 73 Ruminant and Poultry: In livestock metabolism studies, im azosulfuron was the major residue in milk and tissues and in poultry eggs and tissue. IPSN was also a significant residue in ruminant and poultry tissue and in milk and e ggs. Although measurable quanti ties of residues in feed and livestock commodities are not likely from the cu rrent proposed uses, ROCKS recommends that

imazosulfuron be measured for tolerance enforcemen t and imazosulfuron plus IPSN be included in

risk assessment should future new uses of imazosulfuron necessitate livestock commodity

tolerances.

Drinking Water: The environmental degradates of im azosulfuron that are of possible exposure concern for drinking water include the parent compound’s major degradates, HMS, IPSN, IHOA, ADPM, UDPM, and SDPM. HMS is the only degr adate that retains both imidazole (IM) and pyrimidine (Py) ring structures. HMS has been detected in aquatic photolysis, aerobic soil metabolism and anaerobic aquatic metabolism studi es. IPSN and ADPM are included for maximum formation at lower pH. IPSN and ADPM were also major degradates formed in aerobic soil metabolism and aquatic photolysis studies respectiv ely. Imazosulfuron is characterized as being mobile to moderately mobile in the test soils. SDPM, IHOA and HMS ar e categorized as highly mobile in most soils. ADPM and IPSN are categ orized as mobile. Note that IHOA, UDPM, and SDPM are expected to be major residues in drin king water only for use patterns in which aquatic photolysis could be a significant degradation pathway (i.e., rice). As HMS retains both Im and Py ring structures, its toxicity is lik ely comparable to the parent. St ructure-activity relationship (SAR) analysis (Deductive Estima tion of Risk based on Existing Knowle dge or DEREK) revealed the same structural alerts as for the parent compound; ther efore, HMS is considered a residue of concern. DEREK analysis of IPSN, IHOA, ADPM, SDPM, a nd UDPM showed that all of these cleavage products except IHOA (a low molecu lar weight acid) retained at least one of the same structural alerts as the parent. IHOA can thus be excluded as a residue of concern. However, as IPSN, ADPM, SDPM, and UDPM can not be excluded by hazar d considerations and there is potential for exposure; therefore, these compounds can not be excluded as residues of concern.

Recommended Tolerance Expression:

The ROCKS recommends the following language for the toleran ce expression for plant and livestock

commodities:

Tolerances are established for residues of the herbicide im azosulfuron, including its metabolites and degradates, in or on the commodities listed below. Compliance with the tolerance levels specified below is to be determined by measuring only 2- chloro-N-[[(4,6-dimethoxy-2-pyrimid inyl)amino]carbonyl]imidazo[1,2- α ]pyridine3-sulfonamide, in or on the commodity.

5.2 Food Residue Profile

Crop Field Trials

The submitted residue data for pepper, rice, and toma to are tentatively considered to be adequate, pending submission of supporting storage stability da ta for each crop. The studies reflected the proposed use patterns for peppers, ri ce, and tomatoes, and the number and location of field trials areImazosulfuron Human Health Risk Assessment DP No. 362653

Page 29 of 73 in accordance with OPPTS Guideline 860.1500 for each crop. Samples were analyzed for residues of imazosulfuron and UDPM using an acceptable method.

All trials reflected exaggerated-rate applicati on (3x for pepper and tomato and 1.7-2.5x for rice); however, because residues of imazosulfuron were ≤ LOQ in/on all samples, the exaggerated rates will not affect determination of appropriate tolerances for pepper, rice and tomato.

The available data will support the proposed toleran ces of 0.02 ppm each for pepper, rice grain, and

tomato. HED notes in addition that the submitted crop field trial data for pepper and tomato would support a crop group tolerance of 0.02 ppm for fruiting vegetables, group 8.

Table 5.2.1. Summary of Residue Data from Crop Field Trials with Imazosulfuron

Imazosulfuron Residue Levels (ppm) Crop matrix Total Applic.

Rate (lb ai/A) PHI (days) n Min. Max. HAFT 1 Median Mean Std.

Dev.

PEPPERS (bell and non-bell): (proposed use = 0.3 lb ai/A total application rate, 21-day PHI)
Pepper, bell 0.886-0.914 20-22 16 <0.02 <0.02 0.02 0.02 0.02 NA

Pepper, nonbell 0.873-0.919 20-21 6 <0.02 <0.02 0.02 0.02 0.02 NA

RICE: (proposed use = 0.3 lb ai/A to tal application rate, up to 2-inch internode growth stage or early boot or BBCH 41)
Rice, grain 0.491-0.557; 0.753 (one trial) 52-83 32 <0.02 0.02 0.02 0.02 0.02 NA

TOMATO (proposed use = 0.3 lb ai/A total application rate, 21-day PHI)

Tomato (bedded) 0.875-0.917 20-21 32 <0.02 <0.02 0.02 0.02 0.02 NA

Tomato (staked) 0.871-0.919 6-7 12 <0.02 <0.02 0.02 0.02 0.02 NA

1 HAFT = Highest average field trial result. For pur poses of calculating the HAFT, median, mean, and standard deviation, values reported as <0.02 ppm are assumed to be equal to 0.02 ppm.

Processing Studies

The submitted processing data for rice and tomato are tentatively considered to be adequate, pending submission of supporting storage stability data for rice, tomato, and tomato paste. The processing study field trials reflect the same degree of exaggeration as the co rresponding crop field trials: 1.7x

for rice and 3x for tomato. OPPTS 860.1520 recomme nds use of exaggerated application rates (up to 5x) in cases when residues near or below the LOQ are expected in the raw agricultural commodity (RAC) from the maximum proposed rate. No add itional data are required because residues were non-detectable in/on all RAC and processed commod ity samples, and were at or below the LOQ in/on all samples from the associated field trials which reflected the same degree of exaggeration. Furthermore, for rice, where application is restricted to a late vegetative stage, it is anticipated that residues would be unlikely to oc cur in rice grain. Samples we re analyzed for residues of imazosulfuron and UDPM using an acceptable method.Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 30 of 73 The processing data indicate that residues of imazosulfuron and UDPM do not concentrate in rice hulls, bran, or polished rice or in to mato puree or paste; therefore, tolerances are no t required for the processed commodities of rice or tomato.

Storage Stability

In conjunction with the associated field trials, th e registrant has submitted the interim results of storage stability studies with im azosulfuron and its metabolite UDPM in/on bell pepper, rice, tomato, and tomato paste. Untreated samples of bell pepper, rice, tomato, and tomato paste were fortified with imazosulfuron or UDPM at 0.100 ppm and stored fr ozen (-20 to -10 °C). Stored fortified and unfortified samples were analyzed at storage intervals of 0, 34, 60, 90, 125 and 194 days for bell peppers; 1, 31, and 113 days for rice grain; 0, 33, 58, 98, 195, and 224 days for tomatoes; and 0 and 44 days for tomato paste. Fresh fortification sample s were also analyzed at each interval. No details were provided concerning the preparation of sample s or fortification solu tions for the study. The petitioner has indicated that the fi nal results of the storage stability study will be submitted at a later

date. The interim results indicate that under fr ozen storage conditions, residues of imazosulfuron and UDPM are relatively stable in/o n bell peppers for up to 194 days (6.4 months), rice grain for up to 113 days (3.7 months), tomatoes for up to 224 da ys (7.4 months), and tomato paste for up to 1.4

months.

Additional storage stability data ar e necessary to verify the stability of the imazosulfuron residue for the maximum interval of frozen field trial sample storage. The interim report shows no loss of

residue over 4 – 7 months for three commodities of interest. There is no expectation that there would be appreciable loss of resi due over extended periods, but this needs to be verified. Also, sulfonylurea herbicides have been sh own in general to be stable in commodities stored frozen. Thus, HED does not anticipate a need to increase residue level estimates to correct for loss of residue in storage of analytical samples.

Meat, Milk, Poultry and Eggs

There are livestock feedstuffs associated with th e proposed use on rice: rice grain and bran. The maximum reasonable dietary burdens are 0.008 ppm for cattle and 0.006 ppm for poultry and swine. It is not possible to establish with certainty whet her finite residues will be incurred, but there is no reasonable expectation of finite residues from the calculation of dietary burd en to livestock (40 CFR 180.6, Category 3).

Rotational Crops

The petitioner previously indicated that a wheat field rotational crop study was planned. This study has not been submitted. The need for additional field rotational crop studies will be addressed after evaluation of the wheat rotational crop study. HE D does not consider the low levels of IPSAconjugates at the 365-day PBI toxicologically sign ificant, but will reasse ss the situation at the various plantback intervals based on the wheat rotational crop study.

The field rotational crop study is n ecessary to provide confirmatory information on the levels of imazosulfuron metabolites in follow-on crops of grai n, forage, and fodder. The confined study withImazosulfuron Human Health Risk Assessment DP No. 362653

Page 31 of 73 radiolabeled imazosulfuron was conducted at a 3X exaggeration (relative to the use pattern for primary crops). While no imazosulfuron was found in any rotated crop, low levels of metabolites were found, TRR 0.02 – 0.9 ppm at all plantback interv als in grain commodities . Much of this was

related to feed commodities and not human food items. However, tota l residue in grain was as much as 0.04 ppm. This level is low and exaggerated (3 X) and will most likely be lower in the pending field rotational crop study. HED concluded that rotational crop residues w ill make a negligible contribution to the human dietary expos ure, but this must be confirmed.

5.3 Water Residue Profile

Tier 1 EDWCs for surface water were generated using FIRST, dated August 5, 2001. FIRST is a screening model designed by the Environmental Fate and Effects Division (EFED, 2001a) of the Office of Pesticide Programs (OPP) to estimate the concentrations found in drinking water from

surface water sources for use in human health risk assessment. As such, it provides upper bound values on the concentrations that might be found in drinking water due to the use of a pesticide. FIRST is a single-event model (one runoff event) , but can account for spray drift from multiple applications. FIRST is hardwire d to represent the Index Reservoi r, a standard water body used by OPP to assess drinking water exposure (Office of Pes ticide Programs, 2002). It is based on a real reservoir, Shipman City Lake in Illinois, which is known to be vulnerable to pesticide contamination. The single runoff event moves a maxi mum of 8% of the applied pesticide into the reservoir. This amount can be reduced due to degr adation on the field and the effects of binding to

soil in the field. FIRST also uses a Percent Cropped Area (PCA) factor to adjust for the area within the watershed that is planted to the modeled crop. The national de fault PCA of 0.87 was applied in

this assessment.

The EFED Rice Model (USEPA, 2007) was used to estimate the concentration of imazosulfuron expected in surface water potentia lly used for drinking water following application to rice. The model calculates exposure as a func tion of the amount of pesticide applied and the pesticide’s soilto-water partition coefficient. Concentrations are assumed to immediately and evenly distribute throughout the rice paddy water. Dissipation pr ocesses, such as degr adation, volatilization, and potential dilution with uncontaminated water outsid e the paddy are not accounted for by the model. The single exposure estimate produced with the Rice Model is used as both an acute and a chronic screening exposure estimate that is expected to represent high -end exposure in released flood water (tailwater). The EDWC produced by the Rice Model was not adjusted by an agricultural Percent Cropped Area (PCA) value because these values ma y not apply to semi-aquatic agriculture. PCA values were designed for exposure estimates in runoff from terrestrial crops, not for exposure estimates in tailwater from flooded crops.

Tier 1 EDWCs for ground water were generated with SCI-GROW 2.3, dated July 29, 2003 (EFED, 2001b). SCI-GROW is a regression model used as a screening tool for ground water used as drinking water. SCI-GROW was developed by re gressing the results of Prospective Ground Water studies against the Relative Index of Leaching Pote ntial (RILP). The RILP is a function of aerobic soil metabolism and the soil-water partition coefficient. The output of SCI-GROW represents the concentrations that might be expected in shallow unconfined aquifers under sandy soils.

The FIRST, RICE and SCI-GROW output files are detailed in the memo, Tier I Drinking WaterImazosulfuron Human Health Risk Assessment DP No. 362653

Page 32 of 73 Assessment for the Section 3 Propos ed Registration of Imazosulfuron on Turf, Tomato, Peppers (Bell and Non-bell) and Rice , DP#D362654, Faruque Khan, 5/13/2010. Based on the results of these simulations, EFED recommends an acute and chroni c surface water EDWC of 278.9 μg/L for use in

the human health risk assessment. These recomme ndations are based on the use of imazosulfuron on rice at an annual application rate of 0.3 lb a.i./A/year. The re commended EWDC for ground water is 4.8 μg/L and is based on maximum applications at 0.67 lb a.i./A of two application per year for the

use of imazosulfuron on turf. The estimated dri nking water concentrations (EDWCs) for various

scenarios are listed in Table 5.3.1.

Table 5.3.1. Tier I EDWCs for Imazosulfuron for Turf, and Food Uses c

Drinking Water Source Models Use rate (lbs ai/A/year) Acute ( μ g/L) Chronic ( μ g/L)

RICE 0.3 278.9.0 d 278.9 d .0

1.34 b 101.25 d 33.27 d Surface water

FIRST 0.3 c 23.47 d 7.71 d

Ground water SCI-GROW 1.34 b 4.8 d 4.8 d

a Input parameters for all models are tabulated in DP362654, Faruque Khan, 5/13/2010

b Application rate for turf

c Application rate for tomato and pepper

d Drinking water exposure to total toxic residue (parent plus the 5 metabolites, HMS, IPSN, UDPM, ADPM, and SDPM) was considered in this assessment

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

HED has determined that the residue of concern fo r dietary risk assessment purposes is the sum of imazosulfuron and its metabolite, UDPM, expresse d as equivalents of imazosulfuron. DEEMFCIDTM Version 7.81 default processing factors were assumed for the requested crop uses. The highest estimated drinking water co ncentration (EDWC) for imazosulf uron resulted from the Tier I

RICE model. This recommended EDWC of 278.9 μ g/L used in the acute and chronic assessment is based on aerial spray app lication of 0.3 lbs. a.i. /A per year for rice.

