IMAZ O SULFU R ON Human Hea l th Risk Assessment DP No

. D409228

UN ITED STATES ENVIRONMENTAL PR OTEC TION AGE N CY
WASHINGTON, D.C. 20460

MEMORANDUM

Date: February 15,2013 OFFICE OF CHEMICAL S AFETY AND POLLUTION PREVE NTIO N

SUBJECT: Imazosulfu r o n: Hum a n H ealth Risk Assessment for Prop osed Uses on Melon (Crop Subg r o up 9A) and Tuberous and Corm Vegetables (Crop Subgroup lC).

PC Code: 118602 Decision No. : 464490 Petition No.: 2£8025 DP Barcode: 409228
R eg i st r at i o n No.: 59639- 1 54 & 59639- 1 66 R eg ul atory Action: Section 3 Registration Case No

. : None Risk Assessment Type: S i ngle Chemical / Aggregate TXRNo.: NA CAS No.: 122548-33-8 40 CFR: 180.651 MRID N o.: NA

FROM: Sheila Hea l y,

# Toxicologis**~** IJ (ff _l Steve Funk, Chem i st .,(

## ~ ;;:;:..JtCassi Walls, Biologist

## ~ ;t.L.>J2.9h Ri sk Assessme n t Branch III H ealth Effects Division (7509P)

THROUGH: Christine Olinger, Chief 

# Jfo f

R isk Asses s ment Branch I Hea l th Effects Divi sion (7

, )

TO: Barbara Madden/Andrew Ertman (RM 05) Ri sk Integration, Minor Use & Emergency Response Branch R egistration Division (7505 P )

Page 1 of 37IMAZOSUL FURON Human H ealth Risk Assessment DP No. 0409228

1.0 Executive Summary

. .. .. . .. .. .. . .. .. .. .. ...................................................................................... 4 2.0 HED Recommendations

.................................... . ... . ... . ... . ... . ... . .. .. .. .. .. .. .. ............................. 6 2.1 Data Deficiencies

. .. .. . .. .. .. . ... . .. .. .. . ... . ...... .. ... . ...................................... . ............... . ... .. . ... . ... 6 2.2 Tolerance Considerations

........................................ .. .. . .. .. .. .. .. . ... .. . .................... . ........... 6 2 .2. 1 Enforcement Analytical Method

........... . ... . .. .. .. .. .. .. .. .. .. . ... .. . ...... . ............................... 6 2.2.2 Inte rnational Harmonization

................................ ...... .......... . ... . ....... . .. .. .. .. ... . ... . ... .. .. . 7 2.2.3 Recommended Tolerances

. .. . .. ... . .. .. .. .. .. . .. .. ... . ....... . ... .. .. .. . .. .. ... . .. .. .............................. 7 2.2.4 Revisions to Petitioned-For Tolerances

............................. . ...... .. .. . .. . ... ... .. .. .. .. .. ... .. .. . 7 2.3 Labe l Recommendations

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

. .. .. .. . .. .. .. . .. . .......... . .. ...... .. .. .. . ............................................................................ 7 3.1 Chemical Identity

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

. 2 PhysicaVChemical Characteris t ics

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

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

. 4 Anticipated Exposure Pathways

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

...................................................................... 9 4.0 Hazard Characterization and Dose

- Response Assessment

. . ............... .. . ... .. .. .. ... . ... .. . ... I 0 4.1 Summary of Toxicological Effects

.............................................................................. I 0 4

. 2 Safety factor for Infants and Children (FQPA Safety Factor)

................................ II 4.2.1 Completeness of the Toxicology Database

. . .. ... . .. .. .. .. .. .. .. .. .. .. . ... . .. .. .. .. ... . ... . ............ . 12 4

. 2.2 Evidence of Neurot oxicity

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

... .. . 12 4.2.4 Residual Uncertainty in the Exposure Database

..................... .. .. . ... .. . ... .. .. . ... .. .. ... . 12 4

. 3 Toxicity Endpoint and Point of Departure Selections

.............................................. 13 5.0 Dietary Exposure and Risk Assessment

.. .. .. . ... . ...... .. .. .. ... . ... . .. .. ..... . ................................ 15 5.1 Residues of Concern Summary and Rationale

............................................. . .. ... .. . .... 15 5.2 Food Residue Profile

. .. .. . ... . .. .. .. . .......... . ... .. .. . ... . .............................. .. ...... .. ............... ..... 

### I5 5.3 Water Residue Profile

............................................. . ........................ . ........ . .. .. .. .. ... .. .. .. . 16 5.4 Dietary Risk Assessment

.. .. .. .. .. . .. .. .. . ... . ... . ... . ...... .. .. .. .. .. .. .. .. .. .. . ....... . ... . ......................... I7 5.4.1 Description of Residue Data Used in Dietary Assessment

.. .. .................. .. ... . . ... .. .. I7 5.4.2 Percent Crop Treated Used in Dietary Assessment

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

. 3 Acute Dietary Risk Assessment

.................................... . ..... ... . ........... .. . .. ... .. .. . ... .. ... . I 7 5.4.4 Chronic Dietary Risk Assessment

. .. .. .. ... . .. ... . ... . .......................... . ...... . .................... 17 5.4.5 Cancer Dietary Risk Assessment..

. .. ... . .. .. ... . . ... .. .. .. .. .. .. .. ... ..... . ....... .. .............. .... ...... 18 5.4

. 6 Summary Table

........................ .. ....... . .................................... . .. ......... ... . ... .. .. .. ... . ... . .. 18 6 .0 Residential (Non-Occupational) Expos ure/Risk Characterization

... . ......................... 19 6.1 Residential Hand ler Exposure

... . ... . .. .. .. ... . .. .. . . .. .. .. .. .. .. .. . .. ........... . ... . ........................... 19 6.3 Combined Exposure

. ................................................................ .. . ... .. .. .. . ... .. .. .. .. ...... .. .. .. 21 6.4 Residential Bystander Postapplication Inhalation Exposure

................................... 21 6.5 Spray Drift

.......................... . ...... .. ...... . .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. . ... .. .. .. ..... .. ....... . ................... 2I 7.0 Aggregate Exposure/Risk Characterization

........... . ....... . ... . .. .. . ... . ... . ... . ... . ....... .. ... . ... .. .. . 22 7.1 Acute Aggregate Risk.

