Imazosulfuron Human Health Risk Assessment DP No. 362653 

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

 OFFICE OF CHEMICAL SAFETY AND 

 POLLUTION PREVENTION 

 

MEMORANDUM

Date: November 3, 2010 

SUBJECT: Imazosulfuron: Human Health Risk Assessment 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 Division 
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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 Registration Division (RD) of 

OPP has requested that HED evaluate hazard and exposure data and conduct dietary, occupational, 

residential and aggregate exposure assessments, as needed, to estimate the risk to human health that 

will result from the proposed food use of imazosulfuron on tomatoes, peppers and rice. Risk was 

previously assessed for non-food use on turf and ornamentals, and has been incorporated into the 

aggregate risk assessment presented 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 imazosulfuron. 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 general 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/residential assessments), Cassi Walls (dietary 

assessment), Steve Funk (residue chemistry data review) and Sheila Healy (hazard evaluation and 

risk assessment). Faruque Khan, Senior Scientist, Environmental Risk Branch I (ERB1), 

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

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1.0 Executive Summary................................................................................................................ 5 

2.0 HED Recommendations ......................................................................................................... 7 

2.1 Data Deficiencies/Conditions of Registration................................................................... 8 

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

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

2.2.2 International Harmonization....................................................................................... 10 

2.2.3 Recommended Tolerances............................................................................................ 10 

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

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

2.3.1 Recommendations from Residue Reviews.................................................................. 10 

2.3.2 Recommendations from Occupational Assessment................................................... 11 

2.3.3 Recommendations from Residential Assessment....................................................... 11 

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

3.1 Structure and Nomenclature ........................................................................................... 11 

3.2 Physical/Chemical Characteristics.................................................................................. 12 

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

4.0 Hazard Characterization and Dose-Response Assessment............................................... 16 

4.1 Toxicology Studies Available for Analysis...................................................................... 16 

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME).................................. 16 

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

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

4.4 Safety Factor for Infants 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 Recommendation 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 Toxicity 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 Metabolic 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 Assessment................................................... 32 

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

5.4.4 Chronic Dietary Risk Assessment ............................................................................... 33 
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5.4.5 Cancer Dietary Risk Assessment................................................................................. 33 

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

6.0 Residential (Non-Occupational) 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 Characterization....................................................................... 39 

7.1 Acute Aggregate Risk ....................................................................................................... 39 

7.2 Short- and Intermediate-Term Aggregate Risk............................................................. 39 

7.3 Chronic Aggregate Risk ................................................................................................... 40 

7.4 Cancer Aggregate Risk..................................................................................................... 40 

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

9.0 Occupational Exposure/Risk Characterization ................................................................. 40 

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

9.2 Short- and Intermediate-Term Post-Application Risk.................................................. 43 

10.0 Incidents................................................................................................................................. 43 

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

12.0 References.............................................................................................................................. 44 

Appendix A. Toxicology Profile and Executive Summaries........................................................ 45 

A.1 Toxicology Data Requirements........................................................................................ 45 

A.2 Toxicity Profiles ................................................................................................................ 46 

A.3 Hazard Identification and Endpoint Selection............................................................... 50 

A.4 Executive Summaries........................................................................................................ 52 

A.5 Toxicology Data Required as a Condition of Registration............................................ 65 

Appendix B. Metabolism Summary Table .................................................................................... 65 

Appendix C. Review of Human Research...................................................................................... 72 
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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 conjunction with a pending registration on turf grass 

(residential, commercial, golf courses and sod farms), ornamentals and bare-ground non-crop areas. 

Imazosulfuron (V-10142) is to be formulated as a 75% ai water-dispersible granule (WG). This 

granular formulation is to be added to water, resulting in a dispersion of finely divided herbicide 

particles suspended in water to be applied for weed control. 

V-10142 may be applied to tomatoes and rice prior to crop planting (pre-emergent) and shortly 

following new crop plantings (post-emergent). Applications to peppers may only be made to well 

established peppers (at least 10 inches tall). Application timing may also vary depending on the 

target weed (pre-emergence or post-emergence weeds). However, only one application may be 

made per season for all three crops: tomatoes, peppers, and rice. The application rates range from 

0.2 lb ai/A to 0.3 lb ai/A for tomatoes, peppers, and 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 indicate 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 adverse eye effects were observed in rats fed > 1000 mg/kg beginning at 3 

months in the chronic toxicity/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 imazosulfuron 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 detected 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) methylation of the hydroxyl group, 4) opening of the 

pyrimidine ring and formation of guanidine and 5.) hydrolysis of the sulfonylurea bridge.

In a 21-day dermal toxicity study in rats, no localized dermal or systemic effects were seen at the 

limit dose of 1000 mg/kg/day, the dermal 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 rabbit 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 combined chronic toxicity and carcinogenicity study in 

rats, as well as the 18-month carcinogenicity study in mice, 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. 
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The oral LD50 of imazosulfuron is greater than 5000 mg/kg; the acute inhalation LD50 is greater than 

2 mg/L; and the acute dermal LD50 is greater than 2000 mg/kg. All acute studies are in Toxicity 

Category III or IV. Imazosulfuron is not irritating 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 assessment is conservative. 

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

Acute: An unrefined acute dietary risk analysis was conducted with the DEEM-FCIDTM model, 

assuming 100% crop treated (CT) and tolerance level residues, to form a conservative evaluation of 

exposure for imazosulfuron. At the 95th 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 calculated at <1% of the aPAD for the 

general population. For the subgroup with the highest calculated exposure, all infants (< 1 year old), 

acute aggregate dietary risk occupied 1.4% of the aPAD. 

Chronic: An unrefined chronic dietary risk analysis was conducted with the DEEM-FCIDTM model, 

assuming 100% CT and tolerance-level residues, 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 chronic aggregate 

dietary risk was calculated at <1% of the cPAD for the general U.S. population. For the subgroup 

with the highest calculated exposure, all infants, chronic aggregate dietary risk occupied 2.7% of the 

cPAD. 

Residential Exposure: No new residential uses and no occupational uses at residential sites are being 

requested in this petition; therefore, a new residential risk assessment was not conducted. Residential 

exposure risk was assessed for a pending registration for turf grass, ornamentals and bare-ground non-crop 

areas (DP#349707, Kelly O’Rourke, 02/17/2009) and is incorporated in this 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 dietary 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 dietary 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 potential short- and intermediate-term exposure to 

imazosulfuron via the dietary pathway (which is considered background exposure) and the 

residential pathway (which is considered the primary pathway). Since no dermal hazard was 

identified, the exposure pathways for adults include only the dietary and inhalation (residential 

handler) routes. For children, the exposure pathway includes the dietary exposure and the incidental 

oral post-application residential pathway. 
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All aggregate MOEs are greater than 100; therefore, aggregate exposure is not of risk concern. 

Occupational Exposure/Risk: 

Agricultural Handlers: Occupational short- (1 - 30 days) and intermediate-term (1 – 6 months) 

dermal and inhalation exposures are 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 maximum application rate (0.3 lb ai/A). There is no occupational cancer 

risk associated with imazosulfuron since it is classified 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-cancer dermal risks were not assessed for postapplication activities. Based on the Agency's current practices, a quantitative post-application 

inhalation exposure non-cancer assessment was not performed for imazosulfuron at this time. 

Environmental Justice Considerations: Potential areas of environmental justice concerns, to the 

extent possible, were considered in this human health risk assessment. Dietary and non-dietary 

exposures were considered. 