5.4.2 Percent Crop Treated Used in Dietary Assessment

The dietary analyses assu med that 100% of the crop was treated (100% CT).

5.4.3 Acute Dietary Risk Assessment

An unrefined acute dietary risk analysis was c onducted with the DEEM-FCIDTM model to form a conservative evaluation of exposur e for imazosulfuron. At the 95 th percentile of exposure, all acute analyses yielded risk estimates well below the 100% of the aPAD threshold level of concern for each population subgroup. For food and drinking water, the acu te aggregate dietary ri sk was calculated at <1% of the aPAD with an exposur e level of 0.015 mg/kg/day for the general U.S. population. For the subgroup with the highest calcul ated exposure, all infants (<1 y ear old), acute aggregate dietary risk occupied 1.4% of the aPAD with an expos ure of 0.06 mg/kg/day. For the general U.S.Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 33 of 73 population, acute dietary risk for food only was calculated at <1% of the aPAD with an exposure level of 0.00033 mg/kg/day. For the subgroup with the highest calculated exposure, children 1-2 years old, acute food only dietary risk occupied 0.02% of the aPAD with an exposure of 0.00090 mg/kg/day. An overview summariz ing the results of the acute dietary assessments with the population subgroup having the highest exposure not ed in bold is presented in Table 5.4.6.

5.4.4 Chronic Dietary Risk Assessment

An unrefined chronic dietary risk analysis was conducted with th e DEEM-FCIDTM mode to form a conservative evaluation of exposure for imazosulfuron. All chronic analyses yielded risk estimates
well below 100% of the cPAD threshold level of concern for each population subgroup. For food and drinking water, the U.S. P opulation subgroup chronic aggregate dietary risk was calculated at <1% of the cPAD with an exposur e level of 0.0060 mg/kg/day for th e general U.S. population. For the subgroup with the highest calc ulated exposure, all infants (< 1 year old), chronic aggregate dietary risk occupied 2.7% of the cPAD with an exposure of 0.020 mg/kg/day. For the general U.S. population, chronic dietary risk for food only was calculated at <1% of the cPAD with an exposure level of 0.000084 mg/kg/day. For the subgroup with the highest calculated exposure, children 1-2 years old, chronic food only dietary risk occupied <1% of the cPAD with an exposure of 0.00020 mg/kg/day. An overview summariz ing the results of the chroni c dietary assessment with the population subgroup having the highest exposure not ed in bold is presented in Table 5.4.6.

5.4.5 Cancer Dietary Risk Assessment

Imazosulfuron is classified as “Not Likely to be Carcinogenic to Humans”. Therefore, a cancer dietary exposure assess ment was not conducted.

5.4.6 Summary Table

Table 5.4.6. Result of Acute and Chronic Dietary Exposure and Risk Estimates for Imazosulfuron

DEEM-FCIDTM (food only) DEEM-FCIDTM (food and water) Population Subgroup PAD, mg/kg/day Exposure, mg/kg/day % PAD* Exposure, mg/kg/day %PAD*

Acute Dietary Estimates (95 th Percentile of Exposure)

U.S. Population 0.000333 <1 0.014919 <1

All infants (< 1 yr) 0.000367 <1 0.056034 1.4

Children 1-2 yrs 0.000896 <1 0.023470 <1

Children 3-5 yrs 0.000739 <1 0.021335 <1

Children 6-12 yrs 0.000494 <1 0.014925 <1

Youth 13-19 yrs 0.000313 <1 0.012125 <1

Adults 20-49 yrs 0.000277 <1 0.013800 <1

Adults 50+ yrs 0.000236 <1 0.012433 <1

Females 13-49 yrs 4.0

0.000259 <1 0.013772 <1

Chronic Dietary Estimates

U.S. Population 0.000084 <1 0.006043 <1Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 34 of 73 Table 5.4.6. Result of Acute and Chronic Dietary Exposure and Risk Estimates for Imazosulfuron

DEEM-FCIDTM (food only) DEEM-FCIDTM (food and water) Population Subgroup PAD, mg/kg/day Exposure, mg/kg/day % PAD* Exposure, mg/kg/day %PAD*

All infants (< 1 yr) 0.000069 <1 0.019881 2.7

Children 1-2 yrs 0.000200 <1 0.009043 1.2

Children 3-5 yrs 0.000178 <1 0.008433 1.1

Children 6-12 yrs 0.000121 <1 0.005811 <1

Youth 13-19 yrs 0.000085 <1 0.004372 <1

Adults 20-49 yrs 0.000074 <1 0.005638 <1

Adults 50+ yrs 0.000056 <1 0.005918 <1

Females 13-49 yrs 0.75

0.000069 <1 0.005605 <1
* % PADs are reported to 2 significant figures. The values for the highest population for each type of risk assessment are in bold text.Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 35 of 73 6.0 Residential (Non-Occupational) Exposure/Risk Characterization

A proposal for V-10142 for application to residentia l turf grass and recrea tional sites has been

submitted and assessed in the memo Imazosulfuron. Occupational and Residential Risk Assessment for Proposed Uses of Imazosulfuron on Residen tial Turf, Ornamentals and Bare Ground Non-Crop

Areas . DP#349707, Kelly O’Rourke, 02/17/2009. The re sults are also incorporated in this

assessment.

Imazosulfuron may be applied to turf at rates ranging from 0.50 to 0.75 lb a.i./A, for two applications at an interval of 21 days. The labels do not prohibit homeowners from using these products; therefore, reside ntial handlers may receiv e short-term dermal a nd inhalation exposure to imazosulfuron when mixing, loadin g and applying the formulation. Residential post-application exposure via the inhalation route is expected to be negligible; howev er, dermal exposure is likely for adults and children entering treated lawns. Toddl ers may also experience exposure via incidental non-dietary ingestion (i.e., ha nd-to-mouth, object-to-mouth and soil ingestion) during postapplication activities on treated turf.

Dermal endpoints were not selected for imazosulfur on because no systemic toxicity was observed at the limit dose in the dermal study. Short-term inha lation and incidental oral exposures were assessed using the same NOAEL (235 mg/kg/da y) that was selected for occupa tional exposure. Toxicity by

the inhalation route is assumed to be equivalent to oral toxicity. The LOC is an MOE less than 100.

6.1 Residential Handler Exposure

HED’s Draft Standard Operating Procedures (SOPs) for Residen tial Exposure Assessments, and Recommended Revisions (HED Policy Number 11, re vised 22 Feb 2001), were us ed as the basis for the residential handler exposure calculations. Da ta from the Outdoor Residential Exposure Task Force (ORETF) (MRID 44972201) were used in this assessment in place of PHED data for the garden hose-end sprayer scenario, which provided more confidence in the exposure estimate. There are no unit exposure data for mixing/loading/applyi ng water dispersible gra nules (also called dry flowable) for the residential scenarios. The unit exposure data for liquid formulation are considered to be an adequate/protective surr ogate. As shown in Table 6.1, th e inhalation MOEs for residential

handlers are well above the LOC of 100, and are not of concern.

Table 6.1. Handler Exposure and Risk Es timates for Residential Lawn ApplicatorsImazosulfuron Human Health Risk Assessment DP No. 362653

Page 36 of 73 Handler Scenario Application

Rate 1
(lb a.i./A) Area

Treated 2
(acres/day) Inhalation
Unit Exposure 3
(mg/lb ai) Daily Dose 4
(mg/kg/day) Short-Term

MOE 5

(1) Mix/load and spot application of liquid formulation (low-pressure hand sprayer) 0.75 0.023 (1,000 ft 2 ) 0.030 0.0000074 32,000,000

(2) Mix/load and broadcast application of liquid formulation (garden hose-end sprayer) 0.75 0.50 0.017 0.000091 2,600,000

1 Application rate is based on maximum values found in proposed label: V-10142 (EPA Reg. No. 59639-RLL).

2 Area treated is based on the area that can be reasonably treated in a single day based on the application method (standard EPA/OPP/HED values).

3 Inhalation unit exposure values represent no respirator. Value for low-pressure handwan d is reported in the PHED Surrogate Exposure Guide dated August 1998, and that for hose-end sprayer was obtained from the ORETF data.

4 Daily Dose (mg/kg/day) = (Unit Exposure * Ap plication rate * Area treated) / 70 kg.

5 Short-Term MOE = NOAEL (235 mg/kg/day) / Daily Dose. The LOC is 100.

6.2 Post-Application Exposure

No additional residential uses are being requested at this time. However post-application exposure was evaluated previously and is in corporated in this assessment.

Turf transferrable residue (TTR) studies were submitted by the registrant (MRIDs: 47305124 and 47305125) for use in assessing post-applic ation activities. The data from these studies were not used because TTR studies are only relevant for dermal exposure. The incidental ingestion assessment was conducted with standard assumpti ons for the initial fraction of re sidue available as well as other factors as specified by the Recommended Revisions to the Residential SOPs and recommended approaches by HED’s Science Advisory Council for Exposure (ExpoSAC).

The exposure and risk estimates for the residentia l exposure scenarios are assessed for the day of application (day “0") because it is assumed that toddlers could contact the lawn immediately after application. The equations used for the exposure cal culations and the results are presented in Tables 6.2a through 6.2c.

The exposure estimates are based on some upper-per centile (i.e., maximum app lication rate, initial

amount of transferrable residue and duration of e xposure) and some central tendency (i.e., surface area and body weight) assumptions and are considered to be representative of high-end exposures.

The uncertainties associated with this assessment stem from the use of an assumed amount of pesticide available from turf, and assumptions rega rding transfer of chemi cal residues and hand-to mouth activity. The estimated exposures are belie ved to be reasonable high-end estimates based on observations from chemical-specific fi eld studies and professional judgment.

The short-term MOEs for each scenario are greate r than the LOC of 100, and are not of concern. The total short-term MOE resulting from conservatively combining MOEs for children (shown in Table 6.2d) is 17,000, which is also above the LOC of 100, and not of concern.Imazosulfuron Human Health Risk AssessmentDP No. 362653Page 37 of 73Table 6.2a. Post-application OralHand-to-Mouth Exposure and Risk for Children from Treated LawnsApplicationRate(lb ai/A)Postapplicationday (t)Fraction of aiTransferrablefrom theFoliageTurfTransferrableResidue1(μg/cm2)HandSurfaceArea(cm2/event)SalivaExtractionFactorFrequency(events/ hr)BodyWeight(kg)Daily Dose2(mg/kg/day)Short-termOralMOE30.75 0 0.05 0.42 20 50% 20 15 0.011 21,0001Turf Transferrable ResiduePost-application day(μg/cm2) = Application rate (lb ai/A) x Fraction of a.i.Transferrable from the Foliage x (1- Fraction ofResidue That Dissipates Daily, 0.1)Post-application dayx 4.54E+8 μg/lb x 2.47E-8 A/cm22Daily Dose = (Turf Transferrable Residue (μg/cm2) x Hand Surface Area (cm2/event) x Saliva Extraction factor x Frequency (events/hr) x 0.001 mg/μg x Exposure time (2 hrs/day)] / [Body Weight (kg)]3Oral MOE = Oral NOAEL/Daily Dose; where Short-term NOAEL = 235 mg/kg/day.Table 6.2b. Post-application Oral Object-to-Mouth (Turfgrass) Exposure and Risk for Children from Treated LawnsApplication Rate(lb ai/A)Postapplication day(t)Fraction of aiTransferrablefrom the FoliageGrass/ObjectResidue1(μg/cm2)Ingestion Rate(cm2/day)BodyWeight(kg)Daily Dose2(mg/kg/day)Short-termOralMOE30.75 0 0.2 1.7 25 15 0.0028 84,0001Grass/Object residuePost-application day(μg/cm2) = Application rate (lb ai/A) x Fraction of a.i. Transferrable from the Foliage x (1- Fraction of ResidueThat Dissipates Daily)Post-application dayx 4.54E+8 μg/lb x 2.47E-8 A/cm22Daily Dose = [Grass reside (μg/cm2) x Ingestion rate (cm2/day) x 0.001 mg/μg] / [Body Weight (kg)]]3Oral MOE = Oral NOAEL / Daily Dose; where Short-term NOAEL = 235 mg/kg/day.Table 6.2c. Post-application Incidental Soil Ingestion Exposure and Risk for Children from Treated LawnsApplication Rate(lb ai/A)Fraction of aiRetained in theSoilSoilResidue1(μg/g)Ingestion Rate(mg/day)BodyWeight(kg)Daily Dose2(mg/kg/day)Short-termOralMOE30.75 1 5.6 100 15 0.000038 6,300,0001Soil residuePost-application day zero(μg/cm2) = Application rate (lb ai/A) x Fraction of a.i. Retained on the Soil x (4.54E+8 μg/lb x 2.47E-8 A/cm2x 0.67 cm3/g soil2Daily Dose = [Soil reside (μg/g) x Ingestion rate (mg/day) x 0.000001 g/μg] / [Body Weight (kg)]]3Oral MOE = Oral NOAEL/Daily Dose; where Short-term NOAEL = 235 mg/kg/day.Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 38 of 73 Table 6.2d. Children’s Agg regate Exposure and Risk Estimates from Residential Lawn s

Children’s Scenarios TTR/GR/SR 0 (ug/cm 2 or g) 1 PDR 0-norm (mg/kg/day) 2 Short-Term

MOE 3 Total

Short-Term

MOE 4

(1) Hand-to-Mouth 0.42 0.011 21,000

(2) Mouthing Grass 1.7 0.0028 84,000

(3) Soil Ingestion 5.6 0.000038 6,300,000 17,000

1 TTR=turf transferable residue on day “0"; GR=grass residue on day “0"; SR 0 =soil residue on day “0".

2 PDR 0norm =potential dose rate on day “0”.

3 MOE = NOAEL/PDR; where Short-term NOAEL = 235 mg/kg/day.

4 Total MOE = 1/ [(1/MOE Hand-to-Mouth ) + (1/MOE Grass ) + (1/MOE Soil )]

Residential Bystander Post-Appl ication Inhalation Exposure:

Based on the Agency's current practices, a quant itative post-application inhalation exposure assessment was not performed for imazosulfuron at this time primarily because of the low acute inhalation toxicity (Toxicity Categor y IV), low vapor pressure (<3.5 x 10 -6 Pa), low proposed use rate (0.3 lb ai/A), and the soil-directed applic ation method, which does not include the use of air blast resulting in lower pos t-application inhalation exposures. Ho wever, volatilization of pesticides may be a source of post-applicati on inhalation exposure to individuals nearby pest icide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific A dvisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SA P/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post-appli cation inhalation exposure into the Agency's risk assessments. If new polic ies or procedures are de veloped, the Agency may revisit the need for a qu antitative post-applicatio n inhalation exposure assessment for imazosulfuron.Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 39 of 73 6.3 Spray Drift Spray drift is always a potential sour ce of exposure to residents nearby to spraying operations. This is particularly the case w ith aerial application, but, to a lesser extent, could also be a potential source of exposure fr om the ground application method employed for imazosulfuron. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices, and State Lead Agencies for pesticide regul ation 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 la bels/labeling. The Agency has completed its evaluation of the new data base submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is de veloping a policy on how to appr opriately apply the data and the AgDRIFT computer model to its risk assessments fo r pesticides applied by ai r, orchard airblast, and ground hydraulic methods. After the policy is in pl ace, the Agency may impose further refinements in spray drift management practices to reduce off-ta rget drift and risks associ ated with aerial as well as other application types where appropriate. Note that imazosu lfuron is directly applied to

residential turf and does not result in exposures of concern. It is unlikely that spray drift would result in a higher potential for risk of exposure than the scenarios already assessed.