......... .. .. . .. ....... . . ... .. .. .. .. .. .. .. .. .. .. . ... .. . ... . .... . ...... . ................. .. ........ 22 7.2 Short

- and Intermediate- Term Aggregate Risk

............ .. .. .. . ... . ... . .. .. ... . ... . ... . ... . ......... 22 7.3 Chronic Aggregate Risk

..... . ...... .. .. .. .. . ... . ... . ... . ... . ............... . .............. .... ....................... 22 7.4 Cancer Aggregate Risk

................................................ . ... .. . .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. ... . ... . ... 23 8.0 Cumulative Exposure/Risk Characterization

. . ... . .. ............................. . ......................... 23 9.0 Occupational Exposure/Risk Characterization

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

Page 2 of37IMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 3 of 37 9.1 Short

- and Intermediate

- Term Handler Risk

................................ ........................... 24 9.2 Short

- and Intermediate

- Term/ Post

- Application Risk

................................ ............ 25 9.2.1 Dermal Postapplication Risk

................................ ................................ ................... 25 9.2.2 Inhalation Postapplication Risk

................................ ................................ .............. 25 10.0 References

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

................................ .................. 27 A.1 Toxicology Data Requirements

................................ ................................ ................... 27 A.2 Toxicity Profiles

................................ ................................ ................................ ............ 28 Appendix B. Physical/Chemical Properties

................................ ................................ ............. 33 Appendix C. Review of Human Research

................................ ................................ ................ 34 Appendix D. Metabolism Summary Table

................................ ................................ .............. 3 5IMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 4 of 37 1.0 Executive Summary

Use Profile Imazosulfuron(2

- chloro

- N

- [[4,6

- dimethoxy

- 2

- pyrimidinyl)

- amino]carbonyl]imidazo[1,2

-

a ]pyridine

- 3

- sulfonamide), a sulfonylurea herbicide, is currently registered for use on agricultural crops including tomatoes, peppers and rice in addition to ornamentals and established turf grass in residential and recreational areas

. Valent has proposed that the use on the following crops be added to the V

- 10142 Ag Herbicide label: melon crop subgroup 9A (citron melon, muskmelon, cantaloupe, and watermelon) and tuberous and corm vegetables crop subgroup 1C (arracacha, arrowroot, Chinese artichoke, Jerusalem artichoke, edible canna, bitter and sweet cassava, chayote, chufa, taro, ginger, leren, potato, sweet potato, tanier, turmeric, yam bean, and true yam).

Imazosulfuron (V

- 10142 ) is formulated as a 75% ai w ater

- d ispersible g ranule (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

. Imazosulfuron may be applied up to twice a year to tuberous and corm vegetables prior to crop planting (pre

- emergent) and shortly following new crop plantings (post

- emergent)

. However, only one application per year may be made to well established melon plants (at least 5 inches wide). Ap plication timing may vary depending on the target weed (pre

- emergence or post

- emergence weeds). The appli cation rates range from 0.15 lb ai/A to 0.3 lb ai/A for melons and tuberous and corm vegetables. For the proposed uses, V

- 10142 Ag Herbicide may be a pplied with ground or handheld spray equipment.

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 st udy 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

.

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 imazos ulfuron 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 carcinogenic ity. Imazosulfuron is classified as “not likely to be carcinogenic to humans,” based on the absence of significant tumor increases attributed to treatment.IMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 5 of 37 I mazosulfuron is not acutely toxic or irritating to the skin or eyes and is not a dermal sensitize r.

The data for imazosulfuron support a reduction of the FQPA safety factor to 1X.

Dietary Exposure The residue chemistry data and environmental fate data are adequate to assess human exposure. The chronic dietary food exposure assessment is conservati ve. The assessment is based on reliable data and will not underestimate exposure/risk.

Acute: An unrefined dietary assessment was conducted assuming that 100% of crops with the requested uses of imazosulfuron are treated and that all treated crops conta in residues at tolerance level. In addition, default processing factors were assumed for the requested crop uses. Potential residues in drinking water were included in the analyses based on surface water results from the Tier I Rice Model. No population subgroups exceed HED’s level of concern at the 95 th percentile of exposure for food and drinking water. The U.S. population occupied < 1 .0 % of the acute population

- adjusted dose (aPAD), while the most highly exposed population subgroup, all infants (< 1 year old)

, occupied 1.2 % of the aPAD.

Chronic: An unrefined chronic dietary assessment was conducted assuming that 100% of crops with the requested uses of imazosulfuron are treated and that all treated crops contain residues at tolerance level. In addition, default processing factors were assumed for the requested crop uses. Potential residues in drinking water were included in the analyses based on surface water results from the Tier I Rice Model. No population subgroups exceed HED’s level of concern for dietary exposure from food and drinking wate r: the U.S. population occupied < 1% of the chronic population

- adjusted dose (cPAD), while the most highly exposed population subgroup, all infants (< 1 year old), occupied 2.0% of the cPAD.

Residential Exposure There are no proposed residential uses at this time; however, there are existing residential turf uses that have been reassessed to reflect updates to HED’s 2012 Residential SOPs along with policy changes for body weight assumptions. Residential handler scenarios resulted in margins of exposu re ( MOEs ) greater than the level of concern (i.e. the LOC is an MOE < 100) and therefore are not of concern to HED

. The r esidential combined short

- term post

- application incidental oral scenario for children resulted in an MOE greater than the LOC of 100 a nd therefore is not of concern to HED

.
Ag gregate Risk Aggregate a cute risk is equivalent to acute dietary risk via food and drinking water exp osure pathways and comprises 1.2 % of the aPAD for the most highly exposed population, infants < 1 year old. Likewise, chronic dietary risk comprises 2.0% 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 (resi dentialIMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 6 of 37 handler) routes. For children, th e exposure pathway includes the dietary exposure and the incidental oral post

- application residential pathway.

All aggregate MOE s are greater than 100; therefore, aggregate exposure is not of risk concern.

Occupa tional Exposure/Risk Dermal exposure during handling activities was not considered because no systemic toxicity was observed at the limit dose in the dermal study

. The occupational handler exposure and risk estimates indicate that short

- and intermediate

- term non

- cancer inhalation MOEs are not of concern to HED (i.e., MOEs > 100) at baseline (no respirator) attire.

Dermal exposure during post

- application activities was not considered because no systemic toxicity was observed at the limit dose in the derma l study

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

- application inhalation exposure assessment was not performed for imazosulfuron at this time. If new policies or procedures are put into place, the Agency may revisit the n eed for a quantitative occupational post

- application inhalation exposure assessment for imazosulfuron.

Environmental Justice Considerations Potential areas of environmental justice concerns, to the extent possible, were considered in this human health ri sk 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. T here are

no toxicology or residue chemistry issues that would preclude granting a registration for the requested uses of imazosulfuron or establishment of tolerances for residues of imazosulfuron as indicated in 2.2.3

2.1 Data Deficiencies

There are no outstanding data deficiencies or conditions of registration that would preclude the establishment of the tolerances outlined in this document.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical MethodIMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 7 of 37 An adequate high performance liquid chroma tography method with tandem mass spectroscopy detection (LC/MS/MS), Method RM

- 42C

- 3, is available for tolerance enforcement in plant commodities. The method determines residues of imazosulfuron and metabolite UDPM, or ( 4,6

- dimethoxy

- pyrimidin

- 2

- yl)

- urea. The method has been adequately validated by an independent laboratory for the determination of imazosulfuron. A modification of the enforcement method was used for data collection in the melon and potato field trials. The method was adequately validated using control potato sampl es and cantaloupe fortified with imazosulfuron. The lowest level of method validation (LLMV) for residues of imazos ulfuron in/on potato tubers, each
proc essed fraction and cantaloupe was 0.02 ppm. Metabolite UDPM was not analyzed but is not required for potato based on the metabolism study where <1% TRR was reported to be present in potato (D367019, S. Funk, 10/18/2010). UDPM was up to 30% TRR in other metabolism studies and may be conservatively estimated at 30% of the i ma z osulfuron concentration in melons for purposes of dietary risk assessment.

2.2.2 International Harmonization

There are currently no established Codex, Canadian, or Mexican maximum residue limits ( MRLs ) established for imazosulfuron

.