Review of Human Research: This risk assessment relies in part on data from studies in which 

adult human subjects were intentionally exposed to a pesticide or other chemical. These studies 

(listed in Appendix C) have been determined to require a review of their ethical 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 chemistry 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 table 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 ppm 
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Rice, grain...................................................................0.02 ppm 

Tomato ........................................................................0.02 ppm 

2.1 Data Deficiencies/Conditions of Registration 

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

 

RESIDUE CHEMISTRY

860.1200 Directions for Use

The label must be amended to add the following restriction for application to rice: Do not 

apply to rice fields if fields are used for the aquaculture 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 petitioner will need to remove the statement 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 that 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 without cleanup was not conducted or provide the 

results of testing 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). 
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860.1850 Confined Accumulation in Rotational Crops

The HPLC profile for the pyrimidinyl (Py)-label grain storage stability 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 wheat 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 dietary burdens of imazosulfuron to livestock, HED 

recommends that the requirements for ruminant 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 proposed in the future, feeding studies may be 

required. 

TOXICOLOGY

Based on the available toxicity database and the Agency's current practices, the inhalation 

risk for imazosulfuron was assessed using an oral toxicity study. The Agency sought expert 

advice and input on issues related to this route to route extrapolation approach (i.e. the use of 

oral toxicity studies for inhalation risk assessment) from its Federal Insecticide, Fungicide, 

and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency 

received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). 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 inhalation risk assessments, including route to 

route extrapolation of toxicity data. If any new policies or procedures are developed, the 

Agency may revisit the need for 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 method 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) 
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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 quantitation (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 following additional information: 1) the petitioner 

must explain why testing for imazosulfuron under Protocol D through the complete method without 

cleanup was not conducted or provide the results of testing without cleanup 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 (MRLs) 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 table 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 tolerance 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 restriction for application to rice: Do not apply to 

rice fields if fields are used for the aquaculture of edible fish and/or crustaceans. 
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Pending submission of field rotational 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 concerning the use of shorter 

intervals “where local experience has shown crop safety” to specify a minimum rotational interval of 

12 months for cereal grain crops. The remaining rotational crop restrictions 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 classified in Toxicity Category III for acute dermal 

and Toxicity Category IV for primary eye irritation and primary skin irritation. Per the WPS, a 12-

hr restricted entry interval (REI) is required for chemicals classified 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 proposed turf grass, ornamental and bare ground uses of the WDg 

formulation (EPA File symbol 59639-RLL) are recommended. No residential uses or occupational 

uses at residential sites are being requested in this petition. 

3.0 Ingredient Profile

Imazosulfuron is a sulfonylurea herbicide 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 imazosulfuron on peppers, rice and tomatoes in 

addition to the previously requested registration for use on turf, ornamentals, and bare ground. 

In conjunction with this petition, Valent has submitted an application for Section 3 registration of a 

new end-use product, a 75% water-dispersible granule (WG) formulation (V-10142 Ag Herbicide; 

EPA File Symbol 59639-RAA) for use on pepper, rice 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 foliar 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 Nomenclature 
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Table 3.1. Test Compound Nomenclature 

Chemical Structure 

N

N

N

N

N

H

N

H

S

O

O

Cl

O

CH3

O

CH3

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-pyrimidinyl)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 Reference1

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 KOW

(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, x104

acidic 238.5 0.8877 3.55 

 201.0 1.1653 4.66 

neutral 238.0 0.8293 3.32 

47305111 
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Table 3.2. Physical and Chemical Properties 

Parameter Value Reference1

 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. 
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Table 3.3. Summary of Directions 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 interval 
Imazosulfuron Human Health Risk Assessment DP No. 362653 

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Table 3.3. Summary of Directions 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 

Equipment1, 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 trees, non-bearing fruit and nut trees and 

landscape plants)a

Groundboom, 

Low-pressure 

Handheld 

Equipment1

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-Cropa 
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Table 3.3. Summary of Directions 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 ornamental 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 potential of imazosulfuron: 

• Acute: Acute oral toxicity 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 irritation, rabbit; acute dermal irritation, rabbit; dermal sensitization, 

guinea pig and acute neurotoxicity, rat.

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

neurotoxicity, rat.

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

rat.

• Reproduction/developmental: Developmental toxicity, rabbit; developmental 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, Metabolism, & Elimination (ADME) 

No differences in the excretion profile based on gender or radiolabel position were observed in a rat 

metabolism study. The majority of the dose was recovered in the urine (~66%) and a substantial 

amount was isolated in the feces (~33%). Almost all radioactivity isolated in the feces was absorbed 

and excreted in the bile. Thus, the test compound was nearly completely 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 the gastrointestinal contents, organs, tissues and 

residual carcass. Of this residual radioactivity, label was detected 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 tissues 
Imazosulfuron Human Health Risk Assessment DP No. 362653 

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were less than 0.020 μg equiv/g. These data indicate 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-ylsulfonyl)-3-(4-hydroxy-6-methoxypyrimidin-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 demethylation, hydroxylation of the 

pyrimidine ring, methylation or glucuronidation 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 identified. Furthermore, there are no concerns for 
Imazosulfuron Human Health Risk Assessment DP No. 362653 

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developmental or neurological toxicities. The lack of dermal and systemic toxicity may be 

attributable to poor dermal absorption. 

4.3 Toxicological Effects 

Imazosulfuron is a selective herbicide which inhibits the plant enzyme acetolactate synthase (ALS). 

ALS is required to synthesize the essential, branched-chain amino acids, valine, leucine and 

isoleucine. ALS inhibitors exhibit low mammalian toxicity, likely due to the fact that mammals lack 

acetolactate synthase. 

The toxicity database for imazosulfuron suggests that this herbicide possesses relatively low toxicity. 

Many of the effects of single or repeated dosing are observed near or beyond the respective limit 

doses. The primary target organ of imazosulfuron toxicity was the liver in all species tested. Mild to 

moderate thyroid effects were apparent only in the chronic toxicity study in dogs. Dramatic eye 

effects (retinal degeneration, lens vascularization, cataracts and corneal scarring) were observed in 

rats fed > 1000 mg/kg beginning at 3 months in the chronic toxicity/carcinogenicity study. Ocular 

effects, increased incidence of eye opacity, corneal edema, inflammation and neovascularization, 

were also observed in the high-dose males (4577 mg/kg/day) of the 90-day feeding 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 neurotoxicity 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 the study. No neurotoxic effects 

were observed during the subchronic screening battery or noted as clinical 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 rabbits, no developmental effects were observed at 

125 mg/kg/day (highest dose tested) 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 reproduction study at a dose approaching the limit dose (LOAEL = 892 

mg/kg/day) in both the F1 and F2 offspring generations. Mortality was also observed in the parental 

generation at this dose. No qualitative or quantitative offspring susceptibility was apparent in any of 

the submitted studies for imazosulfuron. 

Review of acceptable carcinogenicity and mutagenicity studies provides no indication that 

imazosulfuron is a carcinogen, mutagen or clastogen. 

Study summaries of the acute, subchronic and chronic toxicity 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. There is no evidence of 
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susceptibility following in utero and/or postnatal exposure in the developmental toxicity studies in 

rats or rabbits, or in the 2-generation rat reproduction 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 underestimate exposure/risk. Based on these data and 

conclusions, the FQPA Safety Factor can be reduced to 1X. 

4.4.1 Completeness of the Toxicology Database 

The toxicology database is complete 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 special series 870.7800 immunotoxicity study will 

result in a NOAEL less than 75 mg/kg/day, which 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 consumption effects are seen throughout the 

toxicology database. No treatment-related changes were seen in hematology parameters, 

organ weights (thymus, spleen), gross necropsy (enlarged lymph nodes)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 imazosulfuron is a neurotoxic chemical based 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 neurotoxic effects were observed during the subchronic neurotoxicity 

screen in which adverse effects of decreased body weight, body weight gain and food efficiency 

were observed at 575 mg/kg/day (LOAEL). The acute neurotoxicity 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 activity 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 ACN. 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 in 
Imazosulfuron Human Health Risk Assessment DP No. 362653 

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utero exposure in rabbits. Neither the rat nor rabbit 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 index were observed.in F1

pups of the 2-generation reproductive study in rats. Similarly, decreased live pups/dam and live 

births and viability and lactation indices were noted for F2 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 imazosulfuron in rice grain in the confined rotational 

crop trial and characterize field accumulation, there are no residual uncertainties in the exposure 

database because: 

Storage stability; The interim study showed stability in rice grain 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 analysis and the stability of imazosulfron in those 

commodities for the longer intervals must be demonstrated. Major instability 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 dietary intake risk. Evidence suggests that 

imazosulfuron is stable in/on frozen commodities 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 pesticides 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 stability studies from other sulfonylurea pesticides 

indicate a significant stability in various types of commodities. For example, halosulfuronmethyl shows no degradation for frozen storage intervals of 800 – 1000 days on corn grain, 

soybean seed, wheat grain, lettuce, and sugar beet roots, and rimsulfuron is stable in frozen 

cotton seed oil, orange, and sugarcane 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 completion 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 grain were small (<0.01 ppm at a 365 day plantback interval), 

imazosulfuron was not present, and no metabolites/degradates were considered 

toxicologically significant. 