7.0 Aggregate Exposure/Risk Characterization

For this action, there is potential exposure to imazosulfuron from f ood and drinking water. There is also a concurrent application fo r residential use for which there is potential for exposure from residential use sites (DP#349707). Since hazard was identified via the oral ro ute over both the acute and chronic duration, and via i nhalation for a short-term durat ion, the adult aggregate risk assessment considers exposures from food and dr inking water and residential handler inhalation exposure while the child aggregate includes dietary and post-applicati on incidental oral exposure for

a short-term duration. There is no cancer endpoint for this chemical . Therefore, a cancer aggregate risk assessment was not performed.

7.1 Acute Aggregate Risk

Refer to Section 5.4.3, which discusses acute dietar y exposure (food and drinking water) in detail. The dietary route (food and drinking water) alone is relevant for acu te exposure and risk assessment; and the acute dietary exposure and risk assessment conducted for imazosulfuron is screening-level, wherein the assessment assigns tolerance level resi due values to all food co mmodities proposed to be

treated with imazosulfuron and modeled residue valu es to all drinking water. No aggregate risk

concerns were identified.

7.2 Short- and Intermediate-Term Aggregate Risk

Table 7.2. Short-Term Agg regate Risk Calculations

Short- or Intermediate -Term Scenario

Population LOC for Aggregate

Risk 1 MOE dietary (food + drinking water) 2 MOE

incidental

oral 3 MOE

dermal 4 MOE

inhalation 5 Aggregate MOE (food and residential) 6

Adult Male 100 40,000 N/A N/A 2,600,000 40,000

Adult Female 100 40,000 N/A N/A 2,600,000 40,000Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 40 of 73 Table 7.2. Short-Term Agg regate Risk Calculations

Short- or Intermediate -Term Scenario

Population LOC for Aggregate

Risk 1 MOE dietary (food + drinking water) 2 MOE

incidental

oral 3 MOE

dermal 4 MOE

inhalation 5 Aggregate MOE (food and residential) 6

Child 100 12,000 17,000 N/A N/A 7,000

1 The LOC includes the standard inter- and intra- species uncertainty factors (UF A and UF H

, respectively) totaling 100.

2 MOE food = NOAEL/chronic dietary exposure: Where sh ort- and intermediate-term NOAEL = 235 mg/kg/day and chronic dietary exposure = 0.006043 mg/kg/day (U.S. population), 0.019881 mg/kg/day (All infants < 1 yr).

3 MOE oral = From Table 6.2d..

4 MOE dermal = N/A.

5 MOE inhalation = From Table 6.1.

6 Aggregate MOE (food and residential) = 1 / [(1 / MOE food) + (1 / MOE oral) + (1 / MOE inhalation)]

7.3 Chronic Aggregate Risk

Refer to Section 5.4.4, which discusses chronic diet ary exposure (food and dri nking water) in detail. The dietary route alone is rele vant for long-term/chronic exposu re and risk assessment; and the chronic dietary exposure and risk assessment conducte d for imazosulfuron is health protective (the assessment assigns tolerance-level residue values to all food commodities proposed to be treated

with imazosulfuron and modeled residue values to a ll drinking water.) No chronic aggregate risk

concerns were identified.

7.5 Cancer Aggregate Risk

The cancer classification is “not likely to be carcinogenic to humans” based on the absence of significant tumor increases in two ade quate rodent carci nogenicity studies and, therefore, there is no

concern for cancer risk to humans.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followe d a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to imazosulfuron and any other substances and im azosulfuron does not appear to produce a toxic metabolite produced by other substances. For the pur poses of this tolerance action, therefore, EPA

has not assumed that imazosulfuron has a common mechanism of toxici ty with other substances. For information regarding EPA’s efforts to determin e which chemicals have a common mechanism of toxicity and to evaluate the cumu lative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concer ning common mechanism determinations and procedures for cumulating effects from substa nces found to have a common mechanism on EPA’s

website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

9.1 Short-/Intermediate-/Long-Term Handler RiskImazosulfuron Human Health Risk Assessment DP No. 362653

Page 41 of 73 Imazosulfuron may be applied using ground or ae rial equipment. The application methods, maximum application rates, and use sites are su mmarized in Table 9.1.1. There is potential for exposure to imazosulfuron during mixing, loading, a nd applying activities. Handler exposure is expected to be short- or inte rmediate-term based on information provided on the proposed label.

The quantitative exposure and risk assessment de veloped for occupational handlers is based on the following exposure scenarios:

Mixing/Loading 1) WG (dry flowable) formulations to support groundboom application; 2) WG (dry flowable) formulations to support aerial application;

Applying 3) sprays with groundboom equipment; 4) sprays with aerial equipment; and

Flaggers 5) flagging for aerial application.

The LOC for the MOE is defined by the uncertainty f actors that are applied to the assessment. HED applies a 10X factor to account for inter-species extrapol ation and a 10X factor to account for intraspecies sensitivity. The total un certainty factor that has been applied to the non-cancer risk assessment for imazosulfuron is 100X for occupationa l exposure. Occupationa l exposure and risk resulting in MOEs greater than or eq ual to 100 are not of concern to HED.

Short- and intermediate-term dermal toxicity en dpoints were not identified because no systemic toxicity was seen at the limit dose in a 21- day dermal toxicity study in rabbits.

To determine the short- and intermediate-term risks, daily inhalation exposures (assuming 100% absorption) were compared to the NOAEL of 235 mg/kg/day base d on a two-generation reproduction study and a co-critical 90 -day oral toxicity study in ra ts. The MOEs range from 59,000 (mixing/loading to support ae rial application) to 930,000 (app lying with groundboom equipment).

These risk estimates are not of concern to HED. Table 9.1.1. Proposed Use Pattern for Imazosulfuron

Crop Treatment Type/Target of

Application Application Equipment Maximum Applicatio

n Rate (lb ai/A) Treatment

Interval Preharvest Interval

V-10142 Ag Herbicide, EPA Reg. No. 59639-RLL, WG 75% ai

Tomatoes Soil-Directed Spray Groundboom 0.3 1 application

per year 21 days

Peppers (Bell and Non-Bell) Soil-Directed Spray Groundboom 0.3 1 application

per year 21 days

Rice Soil-Directed Spray,
Flooded Fields Groundboom
or Aerial 0.3 1 application

per year Application may be made up until 2 inch internode stage

of rice.Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 42 of 73 Summaries of the inhalation risk estimates fo r occupational handlers are included in Table 9.1.2. The maximum application rate for each exposure scenar io is presented as the worst case scenario.

The inhalation risks to handlers are not of con cern to HED for any of the handler scenarios

Table 9.1.2. Short- and In termediate-Term Occupational Handler Exposure and Risk for Imazosulfuron

Exposure Scenario Crop or Target App

Rate a

(lb ai/A) Acres

Treated Daily b Baseline

Inhalation
Unit Exposure c (mg/lb ai) Short- and

IntermediateTerm Dose (mg/kg/day)

Inhalation d Short- and

IntermediateTerm MOE

Inhalation e

Mixer/Loader
Mixing/Loading Dry

Flowables for

Groundboom Applications Tomatoes, Peppers (Bell and Non-Bell), Rice 0.3 80 0.00077 0.000264 890,000

Mixing/Loading Dry

Flowables for Aerial Applications Rice 0.3 1200 0.00077 0.00396 59,000

Applicator
Applying Sprays via

Groundboom

Equipment Tomatoes, Peppers (Bell and Non-Bell), Rice 0.3 80 0.00074 0.000254 930,000

Applying Sprays via

Aerial Equipment Rice 0.3 1200 0.000068 0.000350 670,000

Flagger Applying Sprays for

Aerial Equipment Rice 0.3 1200 0.00035 0.000180 130,000

a Application Rates based on proposed uses on label for V-10142 (EPA Reg. No. 59639-RLL). b Exposure Science Advisory Council Policy No. 9.1. c Unit Exposures based on PHED Version 1.1.
d Short- and Intermediate-Term Inhalation Dose (mg/kg/day) = daily unit exposure (mg/lb ai) x applic ation rate (lb ai/acre) x acres treated / body weight (70 kg).
e Short- and Intermediate-Term Inhala tion MOE = NOAEL (235 mg/kg/day) / inha lation daily dose (mg/ kg/day). LOC = 100Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 43 of 73 9.2 Short- and Intermediate-Term Post-Application Risk

Based on the Agency's current practices, a quant itative occupational post- application inhalation exposure assessment was not performed for imazosulf uron at this time primarily because of the low acute inhalation toxicity (Toxicity Cate gory IV), low vapor pressure (<3.5 x 10 -6 Pa), low proposed use rate (0.3 lb ai/A), and the soil-directed application method, whic h does not include the use of air blast resulting in lower post-appli cation inhalation exposures. Howe ver, there are multiple potential sources of post-application inhala tion exposure to individuals perfor ming post-application activities in previously treated fields. Th ese potential sources include vo latilization of pesticides and resuspension of dusts and/or part iculates that contain pesticides. The Agency sought expert advice and input on issues related to vola tilization of pesticides from its Federal Insecticide, Fungicide, and

Rodenticide Act Scientific Advi sory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SA P/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as av ailable post-application 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 post-application inha lation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalati on exposure assessment for imazosulfuron.

10.0 Incidents

No information is available from use in the United States. This is the firs t food-use registration in
the USA.

11.0 Environmental Justice Considerations

Potential areas of environmental ju stice concerns, to the extent possi ble, 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, OP P considers a large variety of consumer subgroups according to well-established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and ar ound the home that involve pesticide use in a residential setting. Extensive data on food c onsumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pestic ide. These data are analyzed and categorized by subgroups based on age, season of the year, ethni c group, and region of the country. Additionally, OPP is able to assess dietary exposure to sma ller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on home use of pesticide products a nd associated risks for adult applicators and for toddlers, youths, and adults ente ring or playing on treated area s post-application are evaluated. Further considerations are currently in developm ent as OPP has committed resources and expertiseImazosulfuron Human Health Risk Assessment DP No. 362653

Page 44 of 73 to the development of specialized software and m odels that consider exposure to bystanders and farm workers as well as lifestyle and traditio nal dietary patterns among specific subgroups.

12.0 References

Kramer, G.F., 12/5/2008, DP#D359190, Imazosulfuron. Report of the Residues of Concern Knowledgebase Subcommittee (ROCKS)

.

Scollon, E., 6/1/2010, DP#D377141, Imazosulfuron. Report of the Residues of Concern Knowledgebase Subcommittee (ROCKS)

.

Khan, F., 11/13/2008, DP#D358472, The Drinking Water Degradates Identification Memorandum for Imazosulfuron.

Funk, S., 6/28/2010, DP#D367019, Imazosulfuron. Request for Sect ion 3 Registration for New Uses on Pepper, Rice, and Tomato. Summary of Analytical Chemistry and Residue Data.

O’Rourke, K., 2/17/2009, DP#D349707, Imazosulfuron. Occupational and residential Risk Assessment for Proposed Uses of Imazosulfuron on Residential Turf, Ornamentals and Bare Ground Non-Crop Areas

.

Tsaur, N.J., 7/9/2010, DP#D36702, Imazosulfuron. Occupational and Residential Exposure Assessment for Proposed Use on Tomatoes , Peppers (Bell and Non-Bell), and Rice.

Healy, S., 3/13/2009, DP#348001, Imazosulfuron: Human Health Risk Assessment for Proposed Uses on Turf and Ornamentals in Non-Crop Areas.

Walls, C., 6/23/2010, DP#D367020, Imazosulfuron: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assess ments for the New Uses on Peppers, Rice, and

Tomato.Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 45 of 73 Appendix A. Toxicology Prof ile and Executive Summaries

A.1 Toxicology Data Requirements The requirements (40 CFR 158.500) for food use for imazosulfuron are in Table A.1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Technical

Table A.1. Toxicology Data Requirements

Required Submitted

870.1100 Acut e Oral T oxicity....................................................... 870.1200 Acute Dermal Toxicity ..................................................

870.1300 Acute Inhalation To xicity..............................................
870.2400 Primar y Eye Irr itation....................................................

870.2500 Primar y Dermal Irritation ..............................................

870.2600 Derm al Sensiti zation...................................................... yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (r odent) ............................................... 870.3150 Oral Subchronic (non-rodent)........................................ 870.3200 21-Day Dermal .............................................................. 870.3250 90-Day Dermal ..............................................................