2.2.3 Recommend ed Tolerances

It is recommended that tolerances be established for residues of the herbicide imazosulfuron ( 2

- chloro

- N

- [[(4,6

- dimethoxy

- 2

- pyrimidinyl)amino]carbonyl]imidazo

- [1,2

- α]pyridine

- 3

- sulfonamide ), including its metabolites and degradates, in or on the plant commodities specified below in Table 2.2.3. 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

- sulfonam ide

.

Table 2

. 2.3. Tolerance Summary for Imazosulfuron

Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity Definition

Melon crop subgroup 9A 0.02 0.02 Melon subgroup 9A Tuberous and corm vegetables crop subgroup 1C. 0.02 0.02 Vegetable, tuberous and corm, subgroup 1C

2.2.4 Revisions to Petitioned

- For Tolerances

There are no revisions the tolerance petition (Table 2.2.3).

2.3 Label Recommendations

HED does not have any additional label recommendations regarding application to proposed crops or occupational or residential assessments.

3.0 In troductionIMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 8 of 37 3.1 Chemical Identity

Table 3. 1. Imazosulfuron Nomenclature

. Chemical structure

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

- u se product (EP) 75% WG ( V

- 10142 Ag Herbicide; EPA Reg. No. 59639

- 166)
Chemical Class Sulfonylurea

3.2 Physical/Chemical Characteristics

The physicochemical properties of the technical grade of imazosulfuron are summarized in Appendix C. The log of the oc tanol/water partition coefficient is

- 0.07 at neutral pH , which indicates a lack of fat solubility and therefore no propensity to bioaccumulate i n fatty tissue or milk. The low coefficient also suggests l ow dermal absorption. The Henry’s Law con stant for imazosulfuron was determined to be 1.67 × 10 - 3 Pa· m 3 /mol and the vapo r pressure , < 6.3x10 - 4 Pa at 25oC )

. Imazosulfuron is soluble in water ( 429 mg/L at 2 0 °C) which suggests dissipation of imazosulfuron in the environment is expected to occur predominantl y via runoff and leaching

. Considering abiotic degradation, imazosulfuron is photolyzed at pH 7 in water ( t 1/2 = 3.5 days). 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.

3.3 Pesticide Use Pattern

Table 3. 3. Summary of Directions for Use of Imazosulfuron. Applic. Timing, Type, and Equip. Formu

- lation Applic.

Rate (lbai/A) Max. No

.

A pplic / Season Max. Rate/

Season (lb ai/A) PHI

(days) Use Directions and Limitations

Melon crop subgroup 9A (citron melon; muskmelon (cantaloupe); watermelonIMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 9 of 37 Table 3. 3. Summary of Directions for Use of Imazosulfuron. Applic. Timing, Type, and Equip. Formu

- lation Applic.

Rate (lbai/A) Max. No

.

A pplic / Season Max. Rate/

Season (lb ai/A) PHI

(days) Use Directions and Limitations

Row middle application 1 (between rows) for plastic or bare soil culture) 75%

W D G 0.19

- 0.3 1 0.3 48 Apply at any time during the cropping season (up to 48 days before harvest) as long as the melons are well established and at least 5 inches wide. Avoid contact with the melon crop. When application is being made to melons grown in plastic mulch culture, adjust equipment to prevent the spray from contacting the plastic. Vegetable, tuberous and corm, subgroup 1C (arracacha; arrowroot; artichoke, Chinese ; artichoke, Jerusalem; canna, edible; cassava, bitter and sweet; chayote (root); chufa; dasheen (taro); ginger; leren; potato; sweet potato; tanier; turmeric; yam bean; yam, true ) 2
Preemergence

75%

W D G 0.19 to 0.3

45 Apply to a well

- prepared moist seedbed after planting to emergence or immediately after hilling. Postemergence 0.15 to 0.19 Apply after emergence if weeds are <3 inches in height as part of a weed program.

Sequential Application (Preemergence application followed early postemergence application ) 3

. 0.15

Followed by

0.15 2 0.3 Apply to a well

- prepared moist seedbed after planting to emergence or immediately after hilling. The postemergence application must not be made any sooner than 21 days after the preemergence application. Emerged weeds must be under 3 inches in height.

1 For ground middle application, d etermine the area to be sprayed and calculate the amount of V

- 10142 AG herbicide and water needed based on a broadcast total spray volume of 20

- 40 gallons of water/A and the herbicide rate of 0.2

- 0.3 lb ai/A. Ensure thorough, uniform coverage.
2 On potato, u se a br o adcast spray volume of 20

- 40 gallons water per acre. Do not apply by air

. Make only 2 applications per
year

. 3 Use of adjuvant is recommended only in the 2 nd (postemergence) spray. A 12 hr. reentry interval is required.

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed new uses of imazosulfuron on all of the registered and proposed agricultural, commercial, and residential use sites. Humans may be expose d to imazosulfuron in food and drinking water, since imazosulfuron may be applied directly to growing crops and application may result in imazosulfuron reaching surface and ground sources of drinking water. There are also residential uses of imazosulfuron , so there is likely to be exposure in residential or non

occupational settings. In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application. There is also a potential for post

a pplication exposure for workers re

- entering treated fields. This risk assessment considers all of the exposure pathways based on the registered and proposed new uses of imazosulfuron

.

3.5 Consideration of Environmental Justice

Potential areas of environ mental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal ActionsIMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 10 of 37 to Address Environmental Justice in Minority Populations and Low

- Income Populations," http://www.epa.gov/environmentaljustice/resources/policy/exec_order_12898.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 U.S. Department of Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age and ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgr oups 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 enter ing or playing on treated areas post

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Asse ssmen t

Hazard characterization of imazosulfuron has been detailed previously in Imazosulfuron : Human Health R isk Assessment for Proposed Uses on Rice, Peppers and Tomatoes . D362653, S. Healy, 03

- NOV

- 2010. This assessment includes summaries of the prior assessment. Since the last risk assessment, an acceptable/guideline immunotoxicity study has been submitted and the inhalation study requirement has been waived (TXR 005 6566 ).

4.1 Summary of 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.

Metabolism studies in the rat indicate that imazosulfuron is extensively absorbed, metabolized and excreted. 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. There were no notable sex

- differences in the excretion profile. 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 wer e 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 was the major metabolite de tected in bothIMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 11 of 37 urine and 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. A dermal absorption stu dy of imazosulfuron is not available ; however it is pertinent to note that dermal hazard was not identified in the toxicology database.

The toxicity database for imazosulfuron suggests that this herbicide possesses relatively low toxicity. Many of the ef

fects 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 incide nce 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 (i.e., decreased motor activity, abnormal gait, upward curvature of the spine and piloerection at the limit d ose 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 repeat

- dose study.

While ≥ 60% mortality was observ ed 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.

4. 2 Safety factor for Infants and Children (FQPA Safety Fact or)

T here 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 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 dieta ry (food and drinking water) exposure assessments are conservative. The dietary andIMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 12 of 37 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. 2 .1 Completeness o f the Toxicology Database

The toxicology database is complete for imazosulfuron.

4. 2 .2 Evidence of N eurotoxicity

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, abno rmal 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 Functional Observational Battery ( FOB ) parameters, gros s and neurohistopathology, motor activity or brain morphometrics of the ACN. The weight of evidence demonstrates that imazosulfuron is not a neurotoxic compound because the clinical findings in the ACN study occurred only at the limit dose and may be attr ibuted to generalized toxicity. A developmental neurotoxicity study is not required at this time.