Field accumulation: The grain (wheat) rotational crop study is needed 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 plantback interval of 12 months is being imposed 

for grains and soybeans. The results of the rotational crop study may allow a shorter 

plantback interval. The confined rotational crop study showed that imazosulfuron and 
Imazosulfuron Human Health Risk Assessment DP No. 362653 

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metabolites will be negligible (<0.01 ppm) on forage, 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 contain 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 chronic 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 reference dose for the general population 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 population subgroup was not identified; there was no 

pre- and/or postnatal toxicity observed in developmental 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 hazard was identified. Intermediate- and short-term 

inhalation and incidental oral endpoints were based on two co-critical subchronic rat studies in 

which decreased body weight, body weight gain 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 (LD50 > 2000 mg/kg, HDT) where the Toxicity Category is III. 

For acute dietary exposure, an acute dose (aRfD) of 4 mg/kg/day was selected for assessment of all 

populations based on a NOAEL of 400 mg/kg/day in the rat acute neurotoxicity study. The LOAEL 

of 2000 mg/kg/day was based on decreased motor activity, piloerection and upward curvature of the 

spine observed in both sexes and decreased motor 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 chronic dietary study in dogs. This study provides the most sensitive 

endpoints point of departure for risk assessment; 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 involving incidental oral 

and inhalation exposure, the NOAEL of 235 mg/kg/day was selected from the rat subchronic toxicity 
Imazosulfuron Human Health Risk Assessment DP No. 362653 

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study. This study was co-critical with the 2-generation reproductive toxicity study in rats and 

provided the best estimate of the NOAEL. Similar effects on body weight were seen at the LOAEL 

of 892 mg/kg/day in the 2-generation 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; therefore, no endpoints were 

selected 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment 

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

are the same. Effects of decreased body weight, body weight gain and food consumption were 

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

oral and short-term/intermediate-term inhalation exposure for risk assessment; therefore, these routes 

of exposure can be combined to estimate aggregate risk. Since no hazard was identified in the 

dermal toxicity study and there are no concerns for developmental neurotoxicity, the dermal route of 

exposure need not be included in aggregate risk estimates. 

4.5.3 Cancer Classification and Risk Assessment Recommendation 

Two adequate rodent carcinogenicity studies were 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 determined 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 classification is “not likely 

to be carcinogenic to humans,” based on the absence of significant tumor increases and therefore, 

there is no concern for cancer risk to humans. 

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

Assessment 

Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for 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 
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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 Effects 

Acute Dietary 

(General 

Population, 

including 

Infants and 

Children) 

NOAEL= 

400 

mg/kg/day 

UFA= 10X 

UFH= 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 spine; 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 females age 13-49 because there 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 

UFA= 10X 

UFH= 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 on 

moderate 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) 

UFA= 10X 

UFH= 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 occurred at the limit dose and the primary toxic effects of concern (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) 

UFA= 10X 

UFH= 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). 
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Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = 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 occurred at the limit dose and the primary toxic effects of concern (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) 

UFA=10X 

UFH=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 point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = 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 substances (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 effects 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 any, 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 substance, and establish a dose-response relationship 

between the dose and the E, A, or T effect. 
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Between October 2009 and February 2010, EPA is issuing test orders/data call-ins for the first group 

of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. This list of 

chemicals was selected based on the potential for 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 known or likely endocrine disruptors. 

Imazosulfuron is not among the group of 58 pesticide active ingredients on the initial list to be 

screened under the EDSP. Under FFDCA Sec. 408(p), the Agency must screen all pesticide 

chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all 

pesticide active ingredients. 

For further information on the status of the EDSP, the policies and procedures, the list of 67 

chemicals, the test guidelines and the Tier 1 screening battery, please 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, and 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-imidazo[1,2-a]pyridine-3-sulfonic acid amide, UDPM, 

or (4,6-dimethoxy-pyrimidin-2-yl)-urea, and ADPM, or 4,6-dimethoxy-pyrimidin-2-ylamine. In 

addition, O-demethylation of the pyrimidine ring yields the only identified double-ring metabolite, 

HMS. See Appendix B, Table B.1 for chemical names and structures of metabolites. Imazosulfuron 

and UDPM were the major residues in rice grain, rice straw, and tomato, but were minor residues in 

potato tuber, where total radioactive residues (TRR) were significantly lower overall. UDPM was 

generally only a fraction of the imazosulfuron concentration, with the exception of tomato fruit. 

HED has determined that the residue of concern 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 demonstrate that metabolism of imazosulfuron is similar in 

ruminants and poultry, and that hydrolysis of the sulfonylurea linkage is the major metabolic 

process. Imazosulfuron was a major residue in ruminant milk and tissues, except fat, and in poultry 

eggs and tissues. An imidazolyl-ring metabolite, 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 identified as a minor metabolite in eggs only, and the 

double-ring metabolite HMS was identified in ruminant milk and kidney and in poultry liver at 

<10% TRR. HED has determined that the residue of concern in livestock commodities for tolerance 
Imazosulfuron Human Health Risk Assessment DP No. 362653 

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enforcement is imazosulfuron. The residue of concern for risk assessment is the sum of 

imazosulfuron and IPSN, expressed as stochiometric equivalents of imazosulfuron. 

A tentatively acceptable confined rotational crop 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 routes 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; however, 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 were identified in rotational sorghum and wheat matrices (except 

grain) that were not identified 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 environments (half-lives 

of 36.5 days and 17 days, respectively). It also degrades 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 environment (pH 4.0) but is stable at neutral and alkaline 

conditions (pH 7-9). Under the field conditions in the soil, the calculated half-life values of 

imazosulfuron are 9.5 days for first application 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 compound’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 been 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 aquatic 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 applied radioactivity. 

5.1.3 Comparison of Metabolic Pathways 

Based on identified metabolites, the proposed mammalian metabolic pathways for imazosulfuron 

are: 1) demethylation, 2) hydroxylation of the pyrimidine 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 environmental degradates, products of aerobic soil 

metabolism. The pyrimidines, ADPM, UDPM and SDPM are products of hydrolysis (ADPM only) 

and aqueous photolysis. 
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Hydrolysis of the sulfonylurea linkage is the major metabolic process 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, and 17% TRR) and UDPM (18, 13, and 30% TRR) 

were detected in rice grain, rice straw, and tomato, respectively, during plant metabolism studies. 

UDPM concentration was usually substantially less than the imazosulfuron concentration, and was 

absent (< 1%) in the potato tuber. The petitioner suggested imazosulfuron as the residue for 

tolerance enforcement. Imazosulfuron and UDPM were not detected in field trials 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 and 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 international practice (Codex) of 

establishing as simple a residue definition as practical. The latter is particularly pertinent in 

situations where no quantifiable residues are anticipated. 