870.3465 90-D ay Inhalation.......................................................... yes

yes

yes

no

no yes

yes

yes

no

no

870.3700a Developmenta l Toxicity (rodent)................................... 870.3700b Developmental Toxicity (non-rodent) ........................... 870.3800 Reproduction ................................................................. yes

yes

yes yes

yes

yes

870.4100a Chronic T oxicity (rodent) ..............................................
870.4100b Chronic Toxi city (non-r odent)....................................... 870.4200a Oncoge nicity (rat).......................................................... 870.4200b Oncogenicity (mouse)....................................................
870.4300 Chronic/ Oncogenicity (rat)............................................ n/a

yes n/a

yes

yes - yes

- yes

yes

870.5100 Mutagenicity—G ene Mutation - bacterial..................... 870.5300 Mutagenicity—Gene Mutation - mammalian................ 870.5375 Mutagenicity—Struc tural Chromosomal Aberrations... 870.5395 Mutagenicity—O ther Genotoxic Effects....................... yes

yes

yes

yes yes

yes

yes

yes

870.6100a Acute Delaye d Neurotox. (hen) ..................................... 870.6100b 90-Day Neurotoxicity (hen)...........................................

870.6200a Acute Neurotox. Screening Batte ry (rat) ....................... 870.6200b 90-Day Neuro. Screening Batte ry (rat).......................... 870.6300 Develop. Neuro.............................................................. no

no

yes

yes

no no

no

yes

yes

no

870.7485 Gene ral Metabo lism ......................................................

870.7600 Dermal Penetration........................................................ 870.7800 Immunotoxicity ............................................................. no

no

yes yes

no

noImazosulfuron Human Health Risk Assessment DP No. 362653

Page 46 of 73 A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile - Test Substance

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

870.1100 Acute oral – rat 47305221 LD 50 > 5000 mg/kg IV

870.1200 Acute dermal – rat 47305227 LD 50 > 2000 mg/kg III

870.1300 Acute inhalation – rat 47305228 LC 50 > 2.12 mg/L IV

870.2400 Acute eye irritation - rabbit 47305229 Non-irritating IV

870.2500 Acute dermal irritation - rabbit 47305230 Non-irritating IV

870.2600 Skin sensitization – guinea pig 47305231 Negative N/A

Table A.2.2 Acute Toxicity Profile - Test Substance

Guideline No. Acute Oral Toxicity in Rat,
Metabolite: MRID(s) Results Toxicity Category

870.1100 IHOA 47305222 LD 50 > 5000 mg/kg IV

870.1100 UDPM 47305223 LD 50 = 677 mg/kg III

870.1100 IPSN 47305224 LD 50 = 415 mg/kg, males; 445 mg/kg, females II

870.1100 M-1 47305225 LD 50 > 5000 mg/kg IV

870.1100 ADPM 47305226 LD 50 = 836 mg/kg IIIImazosulfuron Human Health Risk Assessment DP No. 362653

Page 47 of 73 Table A.2.3 Subchronic, Chronic and Other Toxicity Profile of Imazosulfuron

Guideline

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

870.3100 90-Day oral toxicity (rat) 47305232 (1991); 0, 2500, 10000, 45000

ppm; M: 0, 234.7, 956.3, 4577.2 mg/kg/day; F: 0, 265.7, 1081.4, 5135.7 mg/kg/day
Acceptable/Guideline NOAEL = 235/266 mg/kg/day in males/females;
LOAEL = 956/1081 in males/females based on reduced mean body weights, body weight gains and food efficiency.

870.3100 90-Day oral toxicity (mouse) 47305233 (1991); 0, 2500, 10000, 45000

ppm; M: 0, 456, 1820, 9776 mg/kg/day; F: 0, 692, 2727, 12695 mg/kg/day
Acceptable/Guideline NOAEL = 1820/2727 mg/kg/day in males/females; LOAEL = 9776/12695 mg/kg/day in

males/females based on central lobular hepatocyte hypertrophy and increased liver weights.

870.3150 90-Day oral toxicity (dog) See 47305235; Justification to Bridge Data from a 1-year Chronic Study in Dogs See 47305305

870.3200 21/28-Day dermal toxicity (rat) 47305236 (2006); 0, 100, 300, 1000 mg/kg/day Acceptable/Guideline NOAEL = 1000 mg/kg/day in males and
females.

870.3700a Prenatal developmental (rat) 47305238 (1989); 0, 250, 500, 1000 mg/kg/day. Since no maternal toxicity was observed in the original
treatment groups, an additional treatment group of 1500 mg/kg/day was added to the study.

Acceptable/Guideline Maternal NOAEL = 1000 mg/kg/day (limit); LOAEL = 1500 mg/kg/day based on decreased body weight gain and food consumption. Developmental NOAEL = 1500 mg/kg/day; > limit dose; LOAEL > 1500 mg/kg/day

870.3700b Prenatal developmental (rabbit) 47305301 (1990); 0, 25, 50, 125 mg/kg/dayAcceptable/NonGuideline*

*tested under FIFRA Subdivision F guidelines Maternal NOAEL = 125 mg/kg/day;

LOAEL > 125 mg/kg/day Developmenta l NOAEL = 125 mg/kg/day; LOAEL > 125 mg/kg/dayImazosulfuron Human Health Risk Assessment DP No. 362653

Page 48 of 73 Table A.2.3 Subchronic, Chronic and Other Toxicity Profile of Imazosulfuron

Guideline

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

870.3800 Reproduction and fertility effects (rat) 47305304 (1990); 0, 100, 1,000, 10,000

ppm; M F0 : 0, 7.7, 77.8, 777.4 mg/kg/day;

F F0 : 0, 8.93, 88.4, 868.5 mg/kg/day;

M F1 : 0, 9.0, 89.4, 1006.5 mg/kg/day;

F F1 : 0, 9.6, 96.9, 1097.0 mg/kg/day Acceptable/Guideline Parental/Systemic NOAEL = (1000 ppm) 83.6/92.7 mg/kg/day in males/females (average of both generations); LOAEL = (10,000 ppm) 892/982.7 mg/kg/day in males/females (average of both generations) based on mortality, clinical signs, decreased body weights, body weight gains, and food
consumption

. Reproductive NOAEL = (10,000 ppm) 892/982.7 mg/kg/day in males/females (average of both generations); LOAEL > 892/982.7 mg/kg/day in males/females (not observed).

Offspring NOAEL = (1000 ppm) 83.6/92.7 mg/kg/day in males/females (average of both generations); LOAEL = (10,000 ppm) 892/982.7 mg/kg/day in males/females (average of both generations) based on decreased pup viability and body weights.

870.4100b Chronic toxicity (dog) 47305305 (1990); 0, 75, 150, 300 mg/kg/day Acceptable/Guideline NOAEL = 75 mg/kg/day LOAEL = 150 mg/kg/day based on moderatethyroid hypertrophy (males at mid- and highdose; mild hypertrophy in females at highdose).

870.4200b Carcinogenicity (mouse) 47305307 (1991); 0, 450, 4500, 45000 ppm; M: 0, 72.7, 741.3, 7848.1 mg/kg/day; F: 86.8, 870.0, 10303.5 mg/kg/day

Acceptable/Guideline NOAEL = 73/87 mg/kg/day in males/females. LOAEL = 741/870 mg/kg/day in males/females based on centrilobular swelling of hepatocytes. no evidence of carcinogenicity

870.4300 Chronic toxicity/Carcinogen icity (rat) 47305306 (1991); 0, 200, 2000, 20000 ppm; M: 0, 10.39, 106.10, 1123.99 mg/kg/day; F: 0, 12.94, 132.46, 1554.35 mg/kg/day. Acceptable/Guideline NOAEL = 106/132 mg/kg/day in males/females; LOAEL = 1124/1554 mg/kg/day in males/females based on increased mortality, decreased body weight, decreased body weight gain, clinical ophthalmic observations (cataracts and retinal degeneration) and hepatotoxicity in females.
no evidence of carcinogenicity

870.5100 Bacterial reverse

mutation test 47305308 (1988) Acceptable/Guideline TH-913 Technical: Test article has no reverse mutagenic potential under these experimental

conditions

870.5100 Bacterial reverse
mutation test 47305309 (1990) Acceptable/Guideline UDPM: Test article has no reverse mutagenic potential under these experimental conditionsImazosulfuron Human Health Risk Assessment DP No. 362653

Page 49 of 73 Table A.2.3 Subchronic, Chronic and Other Toxicity Profile of Imazosulfuron

Guideline

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

870.5100 Bacterial reverse

mutation test 47305310 (1993) Acceptable/Guideline IHOA: Test article has no reverse mutagenic potential under these experimental conditions

870.5100

870.5500 Bacterial reverse mutation test; DNA repair test 47305311 (1989) Acceptable/Guideline M-1: Test article has no reverse mutagenic potential under these experimental conditions; negative with or without S9 metabolic

activation

870.5100 Bacterial reverse

mutation test 47305312 (1988) Acceptable/Guideline IPSN: Test article has no reverse mutagenic potential under these experimental conditions

870.5100 Bacterial reverse
mutation test 47305313 (1990) Acceptable/Guideline ADPM: Test article has no reverse mutagenic potential under these experimental conditions

870.5300 In vitro mammalian cell gene mutation

test 47305314 (1999) Acceptable/Guideline Test article is not mutagenic in test system

870.5375 In vitro mammalian
cell chromosome

aberration test 47305315 (1988) Acceptable/Guideline Test article “was considered to induce no
chromosomal aberration because the test substance showed a suspect positive by the

direct method but the same results were not reproduced.” Test article did not induce chromosomal aberrations at any concentration in presence of S9.

870.5395 Mammalian erythrocyte

micronucleus test 47305316 (2007) Acceptable/Guideline Test article has no potential to induce

micronuclei in mouse bone marrow cells under

the conditions of this test

870.6200a Acute neurotoxicity screening battery 47305319 (2007); 0, 80, 400, 2000 mg/kg Acceptable/Guideline NOAEL = 400 mg/kg/day; LOAEL = 2000 mg/kg/day in males and females based on the following clinical signs: abnormal gait, decreased activity, piloerection and upward curvature of the spine and decreased motor activity in males.

870.6200b Subchronic neurotoxicity screening battery 47305320 (2007); 0, 800, 2500, 8000 ppm; M: 0, 54.0, 169.2, 571.3 mg/kg/day; F: 0, 61.9, 200.8, 655.3 mg/kg/day Acceptable/Guideline Systemic NOAEL = 169/201mg/kg/day in males/females; LOAEL = 571/655 mg/kg/day in males/females based on decreased body weight, body weight gain and food efficiency.
Neurotoxicity NOAEL = 571/655 mg/kg/day in males/ females (HDT)
LOAEL > 571.7 mg/kg/day for males and > 655.3 mg/kg/day for femalesImazosulfuron Human Health Risk Assessment DP No. 362653

Page 50 of 73 Table A.2.3 Subchronic, Chronic and Other Toxicity Profile of Imazosulfuron

Guideline

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

870.7485 Metabolism and pharmacokinetics

(rat) 47305322 (2007) Acceptable/Guideline Parent and 5 metabolite s were identified and quantified. Parent was detected only in feces
and amounted to 0.9% of the administered dose (AD). HMS, the predominant metabolite, was found in the urine at 6, 12 and 24 hours amounting to 31.1, 18.4 and 6.2 % of the dose, respectively, and in lesser amounts, in the feces (6.5). The lesser metabolites (< 5% AD), IHDU, HDS, IPSN and AC IS were identified in

urine and feces.

870.7485 Metabolism and pharmacokinetics (rat) 47305323 (2007) Acceptable/Guideline The absorption rate was estimated to be ~100%. Near complete elimination (66.4% urine, 34.0% bile, 2.4% feces) within 24 hours after administration of radiolabeled compound

was observed.

A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD) - Females age 13-49

An Acute Reference Dose, Females age 13-49, was not defined; no developmental effects attributable to a single dose were identified in the t oxicology database.

A.3.2 Acute Reference Dose (aRfD) - General Population

Study Selected: Acute Neurotoxici ty (OPPTS 870.6200a)

MRID: 47305319 Dose and Endpoint for Risk Assessment: NOAEL = 400 mg/kg; aRfD = 4 mg/kg/day based on an

UF of 100. Comments about Study/Endpoint/Uncertainty Factors : This endpoint is very conservative since

the effects occurred at the limit dose and there is a large (5-fol d) dose spread between the NOAEL

and LOAEL. While some individual effects ma y be equivocal, the suit e and prevalence of

treatment-related effects observed at the limit dose is robust. Decr eased motor activity ( ↓ 38%) is seen on the day of exposure only. No other acute eff ects (neurotoxic or otherw ise) were seen in the

database.

A.3.3 Chronic Reference Dose (cRfD)

Study Selected: Chronic Toxicity (Dog; OPPTS 870.4100b)

MRID: 47305305Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 51 of 73 Dose and Endpoint for Risk Assessment: NOAEL = 75 mg/kg/day; cRfD = 0.75 mg/kg/day based

on an UF of 100. Comments about Study/Endpoint/Uncertainty Factors: LOAEL = 150 mg/kg/day based on mild to moderate thyroid hypertrophy. In creased liver weight coincident with increased serum alkaline phosphatase and cholesterol was also observed but cons idered an adaptive rath er than adverse effect.