4. 2 .3 Evidence o f Sensitivity/Su sceptibility in the Developing o r 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 utero exposure in rabbits. Neither the rat nor rabbit developmental studies identified developmental effects. The pare ntal 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, an d viability index were observ ed in F 1 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 F 2 pups. The points of departure are protective of these effects.

4. 2 .4 Residual Uncertai nty in the Exposure Datab ase

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. O ne 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 wa ter or surface water. For these reasons it can be concluded that the DEEM

- FCIDTM analysis does not underestimate risk from chronic exposure to imazosulfuron.IMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 13 of 37 D ata have been previously requested to con firm the metabolic profile of pyrimidine

- labeled imazosulfuron in rice grain in the confined rotational crop trial and to characterize field accumulation

. A grain (wheat) rotational crop study is needed to identify maximum levels of residues in grain and live stock 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. T he confined rotational crop study showed that imazosulfuron and 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. Therefore, d espite this data deficiency, there are no residual uncertainties in the exposure database

.

4. 3 Toxicity Endpoint and Point of D eparture Selections

There have been no changes to the prior dose

- response assessment, endpoints, cancer classification or re commendation to combine routes of exposure. Refer to Table 4.3.1 for a summary or toxicological doses and endpoints.

Table 4.3 .1

. Summary of Toxicological Doses and Endpoints for Imazo sulfuron for Use in Dietary, Non

Occupational and Occupational Human Health Risk Assessments

Exposure/ Scenario Point of

Departure Uncertainty/

Safety Factors RfD, Level of

Concern for Risk Assessment Study and Toxicological Effects

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

400 mg/kg/day UF A = 10 X

UF H = 10 X FQPA SF = 1 X 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 UF A = 10 X

UF H = 10 X FQPA SF = 1 X 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 mid

- and high

- dose; mild hypertrophy in females at high

- dose).IMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 14 of 37 Table 4.3 .1

. Summary of Toxicological Doses and Endpoints for Imazo sulfuron for Use in Dietary, Non

Occupational and Occupational Human Health Risk Assessments

Exposure/ Scenario Point of

Departure Uncertainty/

Safety Factors RfD, Level of

Concern for Risk Assessment Study and Toxicological Effects

Incidental Oral Short

- Term (1

- 30 days) and Intermediate

Term (1

- 6 months) NOAEL=

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

U F H = 10 X FQPA SF = 1 X 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 Short

Term (1

- 30 days) and Intermediate

Term (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 Intermediate

Term (1

- 6 months) NOAEL=

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

UF H = 10 X FQPA SF = 1 X 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 ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of

concern.IMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 15 of 37 5.0 Dietary Exposure and Risk Assessment

5.1 Residues of Concern Summary and Rationale

The residues of concern for dietary risk assessment and the tolerance expression are summarized in Table 5.1 and defined in Appendix D . The parent compound is an adequate indicator of misuse, and is the only residue included in the tolerance expression. The sulfonamide hydrolysis products, UDPM and ISPN are also major residues found in plant and livestock comm odities, respectively, and are included in the dietary risk assessment. The sulfonamide hydrolysis produ cts, IPSN, UDPM, ADPM and SDPM and the demethylation product, HMS were major degradates in the environmental fate studies so are included in the drinki ng water assessment. HMS has a structure similar to the parent compound, so is assumed to have equal toxicity. The hydrolysis products can not be excluded from hazard considerations as there is potential for
exposure. Further information on the metabolis m and degradation may be found in the risk assessment dated 11/03/10 (S. Healy, D362653).

Table 5.1. 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

Plants Primary Crop Imazosulfuron, UDPM Imazosulfuron

Rotational Crop Not Applicable Not Applicable

Livestock Ruminant Imazosulfuron, IPSN Imazosulfuron

Poultry Imazosulfuron, IPSN Imazosulfuron

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

5 .2 Food Residue Profile

The nature of the residue in plants is adequately understood based similar metabolism of imazosulfuron in three dissimilar crops (rice grain, pepper and tomato) : hydrolysis of the sulfonylurea linkage is the major metabolic process. T he residue of concern for tolerance enforcement for plants is imazosulfuron. The residue of concern for dietary risk assessment for plants is the sum of imazosulfuron and the metabol ite UDPM, expressed as equivalents of imazosulfuron . The qualitative nature of the residues of imazosulfuron in livestock is adequately understood based on investigation made on lactating goats and hens. It was demonstrated that metabolism of imazosulfur on is similar in ruminants and poultry. HED concluded that t he residue of concern for tolerance enforcement in livestock is imazosulfuron and t he residue of concern for dietary risk assessment in livestock is the sum of imazosulfuron and the metabolite IP SN, expressed as equivalents of imazosulfuron

.
Crop Field Trials All crop trials on potato reflected a 3x exaggerated

- rate application. Residues of imazosulfuron

w ere <0.02 ppm on potato harvested 42

- 48 days following sequential (preemergence followed byIMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 16 of 37 postemergence) application of the 75% W D G formulation for a total rate of 0.873

- 0.919 lb ai/A. Maximum residues of imazosulfuron were <0.02 ppm in/on cantaloupe harvested 48

- 68 days following 1

- 2 broadcast applications of the 75% WDG formulation of imazos ulfuron, at 0.3 lb ai/A.

T he studies reflect ed the proposed use patterns for potato and cantaloupe. The number and location of field trials are in accordance with OPPTS Guideline 860.1500 for each crop

. The available data on cantaloupe will support the proposed tolerance of 0.02 ppm for melon crop subgroup 9A. The available data on potato support the proposed tolerance of 0.02 ppm for tuberous and corm vegetables crop subgroup 1C.

Processing Studies T he submitted potato processing study is adequate. The residues of imazosulfuron following a 3x application were below the LOQ ( <0.02 ppm) in all samples of potato and potato processed fractions (potato flakes, chips and wet peels)

. Imazosulfuro n residues will not concentrate in potato processed matrices relative to the raw agricultural commodity.

Storage Stability The submitted storage stability data on potato, potato processed commodities, and cantaloupe are adequate. Storage stability data demonstrated that imazosulfuron residues in/on cantaloupe in /on potato RAC and in potato processed commodities (potato chips, flakes, and wet peels) were stable for the storage intervals of samples from the field trials and processing study

.
Meat, Milk, Poultry and Eggs The ruminant and poultry feeding study requirements were waived previously because of the very low anticipated dietary burdens of imazosulfuron in livestock. The situation remains unchanged wit h the addition of potato wastes where residu es are <0.02 ppm

.
Confined Rotational Crops In the c onfined rotational crop study, imazosulfuron was not identified in any rotational crop commodity

. HMS and UDPM were identified as major metabolites in rotational sorghum and wheat matrices (except gra in) at PBIs of 30

– 120 days. In addition, three metabolites were identified in rot ational sorghum and wheat feed matrices (except grain) that were no t identified in primary crops, IPSA

- isoserine, IPSA

- acetylisoserine, and IPSA

- caffeoylisoserine. HED does not consider the low levels of these IPSA

- conjugates at the 365

- day PBI to be toxicologically significant. Appropriate PBIs were required to insure no quantifiable residues in rotational
crops.