In confined rotational studies conducted 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 ppm in rotational kale and radish root at a 144 

day PBI, but significant TRRs were found in rotational 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 conjugates were present at significant amounts (0.03-

0.12 ppm extrapolated to 1X) in small grain hay and straw and matrices (but not in grain). However, 

the Residues of Concern Knowledgebase Subcommittee (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 increased solubility). Therefore, rotational crop tolerances and 

residues of concern are not applicable, but the issue may be revisited upon review of the wheat 

rotational crop field trials currently being conducted. 
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Ruminant and Poultry: In livestock metabolism studies, imazosulfuron 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 eggs. Although measurable quantities of residues in feed and 

livestock commodities are not likely from the current proposed uses, ROCKS recommends that 

imazosulfuron be measured for tolerance enforcement 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 imazosulfuron 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 degradate that retains both imidazole (IM) and 

pyrimidine (Py) ring structures. HMS has been detected in aquatic photolysis, aerobic soil 

metabolism and anaerobic aquatic metabolism studies. 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 respectively. Imazosulfuron is characterized as being 

mobile to moderately mobile in the test soils. SDPM, IHOA and HMS are categorized as highly 

mobile in most soils. ADPM and IPSN are categorized as mobile. Note that IHOA, UDPM, and 

SDPM are expected to be major residues in drinking 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 likely comparable to the parent. Structure-activity relationship (SAR) 

analysis (Deductive Estimation of Risk based on Existing Knowledge or DEREK) revealed the same 

structural alerts as for the parent compound; therefore, HMS is considered a residue of concern. 

DEREK analysis of IPSN, IHOA, ADPM, SDPM, and UDPM showed that all of these cleavage 

products except IHOA (a low molecular 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 hazard 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 tolerance expression for plant and livestock 

commodities: 

Tolerances are established for residues of the herbicide imazosulfuron, 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-pyrimidinyl)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 tomato are tentatively considered to be adequate, 

pending submission of supporting storage stability data for each crop. The studies reflected the 

proposed use patterns for peppers, rice, and tomatoes, and the number and location of field trials are 
Imazosulfuron Human Health Risk Assessment DP No. 362653 

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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 application (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 tolerances 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 

Crop matrix Total Applic. Imazosulfuron Residue Levels (ppm) 

Rate 

 (lb ai/A) 

PHI 

(days) n Min. Max. HAFT1 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 total 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 purposes 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 corresponding crop field trials: 1.7x 

for rice and 3x for tomato. OPPTS 860.1520 recommends 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 additional data are required because residues were 

non-detectable in/on all RAC and processed commodity 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 occur in rice grain. Samples were analyzed for residues of 

imazosulfuron and UDPM using an acceptable method. 
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The processing data indicate that residues of imazosulfuron and UDPM do not concentrate in rice 

hulls, bran, or polished rice or in tomato puree or paste; therefore, tolerances are not required for the 

processed commodities of rice or tomato. 

Storage Stability 

In conjunction with the associated field trials, the registrant has submitted the interim results of 

storage stability studies with imazosulfuron 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 frozen (-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 samples were also analyzed at each interval. No details 

were provided concerning the preparation of samples or fortification solutions for the study. The 

petitioner has indicated that the final results of the storage stability study will be submitted at a later 

date. The interim results indicate that under frozen storage conditions, residues of imazosulfuron 

and UDPM are relatively stable in/on 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 days (7.4 months), and tomato paste for up to 1.4 

months. 

Additional storage stability data are 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 residue over extended periods, but this needs to be verified. Also, 

sulfonylurea herbicides have been shown 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 the 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 whether finite residues will be incurred, but there is no 

reasonable expectation of finite residues from the calculation of dietary burden 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. HED does not consider the low levels of IPSAconjugates at the 365-day PBI toxicologically significant, but will reassess the situation at the 

various plantback intervals based on the wheat rotational crop study. 

The field rotational crop study is necessary to provide confirmatory information on the levels of 

imazosulfuron metabolites in follow-on crops of grain, forage, and fodder. The confined study with 
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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 intervals in grain commodities. Much of this was 

related to feed commodities and not human food items. However, total residue in grain was as much 

as 0.04 ppm. This level is low and exaggerated (3X) and will most likely be lower in the pending 

field rotational crop study. HED concluded that rotational crop residues will make a negligible 

contribution to the human dietary exposure, 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 hardwired to represent the Index Reservoir, a standard water body used by 

OPP to assess drinking water exposure (Office of Pesticide 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 maximum of 8% of the applied pesticide into the 

reservoir. This amount can be reduced due to degradation 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 default 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 potentially used for drinking water following application to rice. The 

model calculates exposure as a function 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 processes, such as degradation, volatilization, and 

potential dilution with uncontaminated water outside 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 may 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 regressing the results of Prospective Ground Water 

studies against the Relative Index of Leaching Potential (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 Water 
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Assessment for the Section 3 Proposed 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 chronic surface water EDWC of 278.9 μg/L for use in 

the human health risk assessment. These recommendations are based on the use of imazosulfuron on 

rice at an annual application rate of 0.3 lb a.i./A/year. The recommended 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 drinking 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 Usesc

Drinking Water Source Models Use rate (lbs 

ai/A/year) Acute (μg/L) Chronic (μg/L) 

RICE 0.3 278.9.0d

 278.9d.0 

1.34b 101.25d 33.27d

Surface water 

FIRST 

0.3c

 23.47d 7.71d

Ground water SCI-GROW 1.34b 4.8d 4.8d

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 for dietary risk assessment purposes is the sum of 

imazosulfuron and its metabolite, UDPM, expressed as equivalents of imazosulfuron. DEEMFCIDTM Version 7.81 default processing factors were assumed for the requested crop uses. The 

highest estimated drinking water concentration (EDWC) for imazosulfuron resulted from the Tier I 

RICE model. This recommended EDWC of 278.9 μg/L used in the acute and chronic assessment is 

based on aerial spray application of 0.3 lbs. a.i./A per year for rice. 

5.4.2 Percent Crop Treated Used in Dietary Assessment 

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

5.4.3 Acute Dietary Risk Assessment 

An unrefined acute dietary risk analysis was conducted with the DEEM-FCIDTM model to form a 

conservative evaluation of exposure for imazosulfuron. At the 95th 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 acute aggregate dietary risk was calculated at 

<1% of the aPAD with an exposure level of 0.015 mg/kg/day for the general U.S. population. For 

the subgroup with the highest calculated exposure, all infants (<1 year old), acute aggregate dietary 

risk occupied 1.4% of the aPAD with an exposure of 0.06 mg/kg/day. For the general U.S. 
Imazosulfuron Human Health Risk Assessment DP No. 362653 

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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 summarizing the results of the acute dietary assessments with the 

population subgroup having the highest exposure noted 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 the 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. Population subgroup chronic aggregate dietary risk was calculated at 

<1% of the cPAD with an exposure level of 0.0060 mg/kg/day for the general U.S. population. For 

the subgroup with the highest calculated 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 summarizing the results of the chronic dietary assessment with the 

population subgroup having the highest exposure noted 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 assessment 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 (95th 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 <1 
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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. 
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6.0 Residential (Non-Occupational) Exposure/Risk Characterization

A proposal for V-10142 for application to residential turf grass and recreational sites has been 

submitted and assessed in the memo Imazosulfuron. Occupational and Residential Risk Assessment 

for Proposed Uses of Imazosulfuron on Residential Turf, Ornamentals and Bare Ground Non-Crop 

Areas. DP#349707, Kelly O’Rourke, 02/17/2009. The results 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, residential handlers may receive short-term dermal and inhalation exposure to 

imazosulfuron when mixing, loading and applying the formulation. Residential post-application 

exposure via the inhalation route is expected to be negligible; however, dermal exposure is likely for 

adults and children entering treated lawns. Toddlers may also experience exposure via incidental 

non-dietary ingestion (i.e., hand-to-mouth, object-to-mouth and soil ingestion) during postapplication activities on treated turf. 