A.3.4 Incidental Oral Exposure (Short- and Intermediate-Term)

Co-Critical Study Selected: Reproduction and Fertility Effe cts (2 generation, rat; OPPTS 870.3800)

MRID: 47305304 Co-Critical Study Selected: 90-Day Oral Toxicity (rat; OPPTS 870.3100)

MRID: 47305232 Dose and Endpoint for Risk Assessment: NOAEL = 235 mg/kg/day; L OAEL = 892 mg/kg/day Comments about Study/Endpoint/Uncertainty Factors: A two-generation study in rats (MRID 47305304; parental NOAEL/LOAEL = 83.6/ 892 mg/kg/day) and subchroni c toxicity study in rats (MRID 47305232; NOAEL/LOAEL = 235/956 mg/kg/day) serve as co-cri tical studies since similar

effects were seen in both ra t studies. The points of depart ure are NOAEL = 235 mg/kg/day (MRID 47305232) and LOAEL = 892 mg/kg/day (MRID 47305304). The parental NOAEL of the 2- generation reproduction study may be artificially low due to the ar tifact of dose selection. The parental LOAEL in this study was based on clinical signs, decreased body weight, body weight gain and food efficiency. Similar effects were seen over a 90-day period in the subchronic rat study. Therefore, these studies are appropriate for both the short- and intermed iate- term time period. Additionally, the NOAEL selected (235 mg/kg/day) is also protective of the effects seen in pups on postnatal days 4 through 21; the effects observed in pups (LOAEL = 892 mg/kg/day) were similar to those seen in parental anim als (LOAEL = 892 mg/kg/day).

A.3.5 Dermal Exposure (Short-, Intermediate- and Long-Term)

Study Selected: 21/28 Day Dermal Toxic ity (Rat, OPPTS 870.3200)

MRID: 47305236 Comments about Study/Endpoint/Uncertainty Factors : A 21-day dermal toxicity study was performed on rats at doses of 0, 100, 300 or 1000 mg/kg/day for 6 hrs/day for 7/days/week. The NOAEL was the highest dose tested (HDT and lim it dose, 1000 mg/kg/day). No compound related

effects were observed in mortal ity, clinical signs of toxicit y, limited FOB, body weight, food consumption, ophthalmoscopic exams, hematology, clinical chemistry, organ weights or gross or microscopic pathology in either ge nder. No hazard was identified and therefore, no dermal endpoint was selected for quantitative ri sk assessment for imazosulfuron.

A.3.6 Inhalation Exposure (Short-, Intermediate- and Long-Term)

Co-Critical Study Selected: Reproduction and Fertility Effe cts (2 generation, rat; OPPTS 870.3800)

MRID: 47305304 Co-Critical Study Selected: 90-Day Oral Toxicity (rat; OPPTS 870.3100)

MRID: 47305232Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 52 of 73 Dose and Endpoint for Risk Assessment: NOAEL = 235 mg/kg/day; L OAEL = 892 mg/kg/day Comments about Study/Endpoint/Uncertainty Factors: A two-generation study in rats (MRID 47305304; parental NOAEL/LOAEL = 83.6/ 892 mg/kg/day) and subchroni c toxicity study in rats (MRID 47305232; NOAEL/LOAEL = 235/956 mg/kg/day) serve as co-cri tical studies since similar

effects were seen in both ra t studies. The points of depart ure are NOAEL = 235 mg/kg/day (MRID 47305232) and LOAEL = 892 mg/kg/day (MRID 47305304). The parental NOAEL of the 2- generation reproduction study may be artificially low due to the ar tifact of dose selection. The parental LOAEL in this study was based on clinical signs, decreased body weight, body weight gain and food efficiency. Similar effects were seen over a 90-day period in the subchronic rat study. Therefore, these studies are appropriate for bot h the short- and interm ediate- term time period.

Two studies were considered co-cr itical in selecting the endpoint for short- and intermediate-term inhalation exposure. The multigenerational re production study (MRID 47305304, also selected for incidental oral exposure for pup e ffects) was selected based on decreased body weights, body weight gains and food consumption in the parental genera tion. Additionally, the 90-da y oral toxicity study in rats (MRID 47305232) was selected to reflect a more accurate NOAEL of 235 mg/kg/day for this exposure scenario (LOAEL = 892 mg/kg/day based on similar adverse, treatment-related effects).

A.4 Executive Summaries

A.4.1 Subchronic Toxicity

870.3100 90-Day Oral Toxicity – Rat

In a subchronic oral toxicity study (MRID 47305232) , 10 Sprague Dawley rats/sex/dose group were exposed to TH-913 (Imazosulfuron; 99.8% a.i.; Lot No.: 11263211) for up to 3 months in the diet at concentrations of 0, 2500, 10,000, or 45,000 ppm (equivalent to 0/0, 235/266, 956/1081, and 4577/5136 mg/kg bw/day in males/females).

No treatment-related effects were observed during ophthalmoscopic examinations or hematology.

At 10,000 ppm, the following systemic effects were observed. Decreased (p ≤ 0.05) body weights

were noted in males for 11 weeks and the fema les for 6 weeks during the treatment period ( ↓ 7-11%). Decreased (p ≤ 0.05) overall (Weeks 0-13) body weight gain s were also noted in both sexes ( ↓ 16- 19%). Food efficiency was decreased (not statis tically significant [NS], except in females at Week 4) 8-9 of the 13 treatment weeks at 10,000 ppm in both sexes, and this effect was considered

treatment-related.

At 45,000 ppm, the following systemic effects were noted. Increased mortality was noted in males (1/10) and females (2/10) vs controls (0/10 each sex). Physical signs observed in most decedents included soft stool, necrosis of the tip of the tail, chromodacryo rrhea, and/or anogenital staining. Emaciation and poor hair coat was noted in 1-2 fe males. Decreased body weights were observed in both sexes throughout the study, and decreased overall (Weeks 0-13) body weight gains were also noted in both sexes. Food consumption was increas ed in the males from Week 7 until terminationImazosulfuron Human Health Risk Assessment DP No. 362653

Page 53 of 73 and in the females during 4 weeks of treatment. The average weekly food consumption during

treatment was increased in both sexes. Food efficiency was genera lly decreased throughout treatment, and occasionally these decreas es were statistically significant.

In the 45,000 ppm males, an increas ed incidence of eye opacity wa s observed grossly, and increased incidences in eye corneal edema, acute/subacu te inflammation, and ne ovascularization were observed microscopically.

Although the liver was affected in the 45,000 ppm group, the findings su ggest an adaptive effect and that the liver was not adversely a ffected. Relative to body liver wei ghts were increased in the both sexes, and minimal to slight centrilobular hepa tocyte hypertrophy was observed in 9/10 rats/sex. The following differences were noted in clinical chemistry parameters: (i) decreased glucose in males; (ii) decreased total cholesterol in males an d females; and (iii) incr eased total bilirubin in males. These changes equivocally indicate an effect on the liver, but the ma gnitude of change from control may not be biologically relevant.

The LOAEL is 10,000 ppm (equivalent to 956/1081 mg/kg/day in males/females), based on decreased body weights, body weight gains, and f ood efficiency in both sexes. The NOAEL is 2500 ppm (equivalent to 235/266 mg/k g/day in males/females).

870.3100 90-Day Oral Toxicity – Mouse

In a subchronic oral toxicity study (MRID 47305233), TH-913 (Imazosulfur on; 99.8% a.i.; Lot No. 11263211) was fed in the diet to 10 CD-1 mice/ sex/dose group at dose levels of 0, 2500, 10,000, or 45,000 ppm (equivalent to 0/ 0, 456/692, 1820/2727, and 9776/12,695 in males/females) for 13

weeks.

All animals survived until scheduled termination. There were no adverse effects of treatment on body weights, body weight gains, food consump tion, food efficiency, ophthalmoscopy, clinical chemistry, or gross pathology.

At 45,000 ppm, absolute, relative (to body weight), and relative (to br ain weight) liver weights were increased by 30-42% over controls in the males and by 11-14% in the females. With the exception of the absolute liver weight in the females, thes e increases were statistica lly significant (p<0.05). Microscopically, centrilobular hepa tocyte hypertrophy was observed in all males and females at this dose, with a severity of slight to moderate in the males (mean severity sc ore = 2.60) and minimal to slight in the females (mean severity score = 1.70). Additionally at this dose, increased incidences of congestion (3/10 treated vs 1/10 controls), hemo rrhage (2/10 treated vs 0/10 controls), and acute/subacute inflammation (5/10 treated vs 1/10 cont rols) were noted in the liver in the males; and microgranuloma(s) were observed in the liver in the females (3/10 treated vs 1/10 controls).

Centrilobular hepatocyte hypertrophy was also obse rved in 5/10 males at 2500 ppm and all males at 10,000 ppm. However, the severity was minimal to slight in these animals, with mean severity scores ranging from 1.20 to 1.50. With the exception of a minor increase in relative to body weight liver weight in the 10,000 ppm males ( ↑ 11%; p ≤ 0.05), the centrilobular hy pertrophy noted at these doses were not corroborated by incr eased organ weights or other mi croscopic findings. Thus, atImazosulfuron Human Health Risk Assessment DP No. 362653

Page 54 of 73 these dose levels, these findings were considered to be an adaptive re sponse of the liver to the test

substance and not adverse.

The LOAEL is 45,000 ppm (equivalent to 9776/12,695 mg/kg/day in males/females) based on increased liver weights and on centrilobular hepa tocellular hypertrophy in both sexes. The NOAEL is 10,000 ppm (equivalent to 1820/272 7 mg/kg/day in males/females).

870.3150 90-Day Oral Toxicity – Dog

MRID 47305235, Justification to Bridge Data from a 1- Year Chronic Study in Dogs to a 90-day Subchronic Toxicity Study in Dogs with Imazosulfuron , was submitted in lieu of a 90-day oral toxicity study in dogs.

The 90-day oral toxicity st udy in non-rodents is required under 40 CFR 158.340 and 40 CFR 158.500 (effective December 26, 2007). The require ment for a chronic toxicity study on nonrodents has been eliminated under 40 CF R158.500 because “exte nding a dog study beyond a 13- week duration does not provide addi tional essential toxicity information; eliminating the 1-year dog study does not compromise the data needed for the determination of chroni c RfDs and margins of exposure.”

The registrant submitted a complete toxicology database for imazosulfuron/TH-913 that meets the data requirements listed in 40 CFR 158.340 with th e exception of a 90-day oral toxicity study in non-rodents (dogs). A chronic t oxicity study of TH-913 in dogs was submitted along with a cognate 4-week oral range-finding study.

The toxicology database for this compound reveals a relatively safe profile. Data show fairly consistent endpoints within and between species for the various subchronic/chronic studies. No apparent acute, developmental, reproductive neurologi cal or gene toxicities were observed under the experimental conditions described. Imazosulf uron/TH-913 is not apparently carcinogenic. While evidence of liver and thyroid toxicity and some hematological and bi ochemical effects were observed in mid- and high-dose group animals in the 1-year chronic toxicity study (dog), it is unlikely that a 90-day subchronic toxicity study in dogs would yield NOAELs and LOAELs more protective than those observed in Spicer, E.J.F. (1990). One Year Or al Toxicity Study in Dogs with

TH-913

870.3200 21/28-Day Dermal Toxicity – Rat

In a 21-day dermal toxicity study (MRID 47305236) , Imazosulfuron (98.6% a.i., batch number 52027641) was applied to the shaved skin of 10 Sprague Dawley rats/sex/dose at dose levels of 0, 100, 300, or 1000 mg/kg bw/day, 6 hours/day for 7 days/week during a 21-day period.

No compound-related effects were observed in mortality, clinical signs of toxicit y, limited FOB, body weight, food consumption, ophthalmoscopic ex ams, hematology, clinical chemistry, organ weights or gross or microscopi c pathology in e ither gender.Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 55 of 73 The LOAEL was not observed. The NOAEL is 1000 mg/kg/day (limit dose) for both males and

females

A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study – Rat

In a developmental toxicity study (MRID 47305238) , TH-913 (Imazosulfuron; 99.6-99.7%; Lot Nos. 50031740 and 50035240) in 0.5% carboxymethylcellulose was administered via daily oral gavage in a dose volume of 10 mL/kg to 25 time-mated Sprague-Dawley-derived COBS ® CD ® rats at doses of 0, 250, 500, 1000, or 1500 mg/kg/day from gestation da ys (GD) 6-15. On GD 20, all dams were euthanized; each dam’s uterus was removed via cesar ean section and its contents examined. Fetuses were examined for external, visceral, a nd skeletal malformations and variations.

All dams survived until scheduled termination. Th ere were no clinical si gns of toxicity and no effects of treatment on gross pathology.

Maternal body weight gains were decreased by 21% (not statistically signifi cant) at 1500 mg/kg/day compared to concurrent controls during the treatment interval (GD 6-16). Body weight gains in this group were comparable to controls during the pr e-treatment and post-treatment intervals. Body weight gains of the remaining treated groups were comparable to their respective control groups throughout the study.

Maternal food consumption was decreased by 13% (p<0.05) at 1500 mg/kg/day compared to concurrent controls during the GD 6-7. Ther e were no other effects of treatment on food consumption.

The maternal LOAEL is 1500 mg/kg/day based on decreased body weight gain and food consumption. The maternal NOAEL is 1000 mg/kg/day (limit dose).

There were no abortions or complete litter resorptions. There were no effects of treatment on the sex ratio or on the numbers of litters, live fetuses, de ad fetuses, or late resorptions. At 1000 and 1500 mg/kg/day, the numbers of early resorptions we re decreased and post-implantation losses were increased compared to their respective controls. However, these differences were not considered

adverse.

There were no effects of treatment on growth or development of the fetuses. Fetal weights and placental weights of the treated groups were compar able to controls, and there were no treatmentrelated effects on ossification of the skeleton.

There were no treatment-related external, viscer al, or skeletal variations or malformations.

The developmental LOAEL was not observed. The developmental NOAEL is 1500 mg/kg/day.

870.3700b Prenatal Developmenta l Toxicity Study - RabbitImazosulfuron Human Health Risk Assessment DP No. 362653

Page 56 of 73 In a developmental toxicity study (MRI D 47305301) TH-913 (99.6%, lot number 50035240) was

administered to 20 female New Zealand White SPF rabbits/dose by gavage at dose levels of 0, 25, 50, or 125 mg/kg bw/day from days 7 through 19 of gestation.