5.3 Water Residue Profile

A Tier I screening

- leve l drinking water assessment was conducted to support the human health risk assessment for the Section 3 proposed new use registration of imazosulfuron

. Modeled application rates represent the maximum application rates on the proposed label for use on the

m elon subgroup 9A and the tuberous subgroup 1 C. Tier 1 surface water and groundwater modeling was conducted for two ground spray applications with a 45

- day interval for the tuberous and corm subgroup 1C at a rate of 0.15 lb a.i./A . In addition, Tier 1 sur face waterIMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 17 of 37 modeling was also conducted for one ground spray application for melon subgroup 9A use at a rate of 0.3 lb a.i./A per year (D402305, F. Khan, 16

- NOV

- 2012)

.
The estimated drinking water concentrations (EDWCs) for Tier 1 models are lower than t he previously reported EDWC of 278.9 μg/L for acute and chronic exposure s for surface water based on the rice scenario and 4.8 μg/L for acute and chronic exposures for ground water based

on the turf scenario (Table 5.3)

. Therefore, the previously recommended EDWCs should be retained for drinking water exposure assessment for human health risk assessment purposes.

Table 5. 3 Summary of Estimated Surface Water and Groundwat er Concentrations

for Imazosulfuron

. Scenario Surface Water Conc., ppb a Groundwater Conc., ppb b

Acute 278.9 4.8 Chronic (non

- cancer) 278.9 4.8

a From the RICE model. I nput parameters for all models are tabulated in DP362654, Faruque Khan, 5/13/2010
b From the SCI

- GROW model.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Unrefined acute and chronic dietary assessments were conducted using field trial data and assuming 100% of the crops were treated and that all treated crops contained residues at tolerance levels. D e fault processing factors were assumed for the requested crop uses. T he highest estimated drinking water concen tration (EDWC) for imazosulfuron resulted from the Tier I RICE model. This recommended EDWC of 278.9 μg/L used in the acute and chronic

assessmen t 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

Acute dietary risk a nalyses were conducted with the DEEM

- FCID model to form a conservative evaluation of exposure for imazosulfuron

. At the 95 th percentile of exposure, all acute analys e s yielded risk estimates well below the 100% of the aPA D threshold level of concern for each population subgroup. For food and drinking water, the U.S. Population subgroup acute aggregate dietary risk was calculated at <1% of the aPAD with an exposure level of 0.015 mg/kg/day. For the subgroup with the highe st calculated exposure, all infants

, acute aggregate dietary risk occupied 1.2 % of the aPA D with an exposure of 0.0 48 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 AssessmentIMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 18 of 37 C hronic dietary risk a nalyses were conducted with the DEEM

- FCIDTM model to form a conservative evaluation of exposure for imazosulfuron

. All chronic analys e s yielded risk

es timates well below the 100% of the c PA D 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 <1.0% of the cPAD with an exposure level of 0.0060 mg/kg/day. For the subgroup with the highest calculated exposure, all infants , chronic aggregate dietary risk occupied 2.0 % of the c PA D with an exposure of 0.020 mg/kg/day

. An overview summarizing the results of the chronic dietary assessment with the po pulation subgroup h aving 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 n ot conducted.

5.4.6 Summary Table

Table 5.4

. 6. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Imazosulfuron

Population Subgroup Acute Dietary

(95th Percentile) Chronic Dietary Cancer
Dietary Exposure (mg/kg/day) %

aPAD* Dietary

Exposure (mg/kg/day) %

cPAD* Dietary

Exposure (mg/kg/day) Risk

General U.S. Population 0.01536 1 < 1 0.00595 7 < 1

N/A N/A All Infants (<1 year old) 0.0477 50 1.2 0.0152 10 2.0

Children 1

- 2 years old 0.023786 < 1 0.008712 1.2

Children 3

- 5 years old 0.019404 < 1 0.007367 1.0

Children 6

- 12 years old 0.014765 < 1 0.005292 < 1

Youth 13

- 19 years old 0.012823 < 1 0.004362 < 1

Adults 20

- 49 years old 0.015069 < 1 0.005927 < 1

Adults 50

- 99 years old 0.013496 < 1 0.005848 < 1

Females 13

- 49 years old 0.015336 < 1 0.005898 < 1
* % PADs are reported to 2 significant figures. The values for the highest population for each type of risk assessment are bolded.IMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 19 of 37 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no proposed residential uses at this time; however, there are existing residential uses that have been reassessed in this document to reflect updates to HED’s 2012 Residential SOPs 1 along with policy changes for body weight assumptions. The revisio n of residential exposures impact s the human health aggregate risk assessment for imazosulfuron.

6.1 Residential Handler Exposure

Residential handler exposure is expected to be short

- term in duration. Intermediate

- term exposures are not likely because of the intermittent nature of applications by homeowners

. 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 int ra

- species sensitivity. The total uncertainty factor that has been applied to the non

- cancer risk assessment for imazosulfuron is 100X for residential exposure. Residential exposure and risk resulting in MOEs greater than or equal to 100 are not of conce rn 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

- term risks, d aily inhalation exposures we re 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 140 ,000 ( manually pressurized handwand application) to 50,000 ,000 ( sprinkler can application ). These risk estimates are not of concern to HED.

Summaries of the inhalation risk estimates for residential handlers a re included in Table 5.1

. The maximum application rate for each exposure scenario is presented as the worst case scenario. T he inhalation risks to handlers are not of concern to HED for any of the residential handler scenarios.

Table 6.1 . Residential Handler Non

- cancer Exposure a nd Risk Estimates for Imazosulfuron

.

Exposure Scenario Level of Concern Inhalation Unit

Exposure (mg/lb ai) Maximum

Application Rate 1 Area Treated or

Amount Handled Daily 2 Inhalation

Dose (mg/kg/day) 3 MOE 4

Mixer/Loader/Applicator Lawn/turf : manually pressurized handwand 100 1.1 0.025 lb ai/gal 5 gal 0.0017 140,000

Lawn/turf : hose

- end
sprayer 100 0.022 0.75 lb ai/A 0.5 A 0.00010 2,300,000

Lawn/turf : backpack
sprayer 100 1.1 0.025 lb ai/gal 5 gal 0.0017 140,000

Lawn/turf : sprinkler

can 100 0.022 0.000017 lb ai/ft 2 1000 ft 2 0.0000047 50,000,000

1 Based on registered label (EPA Reg. No

. 59639

- 155 ).

1 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.htmlIMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 20 of 37 2 Based on HED’s 2012 Residential SOPs ( http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html ). 3 Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A

/day or gallons/day) ÷ BW ( 80 kg). 4 Inhalation MOE = Inhalation NOAEL ( 235 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

6.2 Post

- Application Exposure

There is the potential for post

- application exposure for individuals exposed as a result of being in an environment that has been previously treated with imazosulfuron . The quantitative exposure/risk assessment for residential post

- a pplication exposures is based on the following scenarios: i ncidental oral exposure from treated turf via hand to mouth activities ; i ncidental oral exposure from treated turf via object to mouth activities ; and i ncidental oral exposure from treated turf via soil ingestion

The lifestages selected for each post

- application scenario are based on an analysis provided as an Appendix in the 2012 Residential SOPs 2 . These lifestages are not the only lifestages that could be potentially exposed for these post

- application scenarios; however, the assessment of these lifestages is health protective for the exposures and risk estimates for any other potentially exposed lifestages.