Dermal endpoints were not selected for imazosulfuron because no systemic toxicity was observed at 

the limit dose in the dermal study. Short-term inhalation and incidental oral exposures were assessed 

using the same NOAEL (235 mg/kg/day) that was selected for occupational 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 Residential Exposure Assessments, and 

Recommended Revisions (HED Policy Number 11, revised 22 Feb 2001), were used as the basis for 

the residential handler exposure calculations. Data 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/applying water dispersible granules (also called dry 

flowable) for the residential scenarios. The unit exposure data for liquid formulation are considered 

to be an adequate/protective surrogate. As shown in Table 6.1, the inhalation MOEs for residential 

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

Table 6.1. Handler Exposure and Risk Estimates for Residential Lawn Applicators
Imazosulfuron Human Health Risk Assessment DP No. 362653 

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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 ft2

) 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 handwand 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 * Application 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 incorporated in this assessment. 

Turf transferrable residue (TTR) studies were submitted by the registrant (MRIDs: 47305124 and 

47305125) for use in assessing post-application 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 assumptions for the initial fraction of residue 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 residential 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 calculations and the results are presented in Tables 

6.2a through 6.2c. 

The exposure estimates are based on some upper-percentile (i.e., maximum application rate, initial 

amount of transferrable residue and duration of exposure) 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 regarding transfer of chemical residues and hand-to 

mouth activity. The estimated exposures are believed to be reasonable high-end estimates based on 

observations from chemical-specific field studies and professional judgment. 

The short-term MOEs for each scenario are greater 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 Assessment DP No. 362653 

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Table 6.2a. Post-application Oral Hand-to-Mouth Exposure and Risk for Children from Treated Lawns

Application 

Rate 

(lb ai/A) 

Postapplication 

day (t) 

Fraction of ai 

Transferrable 

from the 

Foliage 

Turf 

Transferrable 

Residue 1

(μg/cm2) 

Hand 

Surface 

Area 

(cm2/event) 

Saliva 

Extraction 

Factor 

Frequency 

(events/ hr) 

Body 

Weight 

(kg) 

Daily Dose2

(mg/kg/day) 

0.75 0 0.05 0.42 20 50% 20 15 0.011 

1 Turf Transferrable Residue Post-application day (μg/cm2) = Application rate (lb ai/A) x Fraction of a.i. Transferrable from the Foliage x (1- F

Residue That Dissipates Daily, 0.1) Post-application day x 4.54E+8 μg/lb x 2.47E-8 A/cm2

2 Daily Dose = (Turf Transferrable Residue (μg/cm2) x Hand Surface Area (cm2/event) x Saliva Extraction factor x Frequency (events/h

μg x Exposure time (2 hrs/day)] / [Body Weight (kg)] 

3 Oral 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 Lawns

Application Rate 

(lb ai/A) 

Postapplication day 

(t) 

Fraction of ai 

Transferrable 

from the Foliage 

Grass/Object 

Residue 1

(μg/cm2) 

Ingestion Rate 

(cm2/day) 

Body 

Weight 

(kg) 

Daily Dose2

(mg/kg/day) 

0.75 0 0.2 1.7 25 15 0.0028 

1Grass/Object residue Post-application day (μg/cm2) = Application rate (lb ai/A) x Fraction of a.i. Transferrable from the Foliage x (1- Fraction 

That Dissipates Daily) Post-application day x 4.54E+8 μg/lb x 2.47E-8 A/cm2

2 Daily 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 Lawns

Application Rate 

(lb ai/A) 

Fraction of ai 

Retained in the 

Soil 

Soil 

Residue 1

(μg/g) 

Ingestion Rate 

(mg/day) 

Body 

Weight 

(kg) 

Daily Dose2

(mg/kg/day) 

Short-term 

Oral 

MOE3

0.75 1 5.6 100 15 0.000038 6,300,000 

1 Soil residue Post-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 A2 Daily Dose = [Soil reside (μg/g) x Ingestion rate (mg/day) x 0.000001 g/μg] / [Body Weight (kg)]] 3 Oral MOE = Oral NOAEL/Daily Dose; where Short-term NOAEL = 235 mg/kg/day. 
Imazosulfuron Human Health Risk Assessment DP No. 362653 

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Table 6.2d. Children’s Aggregate Exposure and Risk Estimates from Residential Lawns 

Children’s Scenarios 

TTR/GR/SR0

(ug/cm2 or g) 1

PDR0-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"; SR0=soil residue on day “0". 2

 PDR0norm=potential dose rate on day “0”. 3 MOE = NOAEL/PDR; where Short-term NOAEL = 235 mg/kg/day.

4

 Total MOE = 1/ [(1/MOEHand-to-Mouth) + (1/MOEGrass) + (1/MOESoil)] 

Residential Bystander Post-Application Inhalation Exposure: 

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for imazosulfuron at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category 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, which does not include the use of air 

blast resulting in lower post-application inhalation exposures. However, volatilization of pesticides 

may be a source of post-application inhalation exposure to individuals nearby pesticide applications. 

The Agency sought expert advice and input on issues related to volatilization of pesticides from its 

Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 

2009, and received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report and may, as appropriate, develop policies and procedures to 

identify the need for and, subsequently, the way to incorporate post-application inhalation exposure 

into the Agency's risk assessments. If new policies or procedures are developed, the Agency may 

revisit the need for a quantitative post-application inhalation exposure assessment for imazosulfuron. 
Imazosulfuron Human Health Risk Assessment DP No. 362653 

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6.3 Spray DriftSpray drift is always a potential source of exposure to residents nearby to 

spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could 

also be a potential source of exposure from 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 regulation and other parties to develop the best spray 

drift management practices. The Agency is now requiring interim mitigation measures for aerial 

applications that must be placed on product labels/labeling. The Agency has completed its 

evaluation of the new data base submitted by the Spray Drift Task Force, a membership of U.S. 

pesticide registrants, and is developing a policy on how to appropriately apply the data and the 

AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast, and 

ground hydraulic methods. After the policy is in place, the Agency may impose further refinements 

in spray drift management practices to reduce off-target drift and risks associated with aerial as well 

as other application types where appropriate. Note that imazosulfuron 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 food and drinking water. There is 

also a concurrent application for residential use for which there is potential for exposure from 

residential use sites (DP#349707). Since hazard was identified via the oral route over both the acute 

and chronic duration, and via inhalation for a short-term duration, the adult aggregate risk 

assessment considers exposures from food and drinking water and residential handler inhalation 

exposure while the child aggregate includes dietary and post-application 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 dietary exposure (food and drinking water) in detail. 

The dietary route (food and drinking water) alone is relevant for acute exposure and risk assessment; 

and the acute dietary exposure and risk assessment conducted for imazosulfuron is screening-level, 

wherein the assessment assigns tolerance level residue values to all food commodities proposed to be 

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

concerns were identified. 

7.2 Short- and Intermediate-Term Aggregate Risk 

Table 7.2. Short-Term Aggregate Risk Calculations 

Short- or Intermediate-Term Scenario 

Population LOC for 

Aggregate 

Risk1

MOE dietary 

(food + drinking 

water)2

MOE 

incidental 

oral3

MOE 

dermal4

MOE 

inhalation5

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 40,000 
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Table 7.2. Short-Term Aggregate Risk Calculations 

Short- or Intermediate-Term Scenario 

Population LOC for 

Aggregate 

Risk1

MOE dietary 

(food + drinking 

water)2

MOE 

incidental 

oral3

MOE 

dermal4

MOE 

inhalation5

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 (UFA and UFH, respectively) totaling 100. 2

 MOE food = NOAEL/chronic dietary exposure: Where short- 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 dietary exposure (food and drinking water) in detail. 

The dietary route alone is relevant for long-term/chronic exposure and risk assessment; and the 

chronic dietary exposure and risk assessment conducted 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 all 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 adequate rodent carcinogenicity 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 followed 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 imazosulfuron does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA 

has not assumed that imazosulfuron has a common mechanism of toxicity with other substances. For 

information regarding EPA’s efforts to determine which chemicals have a common mechanism of 

toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released 

by EPA’s Office of Pesticide Programs concerning common mechanism determinations and 

procedures for cumulating effects from substances found to have a common mechanism on EPA’s 

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

9.0 Occupational Exposure/Risk Characterization

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

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Imazosulfuron may be applied using ground or aerial equipment. The application methods, 

maximum application rates, and use sites are summarized in Table 9.1.1. There is potential for 

exposure to imazosulfuron during mixing, loading, and applying activities. Handler exposure is 

expected to be short- or intermediate-term based on information provided on the proposed label. 