One animal in the high dose group was sacrificed in extremis on gestation day 17 due to impaired

hind limb function. The reviewer does not attribute th is death to treatment. Necrotic foci in multiple lobes of the lung were observed in this animal as well as in one other an imal receiving 25 mg/kg/day and two other animals receiving 50 mg/kg/day. In the absence of serum chemistry and histopathological data, these gr oss pathological findings are c onsidered incidental under the experimental conditions tested. There were no other antemortem or necropsy observations suggestive of TH-913 toxicity. There was no appa rent difference in maternal body weight gain among treatment groups. There were no treatment -related adverse effects on body weight and food consumption.

The maternal LOAEL was not observed under thes e experimental conditions. The maternal NOAEL is 125 mg/kg bw/day.

There were no treatment-related effects in developmental parameters measured

.

The developmental LOAEL was not observed under these experimental conditions. The developmental NOAEL is 125 mg/kg bw/day.

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects – Rat

In a two-generation reproduction toxicity st udy (MRID 47305304), TH-913 (imazosulfuron; 99.6%; Lot # 50035240) was administered in the diet to 26 Crl:CD VAF/Plus ® rats/sex/dose group at dietary levels of 0, 100, 1000, or 10,000 ppm (equivalent to 0/0, 8.3/9.3, 83.6/92.7, and 892.0/982.7 mg/kg/day in males/females duri ng pre-mating) for two successive generations with one litter per generation. The P generation animals were fed the test diets for a minimu m of 56 days prior to mating to produce the F1 litters. The F1 litters we re culled on post-natal (P ND) 4 to eight pups/litter (four/sex where possible). On PND 28, 26 males and females from each dose group were selected

and fed the same test diet concentration as their dam. These animals were fed the test diets for a minimum of 58 days prior to mating (at 14 weeks of age).

No effects of treatment were observed duri ng macroscopic or microscopic examinations.

Toxicity was observed at 10,000 ppm. In the P ge neration, one male died during Week 6, and one female died during Week 2. In the F1 generation, five males died prior to observation during Week 4, one male was killed in extremis during Week 17, and two females died, one during Week 4 and the other during Week 5. Clinical signs of toxi city noted included scabbed areas around the head and shoulders in the males and females of both generations, emaciated P and F1 females, and small

in size F1 males and females.Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 57 of 73 Additionally at this dos e, body weights and body weight gains we re decreased throughout treatment in the P and F1 males, and throughout pre-mating in the P and F1 females. Food consumption was decreased throughout pre-mating in the P and F1 ma les and females. Additional decreases in food consumption were observed after the mating period in the P and F1 males. Body weights were decreased throughout gestation in the P and F1 fe males, resulting in decreased overall (GD 0-20) gestational body weight gains. Overall gestational food consumpti on was also decreased in these animals. Body weights and food consumption were decreased throughout lactation in the P and F1

females.

The LOAEL for parental toxicity is 10,000 ppm (equivalent to 892.0/982.7 mg/kg/day in males/females), based on mortality, clinical si gns, decreased body weights, body weight gains, and food consumption. The NOAEL is 1000 ppm (equivalent to 83.6/92.7 mg/kg/day in males/females).

No effects of treatment were observed on pup se x ratio or during macroscopic examinations.

It was stated that a high incidence of the 10,000 pp m F1 and F2 pups were small in size, correlating with decreased pup body weights. Also, the numbe r of offspring missing from their cages and presumed cannibalized increased slightly in the F1 pups and increased markedly in the F2 pups.

At 10,000 ppm, decreased numbers of implants/dam, total pups/dam, live pups/dam on PND 0, and viability index were observed in the F1 pups. Si milarly, in the F2 pups, decreased live pups/dam on PND 0, and live birth, viability, and lactation indi ces were noted. Additionally at this dose,

treatment-related decreases in pup body weights were observed in the F1 pups from PND 4 (precull) through PND 21 and in the F2 pups from PND 0 through PND 21.

The LOAEL for offspring toxicity is 10,000 ppm (equivalent to 892.0/982.7 mg/kg/day in males/females), based on decreased pup viability and body weights. The NOAEL is 1000 ppm (equivalent to 83.6/92.7 mg/kg/ day in males/females).

There were no effects of treatment on mating, fertil ity, pregnancy, or gestati on indices. Copulatory interval and gestation dura tion were similar to contro ls in all treated groups.

The LOAEL for reproductive toxicity was not observed. The NOAEL is 10,000 ppm (equivalent to 892.0/982.7 mg/kg/ day in males/females).

A.4.4 Chronic Toxicity

870.4100b Chronic Toxicity – Dog

In a chronic study (MRID 47305305), TH-913 (99.6 – 99.7% pure, lot numbers 50035240 and 50031740) was administered daily via capsules to 4 b eagle dogs/sex/group at dose levels of 0, 75, 150 or 300 mg/kg/day. Though mortality was not clearl y attributable to test article treatment, 2 animals in the high dose group died during the course of the study. One male animal died of acute severe bilateral pyelonephritis on day 57 and one female died of chronic active bronchopneumonia on day 20. No overt signs of toxicity were observed in any of the surviving animals. No treatment-Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 58 of 73 related changes were observed in food consumption, food efficienc y, body weights or revealed by ophthalmoscopic or physical examination.

Treatment-related decreases in er ythrocyte counts, hemoglobin a nd hematocrit were observed in males receiving 300 mg/kg/day. Though the effect of elevated alkaline phospha tase at 12 months of study is not clearly dose-dependent , the ~ 2-fold increase obser ved in male dogs receiving 150 mg/kg/day and ~ 1.5-fold increase in male dogs recei ving 300 mg/kg/day is considered an effect of treatment. Female dogs receiving 300 mg/kg/day fo r one year also manifested increased alkaline phosphatase activity. Treatment-re lated hypocholesterolemia, in c onjunction with decreased serum phospholipids, was observed at 6 and 12 months of study in males receiving 300 mg/kg/day. A decrease in serum albumin was observed in all male treatment groups comp ared to control at 6 months of study: The low-dose eff ect was transient but the ~ 20 – 25% decreases in albumin seen in male dogs receiving ≥ 150 mg/kg/day at 6 months persisted until study termination. A 15% decreasein albumin was noted for female dogs administered 300 mg/kg/day for 1 year. A slight treatmentrelated decrease in total se rum protein was observed in the male high dose group.

Treatment with TH-913 at leve ls of 75, 150 and 300 mg/kg/day had an apparent dose-dependent effect of increased liver weight . Relative liver weights were significantly increased in males and females receiving ≥ 150 mg/kg/day. Significantly increased thyroid/parathyroid complex weights were observed in males treated with 300 mg/kg/day. High-dose females also e xhibited this effect of treatment though thyroid/parathyroid complex weight s were not statistically greater than control values. Moderate thyroid hypertrophy was seen in male mid- and high-dose groups. Mild thyroid hypertrophy was seen in female s only at high dose levels.

Under these experimental conditions, the LOA EL for TH-913 for male and female dogs is 150 mg/kg/day based on increased relative liver we ights, increased serum alkaline phosphatase activity and moderate thyroid hypertrophy (mal es only at mid-dose). The NOAEL for male and female dogs is 75 mg TH-913/kg/day.

A.4.5 Carcinogenicity

870.4300 Chronic Toxicity/Carcinogenicity Study – Rat

In a combined chronic toxicity/carcinogenicity study (MRID 47305306), 50 CD ® rats/sex/dose were exposed to TH-913 (Imazosulfuron; ≥ 99.6% a.i.; Lot Nos.: 11263211, 50031740, 50033340, 50035240, and 50037940) for up to 24 months in the di et at concentrations of 0, 200, 2000, or 20,000 ppm (equivalent to 0/0, 10/ 13, 106/132, and 1124/1554 mg/kg bw/day in males/females). Additionally, 10 rats/sex/ dose/time point were treated similarly for up to 6, 12, or 18 months and then sacrificed. The 20,000 ppm females were sacr ificed early on Day 666 to preserve sufficient tissues for microscopic assessment.

No treatment-related effects were observed on hematology, clinical chemistry, or urinalysis
parameters.

Systemically, the following findings were noted in the 20,000 ppm group. Decreased survival was

noted in the females. The first marked increase in mortality was observed at Month 13 (12% treatedImazosulfuron Human Health Risk Assessment DP No. 362653

Page 59 of 73 vs 4% controls), and percentage survival in the carcinogenicity animals (terminal sacrifice group) was only 24% at Month 22. Decreased (p ≤ 0.05) body weights were observed in males ( ↓ 10-24%) and females ( ↓ 14-42%) beginning at Week 1. In male s, overall (Weeks 0-104) body weight gain was decreased (p ↓ 0.01) by 23%, and overall (Weeks 0-95) body weight gain was decreased (p ↓ 0.01) by 57% in females. Increased food consumption (g/kg/day) was observed in both sexes. The average food consumption during treatment was incr eased by 7% in males and 17% in females.

At 20,000 ppm, the eyes were a target organ. In the females, lens vascularization and opacity were noted in 3-7% of the animals (vs 0% controls) at Months 3, 6, 12, and 18. Additionally in the females, lens vascularization (6%) and opacity (22%) were also noted at Mont h 22 (vs 0% controls). The Sponsor stated that the males had an increased incidence from controls of chromodacryorrhea, lacrimation, and swollen edematous tissue around the eyes without providing quantitative data. The incidence of conjunctivitis was slightly increas ed in all male treatment groups every time the parameter was evaluated; however, there was no corroborating evidence for ocular effects at <20,000 ppm. In the males, increased incidences of the following findings were observed at Month 24: corneal scarring (8 treated vs 1 control), possible retinal degenera tion (5 treated vs 0 controls), and posterior subcapsular or complete cataract (7 treated vs 0 controls). The possible retinal degeneration and cataracts were b ilateral findings (except 1 unilatera l cataract), but conjunctivitis

and corneal scars were observed both unilaterally and bilaterall y. In the females, retinal degeneration was observed (number treated vs 0 controls) at Months 12 (30) and 18 (21), and posterior subcapsular or complete cataract was ob served at Months 6, 12, and 18 (8-9). These findings were predominantly observed bilaterally. The females were terminated prior to the examination at Month 24. Considering all animals (n=80), increased incidences of eye opacity (12 treated vs 1 control) were noted grossly in the females. Micros copically, bilatera l retinal atrophy was noted in 26/80 males (moderate to marked se verity) and 46/74 females (moderate to marked severity) vs 0/80 controls. Retinal atrophy was not noted in any animal terminated on schedule prior
to the terminal sacrifice in male s; however, retinal atrophy was noted at 12 months in 7/10 females and at 18 months in 4/6 females (vs 0/10 controls). Slight to marked bilateral lens cataracts were

observed in 17/74 females vs 0/80 controls and were noted in 1/ 6 females at Month 18 (vs 0/6 controls).

In the 20,000 ppm females, increased (p ≤ 0.05) relative to body liver weights were observed at Months 6, 12, and 18 ( ↑ 46-99%). Additionally, increased in cidences (% treated vs % controls; n=74-80) of slight to marked liv er congestion (21% vs 11%), sli ght to marked acute inflammation (14% vs 4%), and slight to marked coagul ative necrosis (16% vs 6%) were observed.

In the 20,000 ppm females, other organs may have been affected; however, the evidence was not

conclusive. Increased relative to body ovary weights were noted at Months 12 and 18. Considering all animals, increased incidences of the following gross lesions were noted (# affected in treated vs controls): ovarian cysts, distended uterus, uterus with thick walls, and uterus with abnormal contents. At the interim sacrifices, increased incidences of the following gross lesi ons were noted: ovarian cysts at Month 12, distended uterus at Months 6 and 12, and uterus with thick walls at Month 12. Increased incidences (n=78-80) of ovarian cysts and minimal to severe hydrometra were observed microscopically. All this evidence supports an effect on the reproductive system; however, no effects of treatment at doses up to 10,000 ppm we re observed during macros copic or microscopic examinations of parents in a concurrently subm itted 2-generation reproduc tion and fertility testImazosulfuron Human Health Risk Assessment DP No. 362653

Page 60 of 73 (MRID 47305304). In the reproduction study, no decrea se in fertility was observed, and offspring toxicity was observed at the same dose level as parental toxicity.

The LOAEL is 20,000 ppm (equivalent to 1124/1554 mg/kg/day), based on increased mortality, decreased body weights and body weight gains, increased food consumption, and ophthalmology findings in both sexes, and hepa toxicity in females. The NOAEL is 2000 ppm (equivalent to 106/132 mg/kg/ day in males/females).

At the doses tested, there was no treatment related increase in tumor incidence when compared to controls. Dosing was considered adequate base d on increased mortality, decreased body weights and body weight gains, increased food consump tion, and ophthalmology findings in both sexes.

870.4200b Carcinogenicity (feeding) - Mouse

In a carcinogenicity study (MRID 47305307), TH- 913 (Imazosulfuron; >=99.6% a.i.; Lot Nos. 11263211, 50031740, 50033340, 50035240, and 50037940) was administ ered in the diet to CD1 mice (50/sex/dose) for up to 18 months at dos es of 0, 450, 4500, or 45,000 ppm (equivalent to 0, 73/87, 741/870, and 7848/10,304 mg/kg bw/d ay in males/females).

No treatment-related effects were observed on mortality, clinical signs , hematology, or gross pathology.

At 4500 ppm, body weights were decreased in the ma les from Week 2 through termination, and were significantly decreased (p ≤ 0.05) in 16 of the 29 reported treatment weeks ( ↓ 4-12%). Cumulative body weight gains were decreased (p ≤ 0.05) by 18-44% in the males, contributing to the decreased (p ≤ 0.05) overall (Weeks 0-77) cumulati ve body weight gains of 22%.

At 45,000 ppm, decreased (p ≤ 0.05) body weights were noted in th e males in 26 of the 29 reported treatment weeks ( ↓ 5-14%) and females in 13 of the 29 reported treatment weeks ( ↓ 4-10%). Decreased (p ≤ 0.05) cumulative body weight gains were observed in the males ( ↓ 17-42%) and females ( ↓ 15-30%), contributing to decreased (p ≤ 0.05) overall (Weeks 0-77) cumulative body weight gains in males ( ↓ 28%) and females ( ↓ 30%). The average food consumption (g/kg/day) during treatment was increased by 8% in males and 20% in females.