A series of assumptions and exposure factors served as the basis for completing the residential post

- application risk a ssessment. Each assumption, factor and algorithm used to estimate residential post

- application exposure and dose is detailed in the 2012 Residential SOPs 1

.

The short

- term MOEs for each scenario are greater than t he LOC of 100, and are not of concern (Table 6.2)

.

Table 6.2. Residential Post

- application Non

- cancer Exposure a nd Risk Estimates for Imazosulfuron.

Lifestage Post

- application

Exposure Scenario Application Rate 1 Dose

(mg/kg/day) 2 MOEs 3
Use Site Route of Exposure

Child Turf Incidental oral Hand to mouth 0.75 lb ai/A 0.011 21,000

Incidental oral Object to mouth 0.75 lb ai/A 0.0038 680,000

Incidental oral Soil ingestion 0.75 lb ai/A 0.000025 9,300,000

1 Based on registered label (EPA Reg. No

. 59639

- 155 ). 2 Dose (mg/kg/day) equations: Hand

- to

- Mouth Dose = hand residue loading (mg/cm 2 ) × fraction of hand mouthed (0.127) × surface area of 1 hand (150 cm 2 ) × exposure time (1.5 hrs/day) × # of replenishment intervals/hr (4 int/hr) × (1

- ((1

- saliva extraction factor (0.5))^(Number of hand

- to

- mouth events per hour (13.9 events/hr) ÷ # of replenishment intervals/hr)) ÷ body weight (11 kg). Object

- to

- Mouth Dose = object residue loading (μg/cm 2 ) × unit conversion factor (0.001 mg/μg) × obj ect surface area mouthed / event (10 cm 2 /event) × exposure time (1.5 hrs/day) × # replenishment intervals/hr (4 int/hr) × (1

- ((1

- saliva extraction factor (0.50))^(# Object

- to

- Mouth Events/hr (8.8 events/hr) ÷ # replenishment intervals/hr)) ÷ body weight ( 11 kg).IMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 21 of 37 Soil Ingestion = soil residue (μg/g) × ingestion rate (50 mg/day) × conversion factor (0.000001 g/μg) ÷ body weight (11 kg). TTR for liquid application rate of 0.75 lb ai/A x 1% x (1

- 10%) 0 x conversion factor (ug/lb) x conversion factor (acre/cm 2 )= 0.083 μg/cm 2

. 3 Incidental Oral MOE = Oral NOAEL ( 235 mg/kg/day) ÷ Incidental oral Dose (mg/kg/day).

6.3 Combined Exposure

Dermal and inhalation risks were not com bined in this assessment, since s hort

- and intermediate

term dermal toxicity endpoints w ere not identified

.

6.4 Residential Bystander Postapplication 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 Ca tegory IV), low vapor pressure (< 6.3x10 - 4 Pa at 25oC), and the low proposed use rate ( 0.3 lb ai/A ). However, volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 3 . The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate pos t

- 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 inh alation exposure assessment for imazosulfuron

.

6. 5 Spray Drift

Spra y 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 em ployed 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 (see the Agency’s Spray Dri ft website for more information 4 . The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the Ag DRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off

- target dri ft with specific products with significant risk estimates associated with drift.

It is noted that the 0.75 lb ai/acre application rate for turf was modeled to estimate post

application residential exposure of children. As this rate is equal to or higher than many of agricultural application rates, this scenario is protective of any exposure of farm children via spray drift from agricultural imazosulfuron applications.

3 Available: http://www.epa.g ov/scipoly/SAP/meetings/2009/120109meeting.html

4 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htmIMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 22 of 37 7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

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 co nducted 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

- and Intermediate

- Term Aggregate Risk Calculations

Population Short

- or Intermediate

- Term Scenario

LOC for Aggregate Risk 1 MOE dietary

(food + drinking water) 2 MOE

incidental oral 3 MOE

dermal 4 MOE

inhalation 5 Aggregate MOE

(food and residential) 6

Adult Male 100 4 3 ,000 N/A N/A 140 ,000 33 ,000

Adult Female 100 4 3 ,000 N/A N/A 140 ,000 33 ,000

Child 100 15 ,000 21 ,000 N/A N/A 8,700

1 The LOC includes the standard inter

- and intra

- species uncertainty factors (UF A and UF

H , respectively) totaling 100.
2 MOE food = NOAEL/chronic dietary exposure: Where short

- and intermediate

- term NOAEL = 235 mg/kg/day and chronic dietary exposure = 0.00 5957 mg/kg/day (U.S. population), 0.015210 mg/kg/day (All infants < 1 yr).

3 MOE oral = From Table 6.2.

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 aggrega te risk concerns were identified.IMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 23 of 37 7.4 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 det ermine 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 cumu lating 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

Based on the anticipated u se patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed uses. The quantitative exposure/risk assessment developed for occupational handlers is ba sed on t he following scenarios: m ixing/loading WDG (dry flowable) formulations to support groundboom application; a pplying s prays with groundboom equipment; and mixing/loading/a pplying sprays with mechanically pressurized handgun equipment.

The following series o f assumptions and exposure factors served as the basis for completing the occupational handler risk assessments.

Application Rate Maximum application rates for all proposed uses are shown in Table 3.

Unit Exposures It is the policy of HED to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical

- specific data, include PHED 1.1, the AHETF database, the Outdoor Residential Exposure Task Force (ORETF) database, or other registrant

- submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting handler exposure that are used in thi s assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table 5 ”, which,

5 Available: http://www.epa.gov/opp00001/science/handler

- exposure

- table.pdfIMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 24 of 37 along with additional information on HED policy on use of surrogate data, including descriptions of the various s ources, can be found at the Agency website 6

.

Area Treated Based on HED Expo SAC SOP No. 9.1 , the area treated in a day was assumed to be: 80 acres for mixing/loading and applying to support groundboom applications to typical acreage field crops; 200 acres for mixing/loading and applying to support groundboom applications to high

- acreage field crops; and 1000 gallons for mixing/loading/applying to support mechanically pressurized handgun applications to typical acreage field crops.

Exposure Duration B ased o n the proposed use, short

- and intermediate

- term exposures are expected for imazosulfuron. Imazosulfuron is registered for use on a number of crops for multiple applications; however, the proposed uses restrict applications to once or twice per growing year. Additionally, since the same endpoint and PoD were selected for short

and intermediate

- term durations, short

- term exposure and risk estimates are considered to be protective of intermediate

- term exposure and risk.

Personal Protective Equipment T he imazosulfuron product labels direct mixers, loaders, applicators and other handlers to wear long sleeved shirt, long pants, shoes plus socks , and chemical resistant gloves

. Results are presented for “baseline,” defined as a single layer of clothing con sisting of a long sleeved shirt, long pants, shoes plus socks, no protec tive gloves, and no respirator.

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 intra

- species 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. The MOEs range from 35,000 (mixing/loading to support ground applications to high acreage crops) to 2,300,000 (applying with groundboom equipment to typical acreage crops). These risk estimate s are not of concern to HED. Summaries of the inhalation risk estimates for occupational handlers are included in Table 9.1

.