The quantitative exposure and risk assessment developed 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 factors that are applied to the assessment. HED 

applies a 10X factor to account for inter-species extrapolation and a 10X factor to account for intraspecies sensitivity. The total uncertainty factor that has been applied to the non-cancer risk 

assessment for imazosulfuron is 100X for occupational exposure. Occupational exposure and risk 

resulting in MOEs greater than or equal to 100 are not of concern to HED. 

Short- and intermediate-term dermal toxicity endpoints 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 based on a two-generation 

reproduction study and a co-critical 90-day oral toxicity study in rats. The MOEs range from 59,000 

(mixing/loading to support aerial application) to 930,000 (applying 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 

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Summaries of the inhalation risk estimates for occupational handlers are included in Table 9.1.2. 

The maximum application rate for each exposure scenario is presented as the worst case scenario. 

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

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

Exposure Scenario Crop or Target 

App 

Ratea

(lb 

ai/A) 

Acres 

Treated 

Dailyb

Baseline 

Inhalation 

Unit 

Exposurec

(mg/lb ai) 

Short- and 

IntermediateTerm Dose 

(mg/kg/day) 

Inhalationd

Short- and 

IntermediateTerm MOE 

Inhalatione

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 application rate (lb ai/acre) x acres 

treated / body weight (70 kg). 

e Short- and Intermediate-Term Inhalation MOE = NOAEL (235 mg/kg/day) / inhalation daily dose (mg/kg/day). LOC = 100
Imazosulfuron Human Health Risk Assessment DP No. 362653 

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9.2 Short- and Intermediate-Term Post-Application Risk 

Based on the Agency's current practices, a quantitative occupational post-application inhalation 

exposure assessment was not performed for imazosulfuron at this time primarily because of the low 

acute inhalation toxicity (Toxicity Category 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, which does not include the use of air 

blast resulting in lower post-application inhalation exposures. However, there are multiple potential 

sources of post-application inhalation exposure to individuals performing post-application activities 

in previously treated fields. These potential sources include volatilization of pesticides and 

resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice 

and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and 

Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final 

report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). 

The Agency is in the process of evaluating the SAP report as well as available 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 inhalation exposure into the Agency's risk assessments. If new 

policies or procedures are put into place, the Agency may revisit the need for a quantitative 

occupational post-application inhalation exposure assessment for imazosulfuron. 

10.0 Incidents 

No information is available from use in the United States. This is the first food-use registration in 

the USA. 

11.0 Environmental Justice Considerations

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to 

Address Environmental Justice in Minority Populations and Low-Income Populations," 

http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf). 

As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups 

according to well-established procedures. In line with OPP policy, HED estimates risks to 

population subgroups from pesticide exposures that are based on patterns of that subgroup’s food 

and water consumption, and activities in and around the home that involve pesticide use in a 

residential setting. Extensive data on food consumption patterns are compiled by the USDA under 

the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk 

assessments for all registered food uses of a pesticide. These data are analyzed and categorized by 

subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, 

OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments 

are performed when conditions or circumstances warrant. Whenever appropriate, non-dietary 

exposures based on home use of pesticide products and associated risks for adult applicators and for 

toddlers, youths, and adults entering or playing on treated areas post-application are evaluated. 

Further considerations are currently in development as OPP has committed resources and expertise 
Imazosulfuron Human Health Risk Assessment DP No. 362653 

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to the development of specialized software and models that consider exposure to bystanders and 

farm workers as well as lifestyle and traditional 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 Section 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 Assessments for the New Uses on Peppers, Rice, and 

Tomato. 
Imazosulfuron Human Health Risk Assessment DP No. 362653 

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Appendix A. Toxicology Profile 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. 

Table A.1. Toxicology Data Requirements Technical

Required Submitted

870.1100 Acute Oral Toxicity....................................................... 

870.1200 Acute Dermal Toxicity .................................................. 

870.1300 Acute Inhalation Toxicity.............................................. 

870.2400 Primary Eye Irritation.................................................... 

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

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

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

870.3100 Oral Subchronic (rodent) ............................................... 

870.3150 Oral Subchronic (non-rodent)........................................ 

870.3200 21-Day Dermal .............................................................. 

870.3250 90-Day Dermal .............................................................. 

870.3465 90-Day Inhalation.......................................................... 

yes 

yes 

yes 

no 

no 

yes 

yes 

yes 

no 

no 

870.3700a Developmental Toxicity (rodent)................................... 

870.3700b Developmental Toxicity (non-rodent) ........................... 

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

yes 

yes 

yes 

yes 

yes 

yes 

870.4100a Chronic Toxicity (rodent) .............................................. 

870.4100b Chronic Toxicity (non-rodent)....................................... 

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

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

870.4300 Chronic/Oncogenicity (rat)............................................ 

n/a 

yes 

n/a 

yes 

yes 

- 

yes 

- 

yes 

yes 

870.5100 Mutagenicity—Gene Mutation - bacterial..................... 

870.5300 Mutagenicity—Gene Mutation - mammalian................ 

870.5375 Mutagenicity—Structural Chromosomal Aberrations... 

870.5395 Mutagenicity—Other Genotoxic Effects....................... 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

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

870.6100b 90-Day Neurotoxicity (hen)........................................... 

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

870.6200b 90-Day Neuro. Screening Battery (rat).......................... 

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

no 

no 

yes 

yes 

no 

no 

no 

yes 

yes 

no 

870.7485 General Metabolism ...................................................... 

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

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

no 

no 

yes 

yes 

no 

no 
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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 LD50 > 5000 mg/kg IV 

870.1200 Acute dermal – rat 47305227 LD50 > 2000 mg/kg III 

870.1300 Acute inhalation – rat 47305228 LC50 > 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 LD50 > 5000 

mg/kg 

IV 

870.1100 UDPM 47305223 LD50 = 677 mg/kg III 

870.1100 IPSN 47305224 LD50 = 415 

mg/kg, males; 445 

mg/kg, females 

II 

870.1100 M-1 47305225 LD50 > 5000 

mg/kg 

IV 

870.1100 ADPM 47305226 LD50 = 836 mg/kg III 
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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/day 

Acceptable/NonGuideline* 

*tested under FIFRA 

Subdivision F guidelines 

Maternal NOAEL = 125 mg/kg/day; 

LOAEL > 125 mg/kg/day 

Developmental NOAEL = 125 mg/kg/day; 

LOAEL > 125 mg/kg/day 
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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; 

MF0: 0, 7.7, 77.8, 777.4 

mg/kg/day; 

FF0: 0, 8.93, 88.4, 868.5 

mg/kg/day; 

MF1: 0, 9.0, 89.4, 1006.5 

mg/kg/day; 

FF1: 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 moderate 

thyroid 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 conditions 
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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 females 
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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 metabolites 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 ACIS 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 toxicology database. 

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

Study Selected: Acute Neurotoxicity (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-fold) dose spread between the NOAEL 

and LOAEL. While some individual effects may be equivocal, the suite and prevalence of 

treatment-related effects observed at the limit dose is robust. Decreased motor activity (↓38%) is 

seen on the day of exposure only. No other acute effects (neurotoxic or otherwise) were seen in the 

database. 

A.3.3 Chronic Reference Dose (cRfD) 

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

MRID: 47305305 
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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. Increased liver weight coincident with increased serum alkaline 

phosphatase and cholesterol was also observed but considered an adaptive rather than adverse effect. 