At 45,000 ppm, increased (p ≤ 0.05) relative to body liver weights were observed in the males ( ↑ 31%) and females ( ↑ 18%). Increased incidences of minimal to slight cloudy swelling in the liver was observed in the males (35% treated vs 22% contro ls) and females (26% treated vs 10% controls), and increased incidences of centrilobular hepatocy te swelling was noted in males (24% treated vs 0% controls; slight to moderate se verity) and females (8% treated vs 0% controls; slight severity).

The LOAEL is 4500 ppm (equivalent to 741/870 mg /kg bw/day in males/females), based on decreased body weights and body weight gains in males. The NOAEL is 450 ppm (equivalent to 73/87 mg/kg/day in males/females).

At the doses tested, there was no treatment-related increase in tumor incidence when compared to controls. Dosing was considered adequate based on decreased body weights and body weight gains,Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 61 of 73 increased relative food consumption, and slight hepatotoxicity.

A.4.6 Mutagenicity

Gene Mutation

Guideline 870.5100, Bacterial Reverse

Mutation

MRID 47305308 Acceptable, guideline TH-913 was tested up to the limit dose (5000 μg/plate, +/- S9). Evidence of cytotoxicity (reduction of background lawn) was observed in all Salmonella strains at 5000 μg/plate (+/-S9). No marked increases in the number of revertant colonies compared to controls were observed in any strain (+/-S9). The positive controls induced the appropriate response. There was no evidence of induced mutant colonies over background in any strain in the presence or absence of S9-activation.

Guideline 870.5100, Bacterial Reverse

Mutation

MRID 47305309

Acceptable, guideline UDPM was tested up to the limit dose (5000 μg/plate, +/- S9). No evidence of cytotoxicity (reduction of background lawn) was observed in any strain (+/-S9). No marked increases in the number of revertant colonies compared to controls were observed in any strain (+/-S9). The positive controls induced the appropriate response. There was no evidence of induced mutant colonies over background in any strain in the presence or absence of S9-

activation.

Guideline 870.5100, Bacterial Reverse

Mutation

MRID 47305310

Acceptable, guideline IHOA was tested up to the limit dose (5000 μg/plate, +/- S9). No evidence of cytotoxicity (reduction of background lawn) was observed in any strain (+/- S9). No marked increases in the number of revertant colonies compared to controls were observed in any strain (+/-S9). The positive controls induced the appropriate response. There was no evidence of induced mutant colonies over background in any strain in the presence or absence of S9-

activation.

Guideline 870.5100, Bacterial Reverse

Mutation

Guideline 870.5500, DNA Repair Test

MRID 47305311

Acceptable, guideline M-1 was tested up to the limit dose (5000 μg/plate, +/-S9). No evidence of cytotoxicity (reduction of background lawn) was observed in any strain (+/- S9). No marked increases in the number of revertant colonies compared to controls were observed in any strain (+/-S9). The positive controls induced the appropriate response. There was no evidence of induced mutant colonies over background in any strain in the presence or absence of S9-

activation.

M-1 was tested at up to the limit dose (5000 μg/disk, +/-S9). No zones of growth inhibition were observed at any test concentration in either strain in the presence or absence of S9-activation. The kanamycin negative control demonstrated that a cytotoxic agent caused approximately equal lethality in the two tester strains. The positive controls induced the appropriate response. There was no evidence that DNA damage was induced.

Guideline 870.5100, Bacterial Reverse

Mutation

MRID 47305312

Acceptable, guideline IPSN was tested up to the limit dose (5000 μg/plate, +/- S9). No evidence of cytotoxicity (reduction of background lawn) was observed in any strain (+/- S9). No marked increases in the number of revertant colonies compared to controls were observed in any strain (+/-S9). The positive controls induced the appropriate response. There was no evidence of induced mutant colonies over background in any strain in the presence or absence of S9-

activation.

Guideline 870.5100, Bacterial Reverse

Mutation

MRID 47305313

Acceptable, guideline ADPM was tested up to the limit dose (5000 μg/plate, +/- S9). No evidence of cytotoxicity (reduction of background lawn) was observed in any strain (+/-S9). No marked increases in the number of revertant colonies compared to controls were observed in any strain (+/-S9). The positive controls induced the appropriate response. There was no evidence of induced mutant colonies over background in any strain in the presence or absence of S9-

activation.

CytogeneticsImazosulfuron Human Health Risk Assessment DP No. 362653

Page 62 of 73 Guideline 870.5375, In vitro
Mammalian Cell Chromosome
Aberration Test

MRID 47305315 Acceptable, guideline TH-913 was tested up to the limit of solubility (500 μg/mL, +/-S9). In the absence of S9, slight increases in the percentage of cells with structural aberrations excluding gaps (2.0-5.0% treated vs. 0-0.5% controls) were noted at 500 μg/mL in the 24- and 48-hour groups in both trials. However, the increases did not reach the threshold value of 10% required for a positive response in either trial. In the presen ce of S9, there were no increases in the percentage of cells with aberrations at any dose. The positive controls induced marked increases in the percenta ge of aberrant cells in the presence

and absence of S9. There was no evidence of chromosome aberrations induced over background in the presence or absence of S9-activation.

Other Genotoxicity

Guideline870.5300, In vitro
Mammalian Cell Gene Mutation Test

MRID 47305314 Acceptable, guideline TH-913 was tested up to the limit of solubility ( ≥ 250 μg/mL, +/-S9) in L5178Y mouse lymphoma cells. Upon addition of the test material to the cultures, precipitation of the test material was observed at 250-950 μg/mL (+/-S9) in both trials. However, following the 3-hour treatment incubation period, the precipitate observed at thes e doses had dissolved in both trials. No marked increases in cytotoxicity or mutant frequency were observed at any concentration with or without S9-activation in either trial. The positive controls induced the appropriate response both in the presence and absence of

S9. There was no evidence of induced mutant colonies over background in the presence or absence of S9-activation.

A.4.7 Neurotoxicity

870.6200 Acute Neurotoxicity Screening Battery

In an acute neurotoxicity study (MRID 47305319) , Imazosulfuron (98.6% a.i.; Batch No. 52027641) in 0.5% w/v aqueous carboxymethyl cellulose was administered once via gavage (10 mL/kg) to 10 Wistar rats/sex/group at dose le vels of 0, 80, 400, or 2000 mg/kg (limit dose). Neurobehavioral assessment (functional observational battery [FOB] and motor activity testi ng) was performed on 10 rats/sex/group at Days -7, 1 (4 hours post-dosing; time of peak effect), 8, and 15. At study termination, 5 rats/sex/group were anesthetized and perfused in situ for neuropathological examination. The tissues from the perfused an imals in the control and 2000 mg/kg groups were subjected to histopathological evaluation of brain and periph eral nervous system tissues.

No treatment-related effects were observed on mortality, body weights, b ody weight gains, food consumption, FOB parameters (other than clin ical signs), gross and neuropathology, and brain weights and measurements.

At 2000 mg/kg, the following clinical signs of toxicity were observed (number affected/10 in treated group vs 0/10 in control group): (i ) abnormal gait (tip to e gait and/or splayed ga it) in males (8) and females (9); (ii) activity decrease d in males (7) and females (1); (i ii) piloerection in males (9) and females (4); and (iv) upward curvat ure of the spine in males (2) and females (7). On Day 1, each of the following findings was observed in 1/10 animals and were considered to be equivocal effects: irregular breathing, tremors, re duced righting reflex, decreased visual placement response, and increased response to sound. All of these findings had resolved by Day 2.Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 63 of 73 In the 2000 mg/kg males, overall (1-50 minutes) motor activity was decreased (p ≤ 0.05) by 38% on Day 1. Decreases (p ≤ 0.01) of 66-80% in activity were noted in the s ubsession intervals, minutes 16- 20 and 46-50, and contributed to the decrease in overall activity.

The LOAEL was 2000 mg/kg based on abnormal gait, decreased activity, piloerection, and upward curvature of the spine in both sexes, and decreased motor activity in the males. The NOAEL is 400 mg/kg.

870.6200 Subchronic Neurotoxicity Screening Battery

In a subchronic neurotoxic ity study (MRID 47305320), Imazosulfuron (98.6% a.i., Batch No. 52027641) was administered in the di et to 12 Wistar rats/sex/group at dose levels of 0, 800, 2500, or 8000 ppm (equivalent to 0/0, 54.0/61.9, 169.2/200.8, and 571.3/655.3 mg/kg bw/day in males/females) for at least 90 consecutive days. Neurobehavioral assessment (functional observational battery [FOB] and motor activity testing) was perf ormed in 12 rats/sex/group at Weeks -1, 2, 5, 9, and 14. At study termination, 5 rats /sex/group were anesthetized and perfused in situ for neuropathological examination. Th e tissues from the perfused animals in the control and 8000 ppm groups were subjected to histopa thological evaluation of brain a nd peripheral nervous system

tissues.

No treatment-related effects were observed on mo rtality, clinical signs, functional observational battery parameters, motor activit y, ophthalmoscopic examinations, brain weights, or neuropathology.

In the 8000 ppm group, body weights were decreased (p ≤ 0.05) by 5-13% beginning at Week 3. Cumulative body weight gains were decreased (p ≤ 0.01) by 17-26% in males and 30-47% in females, and overall (Weeks 1-14) body weig ht gain was decreased (p ≤ 0.01) by 23% in males and 33% in females. Decreased (p ≤ 0.05) food utilization (4-w eek intervals) was observed in both sexes throughout treatment, except in the females at Weeks 9-13 ( ↓ 17-52%). Overall (Weeks 1-13) food utilization was decreased (p ≤ 0.01) by 21-29% in both sexes.

No neurological effects were observed at any dose in either sex.

The LOAEL is 8000 ppm (equivalent to 571/655 mg /kg bw/day in males/females) based on slightly decreased body weight, body weight gain, and food utilization in both sexes. The NOAEL is 2500 ppm (equivalent to 169/201 mg/kg bw/day in males/females).

A.4.8 Metabolism

870.7485 Metabolism – Rat

In a rat metabolism study (MRIDs 47305321, 47305322, and 47305323), [imidazopyridinyl-3-

14 C]imazosulfuron or [pm- 14 C]imazosulfuron (>98.6% radiochemical purity for each) in aqueous 0.5% carboxymethylcellulose was administered to Spra gue Dawley rats as a single oral gavage dose at 5 mg/kg body weight. Group sizes were 1 rats/sex in the pilot study, 4 male s in the Tier 1 study, and 3 males in the bile duct-cannulation study. Ex creta (urine, feces, and bile [in some groups]) were collected for up to 72 hours post-dose and radioa nalyzed. Expired air was trapped for the firstImazosulfuron Human Health Risk Assessment DP No. 362653

Page 64 of 73 24 hours in the pilot study. Additionally, pools of sel ected excreta and bile were analyzed to identify and quantify metabolites. Animals we re sacrificed at 3 days post- dose, and selected tissues were collected and radioanalyzed.

Total recovery was 96-103% of the administer ed dose (AD) for the excretion and metabolic profiling. The majority of the dose was recovere d in the urine (66%), a substantial amount was isolated in the bile (34%), and a miniscule am ount was found in the feces (2%). Thus, the test compound was nearly completely absorbed. Most of the compound remains unabsorbed at 6 h postdose (25%), but is mostly absorbed by 12 h post-dose (84%).

In the pilot study, differences in th e excretion profile based on sex or radiolabel position were not existent or not substantial (data from 1 rat/sex/ra diolabeled). Only neg ligible radioactivity was isolated in the expired air ( ≤ 0.1%).

Males excreted 64% AD in the urine and 32% AD in th e feces. Almost all of radioactivity isolated in the feces was absorbed and excreted in the bile. At 72 h post-dose, only 0.25% AD was found in the gastrointestinal contents, organs, tissues, a nd residual carcass. The 5 mg/kg dose was rapidly excreted; most of the dose was excreted within 12 h (56% AD). By 24 h post-dose, 89% of the dose was excreted, and excretion was essentially comple te within 48 h post-dose (96% AD). The rapid excretion of the test compound suggests that bioa ccumulation may not be a concern at this dose

level.

At 3 days post-dose, radioactive residues in th e blood (0.031 μg equiv/g) were exceeded only in the plasma (0.044 μg equiv/g), kidney (0.045 μg equiv/g) , and liver (0.036 μg equi v/g). The radioactive

residue level in the sciatic nerve (0.031 μg equiv/g) was equivalent to blood, and the levels in other organs and tissues were less than blood (<=0.019 μg equiv/g).

HPLC and TLC analyses, combined with enzyme hydrolysis, allowed the identification of 5 metabolites. The identified components accounted for 75-76% AD.

Based on 1 rat/sex/radiolabeled in the pilot study, the metabolic profiles were generally similar regardless of sex or radiolabel position. One identified metabolite was isolated in the feces of rats treated with [imidazopyridinyl-3- 14 C]imazosulfuron, but not in rats treated with [pm- 14 C]imazosulfuron. Conversely, an unidentified organic compound with less than 5 carbons and only C, H, and O atoms was isolated in the feces of rats treated with [pm- 14 C]imazosulfuron, but not in rats treated with [imidazopyridinyl-3- 14 C]imazosulfuron. More 1-(2-c hloroimidazo[1,2-a]pyridin3-ylsulfonyl)-3-(4-hydroxy-6-methoxypyrimidin-2-yl)ur ea (HMS) was isolated in feces in the female (13.4% AD) than the male (5.3% AD) treated with [pm- 14 C]imazosulfuron.