9.1 Short

- and Intermediate

- Term Handler Risk

Table 9.1

. Short

- and Intermediate

- Term Occupational Handler Exposure and Risk for Imazosulfuron.

Exposure Scenario Crop or Target App Rate a (lb ai/A) Acres Treated Daily b Baseline Inhalation Unit Exposure c (mg/lb ai) Short

- and

Intermediate

Term Dose (mg/kg/day) Inhalation d Short

- and

Intermediate

Term MOE Inhalation e

Mixer/Loader

6 Available: http://www.epa.gov/pesticides/science/handler

- exposure

- data.htmlIMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 25 of 37 Table 9.1

. Short

- and Intermediate

- Term Occupational Handler Exposure and Risk for Imazosulfuron.

Exposure Scenario Crop or Target App Rate a (lb ai/A) Acres Treated Daily b Baseline Inhalation Unit Exposure c (mg/lb ai) Short

- and

Intermediate

Term Dose (mg/kg/day) Inhalation d Short

- and

Intermediate

Term MOE Inhalation e
Mixing/Loading Dry Flowables for Groundboom Applications Melons 0.3 80 0.00 896 0.00 27 87,000

Tuberous and corm vegetables 0.3 200 0.00 896 0.00 67 35,000

Applicator Applying Sprays via Groundboom Equipment Melons 0.3 80 0.00034 0.000 10 2,300,000

Tuberous and corm vegetables 0.3 200 0.00034 0.000 26 920,000

Mixer/Loader /Applicator Mechanically pressurized handgun Melons 0.015 (lb ai/gal) 1000 0.0039 0.000 73 320,000

a Application Rates based on proposed uses on label for V

- 10142 (EPA Reg. No. 59639

- 166 ). b Exposure Science Advisory Council Policy No. 9.1

. c Unit Exposu res 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 (8 0 kg).

e Short

- and Intermediate

- Term Inhalation MOE = NOAEL (235 mg/kg/day) / inhalation daily dose (mg/ kg/ day). L OC = 100.

9.2 Short

- and Intermediate

- Term/ Post

- Application Risk

9.2.1 Dermal Postapplication Risk

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. Therefore, post

application dermal exposure was not assessed.

9.2.2 Inhalation Postappli cation Risk

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 III and IV) , low vapor pressure ( < 6

. 3 x10 - 4 Pa at 25 oC )

, and the low proposed use rate (0.3 lb ai/A). However, there are multiple potential sources of post

- application inhalation exposure to individuals performing post

- application activities in previously treated fi elds. 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 Insecti cide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, andIMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 26 of 37 received the SAP’s final report on March 2, 2010 3 . The Agency is in the process of evaluating the SAP report as well as available post

- application inhalation exposur e data generated by the ARTF and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post

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

- application inhalation exposure assessment for imazosulfuron

.
Although a quantitative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post

- application exposure. Therefore, it i s expected that these handler inhalation exposure estimates would be protective of most occupational post

- application inhalation exposure scenarios.

10.0 References

Acierto

, A

., 09 / 05 /201 2 , DP# D402303

, Imazosulfuron. Request for Section 3 Registration f or New Uses on the Melon Crop Subgroup 9A and the Tuberous and Corm Vegetables Crop Subgroup 1C. Summary of Analytical Chemistry and Residue Data

.
Healy, S., 11/03/2010, DP#362653, Imazosulfuron: Human Health Risk Assessment for Proposed Uses on Rice, Pe ppers and Tomatoes.

Khan, F., 11/13/2008, DP# D 358472, The Drinking Water Degradates Identification Memorandum for Imazosulfuron.

Khan, F., 08/16/2012 , DP# D402035, Tier I Drinking Water Assessment for the Section 3 Proposed Registration of Imazosulfuron on Melon Subgroup 9A and Tuberous and Corm Subgroup 1C

Kramer, G.F., 12/5/2008, DP# D 359190, Imazosulfuron: Report of the Residues of Concern Knowledgebase Subcommittee (ROCKS)

.
Rury, K., 02/20/13, TXR 0056566, Imazosulfuron : Summary of Hazard and Science Policy Council (HASPOC) Meeting of January 23, 2013: Recommendations on the requirement of a subchronic inhalation study.

Walls, C. , 01/14/2013, DP#D403364, Imazosulfuron: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the New Uses on the Melon Crop Subgroup 9A and Tuberous and Corm Vegetables Crop Subgroup 1C

Walls

, C

., 01 / 18 / 201 3 , DP#D 403362

, Imazosulfuron : Occupational and Residential Exposure Assessment f

or Proposed Use on Melon Crop Subgroup 9A and Tuberous and Corm Vegetables Crop Subgroup 1C

.IMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 27 of 37 A ppendix A

. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for Food Use for I mazosulfuron are in Table 1. U se 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 yesIMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 28 of 37 A.2 Toxicity Profile s

Table A.2.1 Acute Toxicity Profile

- Test Substance

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

870.1100 Acute oral

– rat 47305221 LD 50 > 5000 mg/kg IV

870.1200 Acute dermal

– rat 47305227 LD 50 > 2000 mg/kg III

870.1300 Acute inhalation

– rat 47305228 LC 50 > 2. 12 mg/L IV

870.2400 Acute eye irritation

- rabbit 47305229 Non

- irritating IV

870.2500 Acute dermal irritation

- rabbit 47305230 N on

- irritating IV

870.2600 Skin sensitization

– guinea pig 47305231 Negative N/A

870.1100 IHOA 47305222 LD 50 > 5000 mg/kg IV

870.1100 UDPM 47305223 LD 50 = 677 mg/kg III

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

870.1100 M

- 1 47305225 LD 50 > 5000 mg/kg IV

870.1100 ADPM 47305226 LD 50 = 836 mg/kg IIIIMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 29 of 37 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/d ay; F: 0, 265.7, 1081.4, 5135.7 mg/kg/d ay 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) 4 7305233 (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/Non

Guideline*

*tested under FIFRA Subdivision F guidelines Materna l NOAEL = 125 mg/kg/day ; LOAEL > 125 mg/kg/day Developmenta l NOAEL = 125 mg/kg/day; LOAEL > 125 mg/kg/dayIMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 30 of 37 Table A.2. 3 Subchronic, Chronic and Other Toxicity Profile of Imazosulfuron

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

870.3800 Reproduction and

fertility effects (rat) 47305304 (1990);

0, 100, 1,000, 10,000
ppm; M F 0 : 0, 7.7

, 77.8

, 777.4 mg/kg/day; F F0 : 0, 8.93

, 88.4

, 868.5 mg/kg/day; M F1 : 0, 9.0

, 89.4

, 1006.5 mg/kg/day; F F1 : 0, 9.6

, 96.9

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

. Reproductive NOAEL = (10,000 ppm) 892/982.7 mg/kg/day in males /females (average of both generations); LOAEL > 892/982.7 mg/kg/day in males /females (not observed). Offspring NOAEL = (1000 ppm) 83.6/92.7 mg/kg/day in males/females (average of both generations) ; LOAEL = (10,000 ppm) 892/982.7 mg/kg/day in males /females (average of both generations) based on decreased pup viability and body weights

.
870.4100b Chronic toxicity

(dog) 47305305 (1990);

0, 75, 150, 300 mg/kg/day Acceptable/Guideline NOAEL = 75 mg/kg/day LOAEL = 150 mg/kg/day based on moderate thyroid hypertrophy (males at mid

- and high

dose; mild hypertrophy in females at high

dose).