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

Co-Critical Study Selected: Reproduction and Fertility Effects (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; LOAEL = 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 subchronic toxicity study in rats 

(MRID 47305232; NOAEL/LOAEL = 235/956 mg/kg/day) serve as co-critical studies since similar 

effects were seen in both rat studies. The points of departure 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 artifact 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 intermediate- 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 animals (LOAEL = 892 mg/kg/day). 

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

Study Selected: 21/28 Day Dermal Toxicity (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 limit dose, 1000 mg/kg/day). No compound related 

effects were observed in mortality, clinical signs of toxicity, limited FOB, body weight, food 

consumption, ophthalmoscopic exams, hematology, clinical chemistry, organ weights or gross or 

microscopic pathology in either gender. No hazard was identified and therefore, no dermal endpoint 

was selected for quantitative risk assessment for imazosulfuron. 

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

Co-Critical Study Selected: Reproduction and Fertility Effects (2 generation, rat; OPPTS 

870.3800)

MRID: 47305304

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

MRID: 47305232
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Dose and Endpoint for Risk Assessment: NOAEL = 235 mg/kg/day; LOAEL = 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 subchronic toxicity study in rats 

(MRID 47305232; NOAEL/LOAEL = 235/956 mg/kg/day) serve as co-critical studies since similar 

effects were seen in both rat studies. The points of departure 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 artifact 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 intermediate- term time period. 

Two studies were considered co-critical in selecting the endpoint for short- and intermediate-term 

inhalation exposure. The multigenerational reproduction study (MRID 47305304, also selected for 

incidental oral exposure for pup effects) was selected based on decreased body weights, body weight 

gains and food consumption in the parental generation. Additionally, the 90-day 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 females for 6 weeks during the treatment period (↓7-11%). 

Decreased (p≤0.05) overall (Weeks 0-13) body weight gains were also noted in both sexes (↓ 16-

19%). Food efficiency was decreased (not statistically 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, chromodacryorrhea, and/or anogenital staining. 

Emaciation and poor hair coat was noted in 1-2 females. 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 increased in the males from Week 7 until termination 
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and in the females during 4 weeks of treatment. The average weekly food consumption during 

treatment was increased in both sexes. Food efficiency was generally decreased throughout 

treatment, and occasionally these decreases were statistically significant. 

In the 45,000 ppm males, an increased incidence of eye opacity was observed grossly, and increased 

incidences in eye corneal edema, acute/subacute inflammation, and neovascularization were 

observed microscopically. 

Although the liver was affected in the 45,000 ppm group, the findings suggest an adaptive effect and 

that the liver was not adversely affected. Relative to body liver weights were increased in the both 

sexes, and minimal to slight centrilobular hepatocyte 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 and females; and (iii) increased total bilirubin in 

males. These changes equivocally indicate an effect on the liver, but the magnitude 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 food efficiency in both sexes. The NOAEL is 

2500 ppm (equivalent to 235/266 mg/kg/day in males/females).

 870.3100 90-Day Oral Toxicity – Mouse 

In a subchronic oral toxicity study (MRID 47305233), TH-913 (Imazosulfuron; 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 consumption, food efficiency, ophthalmoscopy, clinical 

chemistry, or gross pathology. 

At 45,000 ppm, absolute, relative (to body weight), and relative (to brain 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, these increases were statistically significant (p<0.05). 

Microscopically, centrilobular hepatocyte hypertrophy was observed in all males and females at this 

dose, with a severity of slight to moderate in the males (mean severity score = 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), hemorrhage (2/10 treated vs 0/10 controls), and 

acute/subacute inflammation (5/10 treated vs 1/10 controls) 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 observed 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 hypertrophy noted at these 

doses were not corroborated by increased organ weights or other microscopic findings. Thus, at 
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these dose levels, these findings were considered to be an adaptive response 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 hepatocellular hypertrophy in both sexes. The 

NOAEL is 10,000 ppm (equivalent to 1820/2727 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 study in non-rodents is required under 40 CFR 158.340 and 40 CFR 

158.500 (effective December 26, 2007). The requirement for a chronic toxicity study on nonrodents has been eliminated under 40 CFR158.500 because “extending a dog study beyond a 13-

week duration does not provide additional essential toxicity information; eliminating the 1-year dog 

study does not compromise the data needed for the determination of chronic 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 the exception of a 90-day oral toxicity study in 

non-rodents (dogs). A chronic toxicity 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 neurological or gene toxicities were observed under the 

experimental conditions described. Imazosulfuron/TH-913 is not apparently carcinogenic. 

While evidence of liver and thyroid toxicity and some hematological and biochemical 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 Oral 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 toxicity, limited FOB, 

body weight, food consumption, ophthalmoscopic exams, hematology, clinical chemistry, organ 

weights or gross or microscopic pathology in either gender. 
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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 days (GD) 6-15. On GD 20, all dams were 

euthanized; each dam’s uterus was removed via cesarean section and its contents examined. Fetuses 

were examined for external, visceral, and skeletal malformations and variations. 

All dams survived until scheduled termination. There were no clinical signs of toxicity and no 

effects of treatment on gross pathology. 

Maternal body weight gains were decreased by 21% (not statistically significant) 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 pre-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. There 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, dead fetuses, or late resorptions. At 1000 and 1500 

mg/kg/day, the numbers of early resorptions were 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 comparable to controls, and there were no treatmentrelated effects on ossification of the skeleton. 

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

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

 870.3700b Prenatal Developmental Toxicity Study - Rabbit
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In a developmental toxicity study (MRID 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 this death to treatment. Necrotic foci in multiple 

lobes of the lung were observed in this animal as well as in one other animal receiving 25 mg/kg/day 

and two other animals receiving 50 mg/kg/day. In the absence of serum chemistry and 

histopathological data, these gross pathological findings are considered incidental under the 

experimental conditions tested. There were no other antemortem or necropsy observations 

suggestive of TH-913 toxicity. There was no apparent 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 these 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 study (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 during pre-mating) for two successive generations with one litter per 

generation. The P generation animals were fed the test diets for a minimum of 56 days prior to 

mating to produce the F1 litters. The F1 litters were culled on post-natal (PND) 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 during macroscopic or microscopic examinations. 

Toxicity was observed at 10,000 ppm. In the P generation, 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 toxicity 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. 
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Additionally at this dose, body weights and body weight gains were 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 males 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 females, resulting in decreased overall (GD 0-20) 

gestational body weight gains. Overall gestational food consumption 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 signs, 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 sex ratio or during macroscopic examinations. 

It was stated that a high incidence of the 10,000 ppm F1 and F2 pups were small in size, correlating 

with decreased pup body weights. Also, the number 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. Similarly, in the F2 pups, decreased live pups/dam on 

PND 0, and live birth, viability, and lactation indices 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, fertility, pregnancy, or gestation indices. Copulatory 

interval and gestation duration were similar to controls 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 beagle dogs/sex/group at dose levels of 0, 75, 

150 or 300 mg/kg/day. Though mortality was not clearly 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-
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related changes were observed in food consumption, food efficiency, body weights or revealed by 

ophthalmoscopic or physical examination. 

Treatment-related decreases in erythrocyte counts, hemoglobin and hematocrit were observed in 

males receiving 300 mg/kg/day. Though the effect of elevated alkaline phosphatase at 12 months of 

study is not clearly dose-dependent, the ~ 2-fold increase observed in male dogs receiving 150 

mg/kg/day and ~ 1.5-fold increase in male dogs receiving 300 mg/kg/day is considered an effect of 

treatment. Female dogs receiving 300 mg/kg/day for one year also manifested increased alkaline 

phosphatase activity. Treatment-related hypocholesterolemia, in conjunction 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 compared to control at 6 

months of study: The low-dose effect 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% decrease 

in albumin was noted for female dogs administered 300 mg/kg/day for 1 year. A slight treatmentrelated decrease in total serum protein was observed in the male high dose group. 

Treatment with TH-913 at levels 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 exhibited this effect of 

treatment though thyroid/parathyroid complex weights 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 females only at high dose levels. 