In the Tier 1 study, the major metabolite was HMS in the urine (55.7% AD) and feces (6.5% AD).
The other metabolites accounted for <5% AD. Parent was isolated in neg ligible amounts (0.9% AD)

in the feces. Metabolic reacti ons included demethylation, hydr oxylation of the pyrimidine ring, methylation or glucuronidati on of the hydroxyl group, and opening the pyrimidine ring and formation of guanidine.Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 65 of 73 In the bile duct-cannulation st udy, the major metabolites were HM S in the urine (56.9% AD), bile (3.8% AD), and feces (0.8% AD). All other metabolites accounted for ≤ 5.2% AD. Parent was
isolated in minor amounts in the f eces (1.0% AD) and bile (0.2% AD).

A.5 Toxicology Data Required as a Condition of Registration

Guideline Number: 870.7800 Study Title : Immunotoxicity Rationale for Requiring the Data

This is a new data requirement under 40 CFR Pa rt 158 as a part of the data requirements for registration of a pestic ide (food and non-food uses).

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional immunotoxicity testing and is designed to eval uate 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 vira l infections such as tuberc ulosis (TB), Severe Acquired Respiratory Syndrome (SARS), or neoplasia . Because the immune system is highly complex, studies assessing functional i mmunotoxic endpoints are helpful in fully characterizing a pesticide’s pot ential immunotoxicity. These data will be used in combination with data from hematology, lym phoid organ weights, and histopathology in routine chronic or subchronic toxicity st udies to characterize potential immunotoxic

effects.

Practical Utility of the Data

How will the data be used?

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-tetrachlorodibenzop-dioxin) among developmental, reproduc tive, and endocrinol ogic toxicities. Additionally, the EPA has established an oral reference dose (RfD) for tributyltin oxide (TBTO) based on observed immunotoxici ty in animal studies (IRIS, 1997).

How could the data impact the Agency's future decision-making?

If the immunotoxicity study show s that the test material pos es either a greater or a diminished risk than that given in the inte rim decision’s conclusion, the risk assessments for the test material may need to be revise d to reflect the magnitude of potential risk

derived from the new data.

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

Appendix B. Metabolism Summary TableImazosulfuron Human Health Risk Assessment DP No. 362653

Page 66 of 73 Table B.1: Tabular Summary of Metabolites and Degradates
Percent TRR (PPM) 1 Common Name Chemical Name/

Structure Matrix

Matrices – Major

Residue (> 10% TRR) Matrices- Minor Residue (<10% TRR)

Imazosulfuron 2-chloro- N -[[(4,6-dimethoxy-2- pyrimidinyl)amino]carbonyl]imidazo- [1,2- α ]pyridine-3-sulfonamide

N N

N N

N H N H S O

O Cl

O CH 3 O CH 3

O Milk

Muscle (goat) Kidney (goat)

Liver (goat)

Eggs

Muscle (hen)

Fat (hen)

Liver (hen)

Rat feces

Potato

Rice grain

Rice straw

Tomato 46 (0.013) Py 67 (0.020) Im 20 (0.002) Im 23 (0.036) Py 28 (0.045) Im

80 (0.118)Py 71 (0.085)Im 62 (0.008)Py 15 (0.003) Im 54 (0.006) Py 14 (0.001) Im 17 (0.029)PY

28 (0.056) Py 18 (0.034) Im 64 (2.0) Py 61 (1.3) Im 17 (0.009) Py 3.4 (0.015)Py 9.9 (0.022)Im

4.7 (0.012)

0.9% AD 8.4 (0.002) Py 3.6 (0.001) Im

5.3 (0.001) Im

HMS; Odemethylated
imazosulfuron 2-chloro- N -[[(4-hydroxy-6-methoxy-2- pyrimidinyl)amino]carbonyl]imidazo-[1,2-

α ]pyridine-3-sulfonamide

N N

N N

N H N H S O

O Cl

O CH 3 OH

O Milk Kidney (goat) Fat (hen)

Rat urine

Rat feces

Potato

Rice grain
Rice straw

Tomato

Sorghum forage (rotational 30 day) Wheat forage (rotational 120 day) Sorghum forage (rotational 365 day) Sorghum

stover 31% AD

29 (0.065) Py 33 (0.088) Im

11 (0.007)Py

34 (0.20) Py 32 (0.18) Im 3.3 (0.001)Im 1.9 (0.003)Im 9.1 (0.001) Py

6.5% AD 5.2 (0.001) Py 4.1 (0.001) Im 2.6 (0.005) Im 0.9 (0.020)Im 1.9 (0.001)Py (tentative) 8.3 (0.001)Im (tentative)

5.0 (0.004) Im

8.0 (0.003) Im

6.7 (0.007) Py 9.8 (0.009) ImImazosulfuron Human Health Risk Assessment DP No. 362653

Page 67 of 73 Table B.1: Tabular Summary of Metabolites and Degradates
Percent TRR (PPM) 1 Common Name Chemical Name/

Structure Matrix

Matrices – Major

Residue (> 10% TRR) Matrices- Minor Residue (<10% TRR)

(rotational 30 day) Sorghum

stover (rotational 365 day) Sorghum grain (rotational 30 day Sorghum grain (rotational 365 day) 0.7 (<0.001)Py

0.4 (<0.001) Im

IPSN 2-chloro-imidazo[1,2-a]pyridine-3-sulfonic

acid amide

N N

S O

O Cl

NH 2 Milk Muscle (goat) Kidney (goat) Liver (goat) Eggs Muscle (hen) Fat (hen) Liver (hen)
Rat feces

Potato Rice grain 70 (0.007)Im 33 (0.052)Im 31 (0.069)Im 10 (0.012) Im 25 (0.005) Im 29 (0.002) Im 43 (0.11) Im

12 (0.003) Im 6.7 (0.002)Im

<5% AD

5.2 (0.010) Im UDPM (4,6-dimethoxy-pyrimidin-2-yl)-urea

N N

N H NH

2 O CH 3 O CH 3

O Eggs

Potato Rice grain

Rice straw

Tomato Sorghum forage (rotational 30 day) Sorghum forage (rotational 365 day) Wheat hay (rotational 120 day)

Wheat straw (rotational 120 day) Sorghum

stover (rotational 365 day) Sorghum 4.1 (0.006) Py

18 (0.037) Py 13 (0.39) Py 30 (0.016)Py

14 ((0.008) Py

23 (0.066) Py

15 (0.017) Py 0.7 (<0.001)Py

5.7 (0.013) Py

7.9 (0.039) Py

1.9 (0.001) Py

2.0 (0.002) Py

2.5 (<0.001) PyImazosulfuron Human Health Risk Assessment DP No. 362653

Page 68 of 73 Table B.1: Tabular Summary of Metabolites and Degradates
Percent TRR (PPM) 1 Common Name Chemical Name/

Structure Matrix

Matrices – Major

Residue (> 10% TRR) Matrices- Minor Residue (<10% TRR)

grain (rotational 30 day) Wheat grain (rotational 120 day) Sorghum grain (rotational 365 day) ADPM 4,6-dimethoxy-pyrimidin-2-ylamine

N N

NH

2 O CH 3 O CH 3 Potato Rice grain

Rice straw

Tomato Sorghum forage (rotational 30 day) Sorghum forage

rotational 365 day) Sorghum

stover (rotational 30 day) Wheat hay (rotational 120 day)

Wheat straw (rotational 120 day) Sorghum

stover (rotational 365 day) Sorghum grain (rotational 30 day) Wheat grain (rotational 120 day) Sorghum grain (rotational 365 day) 10 (0.006)Py

11 (0.012) Py 0.3 (<0.001)Py 5.5 (0.011) Im 3.3 (0.10) Im 7.7 (0.002)Py 3.2 (0.013) Py

7.8 (0.045) Py

1.4 (0.004) Py

2.2 (0.011) Py

2.5 (0.001) Py

2.0 (0.002) Py

2.1 (<0.001) Py

ADNG glucose conjugate of 4,6-dimethoxypyrimidin-2-ylamine Potato 1.3 (<0.001)PyImazosulfuron Human Health Risk Assessment DP No. 362653

Page 69 of 73 Table B.1: Tabular Summary of Metabolites and Degradates
Percent TRR (PPM) 1 Common Name Chemical Name/

Structure Matrix

Matrices – Major

Residue (> 10% TRR) Matrices- Minor Residue (<10% TRR)

IPSA-isoserine 3-(2-chloro-imidazo[1,2-a]pyridine-3- sulfonylamino)-2-hydroxy-propionic acid

N N

N H S O

O Cl

OH O OH Sorghum forage (rotational 30 day) Wheat forage (rotational 120 day) Sorghum forage (rotational 365 day) Sorghum

stover (rotational 30 day) Wheat hay (rotational 120 day)

Wheat straw (rotational 120 day) Sorghum

stover (rotational 365 day) Sorghum grain (rotational 30 day) Wheat grain (rotational 120 day) Sorghum grain (rotational 365 day) 61 (0.047) Im

16 (0.005) Im

19 (0.10) Im

48 (0.21) Im

40 (0.35) Im

31 (0.027)Im 8.5 (0.023) Im

3.2 (0.001)Im

3.0 (0.001) Im 2.5 (<0.001) Im

IPSAacetylisoserine 2-acetoxy-3-(2-chloro-imidazo- [1,2-a]pyridine-3-sulfonylamino)-propionic
acid Sorghum forage (rotational 30 day) Sorghum forage (rotational 35 (0.093) Im

40 (0.012) Im

25 (0.14) ImImazosulfuron Human Health Risk Assessment DP No. 362653

Page 70 of 73 Table B.1: Tabular Summary of Metabolites and Degradates
Percent TRR (PPM) 1 Common Name Chemical Name/

Structure Matrix

Matrices – Major

Residue (> 10% TRR) Matrices- Minor Residue (<10% TRR)

N N

N H S O

O Cl

O O OH

O CH 3 365 day) Sorghum

stover (rotational 30 day) Sorghum

stover (rotational 365 day) Sorghum grain (rotational 30 day) Wheat grain (rotational 120 day) Sorghum grain (rotational 365 day) 33 (0.029) Im

1.0 (<0.001) Im

1.0 (<0.001) Im

1.0 (<0.001) Im

IPSAcaffeoylisoserine 3-(3,4-dihydroxy-phenyl)-acrylic acid 1-carboxy-2-(2-chloro-imidazo-[1,2-a]pyridine3-sulfonylamino)-ethyl ester

N N

N H S O

O Cl

O O OH

O OH

OH Sorghum forage (rotational 30 day) Sorghum forage (rotational 365 day) Wheat forage (rotational 120 day) Sorghum

stover (rotational 30 day) Wheat hay (rotational 120 day)

Wheat straw (rotational 120 day) Sorghum

stover (rotational 365 day) Sorghum grain (rotational 30 day) 17 (0.075) Im

12 (0.11) Im 7.8 (0.021) Im

4,2 (0.001) Im

6.7 (0.005) Im

6.5 (0.036) Im

4.4 (0.004) Im

6.5 (0.002) Im

2.1 (0.001) Im

1.0 (<0.001) ImImazosulfuron Human Health Risk Assessment DP No. 362653

Page 71 of 73 Table B.1: Tabular Summary of Metabolites and Degradates
Percent TRR (PPM) 1 Common Name Chemical Name/

Structure Matrix

Matrices – Major

Residue (> 10% TRR) Matrices- Minor Residue (<10% TRR)

Wheat grain (rotational 120 day) Sorghum grain (rotational 365 day)

SDPM 4,6-Dimethoxypyridine-2- yl)aminocarbonylsulfamic acid

O S O

O N

O N

N

O O N Water (photolysis) 14% of applied dose

Goat (MRID 47679115): 13 ppm in the diet for 5 days. PSI 23 hrs. Residues in milk appeared to reach a plateau by day 2. Milk results are day 5 PM.

Hen (MRID 47679116): 12 ppm in the diet for 7 days. PSI 22 hrs. Residues in eggs did not appear to achieve a plateau. Egg results are day 7 PM. (MRID 47679116).

Potato (MRID 47679119): 2 applications of a WG formulation at about 0.5 lb ai/acre/application, total application rate 1.1 lb ai/acre. The first application wa s preemergence after hilling; the second application was 64 days later at BBCH 44 (40% of final tuber mass). PHI 46 days. No use is proposed for potatoes, but seasonal rate for tomato, pepper, and rice is

0.3 lb ai/acre.

Rice (MRID 47679117): 2 applications of a WG formulation at ab out 0.2 lb ai/acre were made for a total application rate of 0.4 lb ai/acre. The first application wa s made at the 2-leaf stage; the second application was mad 56 days later to plants at the early boot stage. The proposed use for rice is 2 applications at 0.15 lb ai/acre with application up to the 2-inch internode stage of rice, which is before early boot stage, about BBCH 34 – 39

Tomato (MRID 47679118): 2 applications of a WG formulation. First application 0.5 lb ai/acre to soil 7 days before transplant of tomatoes. Second application 0.3 lb ai/acre 100 da ys later to plants with mature and immature fruits. Total rate was 0.8 lb ai/acre. PHI was 21 – 28 days. The proposed us e for tomato is one application at 0.3 lb ai/acre with a PHI of 21 days. The single application may be pre-transplant to the soil or postemergence “over the top.”
Confined Rotational (MRID 47679126). A WG formulation was applied to soil at a single rate of 0.88 lb ai/ha, or about 3X the maximum seasonal rate for proposed crop uses. PBI intervals ranged from 30 to 365 days.Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 72 of 73 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 to determine their dermal and inhalation exposure. Many such studies, involving exposure to ma ny different pesticides, compri se generic pesticide exposure

databases such as PHED and the Outdoor Reside ntial Exposure Task Force (ORETF). EPA has reviewed all the studies supporting these multi-pest icide generic exposure databases, and has found no clear and convincing evidence that the conduct of any of them wa s either fundamentally unethical or significantly deficient relative to the ethical standards prevailing at the time the research was conducted. All applicable requir ements of EPA’s Rule for the Protection of Hu man Subjects of Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued

reliance on these studies.Imazosulfuron Human Health Risk Assessment DP No. 362653

Page 73 of 73 

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