870.4200b Carcinogenicity

(mouse) 47305307 (1991);

0, 450, 4500, 45000 ppm; M: 0, 72.7, 741.3, 7848.1 mg/kg/day; F: 86.8, 870.0, 10303.5 mg/kg/day Acceptable/Guideline NOAEL = 73/87 mg/kg/day in males/females. LOAEL = 741/870 mg/kg/day in males /females based on centrilobular swelling of hepatocytes. no evidence of carcinogenicity

870.4300 Chronic

toxicity/Carcinogen icity (rat) 47305306 (1991);

0, 200, 2000, 20000 ppm; M: 0, 10.39, 106.10, 1123.99 mg/kg/day; F: 0, 12.94, 132.46, 1554.35 mg/kg/day. Acceptable/Guideline NOAEL = 106/132 mg/kg/day in males/females; LOAEL = 1124/1554 mg/kg/day in males/females based on increased mortality, decreased body weight, decreased body weight gain, clinical ophthalmic observations (cataracts and retinal degeneration) and hepatotoxicity in females. no evidence of carcinogenicity
870.5100 Bacterial reverse

mutation test 47305308 (1988)

Acceptable/Guideline TH

- 913 Technical: Test article has no reverse mutagenic potential under these experimental conditions

870.5100 Bacterial reverse

mutation test 47305309 (1990)

Acceptable/Guideline UDPM: Test article has no reverse mutagenic potential under these experimental conditionsIMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 3 1 of 37 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 chromoso mal aberrations at any concentration in presence of S9.

870.5395 Mammalian

erythrocyte micronucleus test 47305316 (2007)

Acceptable/Guideline Test article has no potential to induce micronuclei in mouse bone marrow cells under the conditions of this test

870.6200a Acute neurotoxicity

screening battery 47305319 (2007);

0, 80, 400, 2000 mg/kg Acceptable/Guideline NOAEL = 400 mg/kg/day; LOAEL = 2000 mg/kg/day in males and females based on the following clinical signs: abnormal gait, decreased activity, piloerection and upward curvature of the spine and decreased motor activity in males.

870.6200b Subchronic

neurotoxicity screening battery 47305320 (2007);

0, 800, 2500, 8000 ppm; M: 0, 54.0, 169.2, 571.3 mg/kg/day; F: 0, 61.9, 200.8, 655.3 mg/kg/day Acceptable/Guideline Systemic NOAEL = 169/201mg/kg/day in males/females; LOAEL = 571/655 mg/kg/day in males/females based on decreased body weight , body weight gain and food efficiency. Neurotoxicity NOAEL = 571/655 mg/kg/day in males/ females (HDT)
LOAEL > 571.7 mg/kg/day for males and > 655.3 mg/kg/day for femalesIMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 32 of 37 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), IH DU, 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.

870.7800 Immunotoxicity

(rat) 48691003 (2011)

Acceptable/Guideline Systemic NOAEL = 222 mg/kg/day Systemic LOAEL = 710 mg/kg/day based on decreased body weight, body weight gain, and relative thymus weights; and increased relative spleen and adrenal weights

I mmunotoxicity NOAEL = 222 mg/kg/day) I mmunotoxicity LOAEL = 7 10 mg/kg/day based on reduced thymus weights and decreased anti

- SRBC PFC responseIMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 33 of 37 Appendix B

. Physical/Chemical Properties

Table B.1

. Physicochemical Properties of Imazosulfuron

. Parameter Value Reference 1
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 at 20 oC 429 mg/L at pH 7; 3936 mg/L at pH 9 47305115 Solvent solubility 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 at 25 oC below LOD (<3.5 x 10 - 6 Pa) 47305116 Dissociation constant, pK a at 20 oC 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( P OW ) at 25 oC 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 A ε, x10 4
acidic 238.5 0.8877 3.55

201.0 1.1653 4.66 neutral 238.0 0.8293 3.32

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 47305111IMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 34 of 37 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 gen eric 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 c onduct 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 Rese arch (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. D 409228

Page 35 of 37 Appendix D. Metabolism Summary Table

Table D .1 : Tabular Summary of Metabolites and Degradates Common Name Chemical Name/

Structure Matrix

Imazosulfuron 2

- chloro

- N

- [[(4,6

- dimethoxy

- 2

- pyrimidinyl)amino]carbonyl]imidazo

- [1,2

- α]pyridine

- 3

- sulfonamide Milk

Muscle (goat) Kidney (goat)

Liver (goat)

Eggs

Muscle (hen)

Fat (hen)

Liver (hen) Rat feces Potato

Rice grain

Rice straw

Tomato HMS; O

demethylated imazosulfuron 2

- chloro

- N

- [[(4

- hydroxy

- 6

- methoxy

- 2

- pyrimidinyl)amino]carbonyl]imidazo

- [1,2

- α]pyridine

- 3

- sulfonamide 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 (rotational 30 day) Sorghum stover (rotational 365 day) Sorghum grain (rotational 30 day Sorghum grain ( rotational 365 day) IPSN 2

- chloro

- imidazo[1,2

- a]pyridine

- 3

- sulfonic

acid amide Milk Muscle (goat) Kidney (goat) Liver (goat)IMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 36 of 37 Table D .1 : Tabular Summary of Metabolites and Degradates Common Name Chemical Name/

Structure Matrix

Eggs Muscle (hen) Fat (hen) Liver (hen) Rat feces Potato Rice grain UDPM (4,6

- dimethoxy

- pyrimidin

- 2

- yl)

- urea 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 grain (rotational 30 day) Wheat grain (rotational 120 day) Sorghum grain (ro tational 365 day) ADPM 4,6

- dimethoxy

- pyrimidin

- 2

- ylamine 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) ADNG glucose conjugate of 4,6

- dimethoxy

pyrimidin

- 2

- ylamine Potato

IPSA

- isoserine 3

- (2

- chloro

- imidazo[1,2

- a]pyridine

- 3

-

sulfonylamino)

- 2

- hydroxy

- propionic acid 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)IMAZOSULFURON Human Health Risk Assessment DP No. D 409228

Page 37 of 37 Table D .1 : Tabular Summary of Metabolites and Degradates Common Name Chemical Name/

Structure Matrix

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

IPSA

acetylisoserine 2

- acetoxy

- 3

- (2

- chloro

- imidazo

-

[1,2

- a]pyridine

- 3

- sulfonylamino)

- propionic acid Sorghum forage (rotational 30 day) Sorghum forage (rotational 365 day) Sorghum stover (rotational 30 day) Sorghum stover (rotational 365 day) Sorghum grain (rotational 30 day) Wheat grain (rotational 120 day) S orghum grain (rotational 365 day)

IPSA

caffeoylisoserine 3

- (3,4

- dihydroxy

- phenyl)

- acrylic acid 1

-

carboxy

- 2

- (2

- chloro

- imidazo

- [1,2

- a]pyridine

3

- sulfonylamino)

- ethyl ester 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) Wheat grain (rotational 120 day) Sorghum grain (rotational 365 day)

SDPM 4,6

- Dimethoxypyridine

- 2

-

yl)aminocarbonylsulfamic acid Water (photolysis)