Under these experimental conditions, the LOAEL for TH-913 for male and female dogs is 150 

mg/kg/day based on increased relative liver weights, increased serum alkaline phosphatase 

activity and moderate thyroid hypertrophy (males 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 diet 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 sacrificed 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% treated 
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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 males, 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 increased 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 Month 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 increased 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 degeneration (5 treated vs 0 controls), 

and posterior subcapsular or complete cataract (7 treated vs 0 controls). The possible retinal 

degeneration and cataracts were bilateral findings (except 1 unilateral cataract), but conjunctivitis 

and corneal scars were observed both unilaterally and bilaterally. 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 observed 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. Microscopically, bilateral retinal atrophy 

was noted in 26/80 males (moderate to marked severity) 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 males; 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 incidences (% treated vs % controls; 

n=74-80) of slight to marked liver congestion (21% vs 11%), slight to marked acute inflammation 

(14% vs 4%), and slight to marked coagulative 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 lesions 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 were observed during macroscopic or microscopic 

examinations of parents in a concurrently submitted 2-generation reproduction and fertility test 
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(MRID 47305304). In the reproduction study, no decrease 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 hepatoxicity 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 based on increased mortality, decreased body weights 

and body weight gains, increased food consumption, 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 administered in the diet to CD1 

mice (50/sex/dose) for up to 18 months at doses of 0, 450, 4500, or 45,000 ppm (equivalent to 0, 

73/87, 741/870, and 7848/10,304 mg/kg bw/day 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 males 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) cumulative body weight gains of 22%. 

At 45,000 ppm, decreased (p≤0.05) body weights were noted in the 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% controls) and females (26% treated vs 10% controls), 

and increased incidences of centrilobular hepatocyte swelling was noted in males (24% treated vs 

0% controls; slight to moderate severity) 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, 
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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.

 Cytogenetics
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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 presence of S9, there were no increases in the 

percentage of cells with aberrations at any dose. The positive controls 

induced marked increases in the percentage 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 these 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 carboxymethylcellulose was administered once via gavage (10 mL/kg) to 10 

Wistar rats/sex/group at dose levels of 0, 80, 400, or 2000 mg/kg (limit dose). Neurobehavioral 

assessment (functional observational battery [FOB] and motor activity testing) 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 animals in the control and 2000 mg/kg groups were 

subjected to histopathological evaluation of brain and peripheral nervous system tissues. 

No treatment-related effects were observed on mortality, body weights, body weight gains, food 

consumption, FOB parameters (other than clinical 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 toe gait and/or splayed gait) in males (8) and 

females (9); (ii) activity decreased in males (7) and females (1); (iii) piloerection in males (9) and 

females (4); and (iv) upward curvature 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, reduced righting reflex, decreased visual placement response, and 

increased response to sound. All of these findings had resolved by Day 2. 
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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 subsession 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 neurotoxicity study (MRID 47305320), Imazosulfuron (98.6% a.i., Batch No. 

52027641) was administered in the diet 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 performed 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. The tissues from the perfused animals in the control and 8000 ppm 

groups were subjected to histopathological evaluation of brain and peripheral nervous system 

tissues. 

No treatment-related effects were observed on mortality, clinical signs, functional observational 

battery parameters, motor activity, 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 weight gain was decreased (p≤0.01) by 23% in males and 33% in 

females. Decreased (p≤0.05) food utilization (4-week 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-

14C]imazosulfuron or [pm-14C]imazosulfuron (>98.6% radiochemical purity for each) in aqueous 

0.5% carboxymethylcellulose was administered to Sprague 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 males in the Tier 1 study, 

and 3 males in the bile duct-cannulation study. Excreta (urine, feces, and bile [in some groups]) 

were collected for up to 72 hours post-dose and radioanalyzed. Expired air was trapped for the first 
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24 hours in the pilot study. Additionally, pools of selected excreta and bile were analyzed to identify 

and quantify metabolites. Animals were sacrificed at 3 days post-dose, and selected tissues were 

collected and radioanalyzed. 

Total recovery was 96-103% of the administered dose (AD) for the excretion and metabolic 

profiling. The majority of the dose was recovered in the urine (66%), a substantial amount was 

isolated in the bile (34%), and a miniscule amount 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 the excretion profile based on sex or radiolabel position were not 

existent or not substantial (data from 1 rat/sex/radiolabeled). Only negligible radioactivity was 

isolated in the expired air (≤0.1%). 

Males excreted 64% AD in the urine and 32% AD in the 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, and 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 complete within 48 h post-dose (96% AD). The rapid 

excretion of the test compound suggests that bioaccumulation may not be a concern at this dose 

level. 

At 3 days post-dose, radioactive residues in the 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 equiv/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-3-14C]imazosulfuron, but not in rats treated with 

[pm-14C]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-14C]imazosulfuron, but not 

in rats treated with [imidazopyridinyl-3-14C]imazosulfuron. More 1-(2-chloroimidazo[1,2-a]pyridin3-ylsulfonyl)-3-(4-hydroxy-6-methoxypyrimidin-2-yl)urea (HMS) was isolated in feces in the 

female (13.4% AD) than the male (5.3% AD) treated with [pm-14C]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 negligible amounts (0.9% AD) 

in the feces. Metabolic reactions included demethylation, hydroxylation of the pyrimidine ring, 

methylation or glucuronidation of the hydroxyl group, and opening the pyrimidine ring and 

formation of guanidine. 
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In the bile duct-cannulation study, the major metabolites were HMS 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 feces (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 Part 158 as a part of the data requirements 

for registration of a pesticide (food and non-food uses). 

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional 

immunotoxicity testing and is designed to evaluate the potential of a repeated chemical 

exposure to produce adverse effects (i.e., suppression) on the immune system. 

Immunosuppression is a deficit in the ability of the immune system to respond to a 

challenge of bacterial or viral infections such as tuberculosis (TB), Severe Acquired 

Respiratory Syndrome (SARS), or neoplasia. Because the immune system is highly 

complex, studies assessing functional immunotoxic endpoints are helpful in fully 

characterizing a pesticide’s potential immunotoxicity. These data will be used in 

combination with data from hematology, lymphoid organ weights, and histopathology in 

routine chronic or subchronic toxicity studies 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, reproductive, and endocrinologic toxicities. 

Additionally, the EPA has established an oral reference dose (RfD) for tributyltin oxide 

(TBTO) based on observed immunotoxicity in animal studies (IRIS, 1997). 

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

If the immunotoxicity study shows that the test material poses either a greater or a 

diminished risk than that given in the interim decision’s conclusion, the risk assessments 

for the test material may need to be revised to reflect the magnitude of potential risk 

derived from the new data. 

 

If the Agency does not have this data, a 10X database uncertainty factor may be applied 

for conducting a risk assessment from the available studies.

Appendix B. Metabolism Summary Table 
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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

CH3

O

CH3

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

CH3

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) Im 
Imazosulfuron 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

NH2

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 2NH O

CH3

O

CH3

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) Py 
Imazosulfuron 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

2NH O

CH3

O

CH3

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)Py 
Imazosulfuron 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) Im 
Imazosulfuron 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

CH3

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) Im 
Imazosulfuron 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

N O

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 was 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 about 0.2 lb ai/acre were made for a total application rate 

of 0.4 lb ai/acre. The first application was 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 days later to plants with mature and immature fruits. Total 

rate was 0.8 lb ai/acre. PHI was 21 – 28 days. The proposed use 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 many different pesticides, comprise generic pesticide exposure 

databases such as PHED and the Outdoor Residential Exposure Task Force (ORETF). EPA has 

reviewed all the studies supporting these multi-pesticide generic exposure databases, and has found 

no clear and convincing evidence that the conduct of any of them was either fundamentally unethical 

or significantly deficient relative to the ethical standards prevailing at the time the research was 

conducted. All applicable requirements of EPA’s Rule for the Protection of Human 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 

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