IMAZOSULFURON Human Health Risk Assessment DP No. D427999 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

DATE: July 7, 2015 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Imazosulfuron. Human Health Draft Risk Assessment for Registration Review. 

PC Code: I 18602 

Decision No.: 506476 

Petition No.: NA 

Risk Assessment Type: Single Chemical/ Aggregate 

TXRNo.: NA 

MRIDNo.: NA 

DP Barcode: D427999 

Registration Nos.: 59639-1 54, 155, 166, 189 

Regulatory Action: Registration Review 

Case No.: 7285-1 

CAS No.: 122548-33-8 

40 CFR: 180.651 

FROM: Nancy J. Keller, Risk , Chemist 

Nancy Dodd, Chemist "1~ "' 

Whang Phang, Toxic og st~\? 

Risk Assessment Branch 3 G 

Health Effects Division (7509P) 

THROUGH: C. hristine Olinger, Chief (F/" , / / 

Risk Assessment Branch 3 rf ,,,, "---_ '" 

Health Effects Division (7509 · 

TO: Caitlin Newcamp, Chemical Review Manager 

Risk Management and Implementation Branch 1 

Pesticide Re-Evaluation Division (7508P) 

The Pesticide Re-Evaluation Division (PRD) has requested a Draft Risk Assessment (DRA) from 

the Health Effects Division (HED) to provide information that supports the registration review of 

imazosulfuron. This assessment addresses the exposures and risk estimates associated with all 

currently registered uses. 

Since the last risk assessment, there have been no changes to the imazosulfuron use profile, 

hazard profile, or residue profile (DP409228, S. Healy, 02115/2013). Furthermore, there have 

been no policy changes that would warrant an update to dietary, residential, aggregate, or 

occupational risk estimates. However, a new assessment for indirect non-occupational spray 

drift has been conducted for registration review. There are no outstanding data deficiencies or 

conditions of registration for imazosulfuron at this time. 

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IMAZOSULFURON Human Health Risk Assessment DP No. D427999 

Table of Contents 

1.0 Executive Summary ..................................................................................... ...................... 2 

2.0 Use Profile ........................................................................................................................... 2 

3.0 Hazard ldentificationff oxicology .................................................................. ................... 3 

3.1 Summary of Toxicological Effects ................................................................................ 3 

3.2 Safety Factor for Infants and Children (FQPA Safety Factor) ................................. 3 

3.3 Toxicity Endpoint and Point of Departure Selections ................................................ 3 

4.0 Residue Chemistry ............................................................................................................. 6 

5.0 Dietary Risk Assessment ................................................................... ................................ 7 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ................. .............. 7 

7.0 Aggregate Exposure/Risk Characterization .................................................................... 8 

8.0 Cumulative Exposure/Risk Characterization .................................... ....... ...................... 9 

9.0 Occupational Exposure/Risk Characterization ............................................................ 10 

10.0 References ......................................................................................................................... 10 

Appendix A. Toxicology Profile for Imazosulfuron ............................................................. 11 

1.0 Executive Summary 

lmazosulfuron(2-chloro-N-[[ 4,6-dimethoxy-2-pyri midi ny 1)-ami no ]carbon yl]imidazo [ 1,2-

a ]pyridi ne-3-sul fonamide ), a sulfonylurea (SU) herbicide, is currently registered for use on 

agricultural crops including melons (crop subgroup 9A), peppers, rice, tomatoes, and tuberous 

and corm vegetables (crop subgroup 1 C), as well as ornamentals and established turf grass in 

residential and recreational areas. Valent U.S.A. (Valent) is the only registrant with 

imazosulfuron end-use products at this time. 

Since the last risk assessment, there have been no changes to the imazosulfuron use profile, 

hazard profile, or residue profile (DP409228, S. Healy, 02115/2013). Furthermore, there have 

been no policy changes that would warrant an update to dietary, residential, aggregate, or 

occupational risk estimates. However, a new assessment for indirect non-occupational spray 

drift has been conducted for registration review. There are no outstanding data deficiencies or 

conditions of registration for imazosulfuron at this time. 

2.0 Use Profile 

Currently, imazosulfuron is only formulated as a water-dispersible granule (WG). This 

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. Currently registered labels include one 

technical label, three agricultural labels, three state labels, and one experimental use pennit label. 

In general, imazosulfuron may be applied up to twice a year. Application timing varies 

depending on the target weed (pre-/post-emergent to weeds or pre-/post-emergent to crop 

plantings). The application rates range from 0.010 lb ai/A to 0.30 lb ai/A for all registered uses. 

Depending on the use site, imazosulfuron may be applied via ground. aerial, chernigation, or 

handheld equipment. 

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IMAZOSULFURON Human Health Risk Assessment DP No. D427999 

3.0 Hazard ldentificationffoxicology 

The toxicology database for imazosulfuron is complete and adequate for risk assessment. HED 

has previously determined that a subchronic inhalation study is not required at this time for 

imazosulfuron (TXR#0056566, Hazard and Science Policy Council, 02/20/20 13). New toxicity 

and/or metabolism data have not been received since the last risk assessment, and the selected 

toxicity endpoints and points of departure (PODs) remain the same. A summary of the acute, 

subchronic, and chronic toxicity profile is presented in Appendix A. 

3.1 Summary of Toxicological Effects 

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

toxicity. Many of the effects of single or repeated dosing are observed near or beyond the 

respective limit doses. The primary target organ of imazosulfuron toxicity was the liver in all 

species tested. Mild to moderate thyroid effects were apparent only in the chronic toxicity study 

in dogs. Dramatic eye effects (retinal degeneration, lens vascularization, cataracts and corneal 

scarring) were observed in rats fed greater than the limit dose beginning at 3 months in the 

chronic toxicity/carcinogenicity study. Ocular effects, increased incidence of eye opacity, 

corneal edema, inflammation, and neovascularization, were also observed at a dose substantially 

greater than the limit dose in a subchronic oral toxicity study in rats. Decreased body weight was 

a frequent finding throughout the toxicology database for imazosulfuron. 

Imazosulfuron did not induce neurotoxicity in either acute or subchronic neurotoxicity screening 

battery or in any other repeat-dose study. Developmental effects were not found in rats or 

rabbits with prenatal treatment. Decreased pup viability was observed in the rat two-generation 

reproduction study at a dose approaching the limit dose in both the Fl and F2 offspring; 

increased mortality was also observed in the parental animals at the same dose level. Therefore, 

neither qualitative nor quantitative susceptibility were apparent in fetuses or pups with prenatal 

or postnatal treatment. 

Imazosulfuron produced no evidence of being a carcinogen, mutagen, or clastogen. Acutely, this 

pesticide also demonstrated rather low toxicity by oral, dem1al, or inhalation route of 

administration (mostly Toxicity Category IV). 

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

The FQPA Safety Factor has been reduced to IX for the following reasons: (I) the toxicity 

database of imazosulfuron is complete and adequate to assess the qualitative or quantitative 

susceptibility in the young; (2) There is no evidence of increased qualitative or quantitative 

susceptibility in the young; (3) imazosulfuron produced no evidence of neurotoxicity; and (4) 

exposure estimates are unlikely to underestimate risk. 

3.3 Toxicity Endpoint and Point of Departure Selections 

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IMAZOSULFURON Human Health Risk Assessment DP No. D427999 

There have been no changes to the prior dose-response assessment and cancer classification. It 

should be noted that the previously selected PODs may be conservative relative to the current 

standards for evaluating toxicity studies and determining adverse effects for establishing 

NOAELs and LOAELs. Furthermore, the risk estimates calculated with these PODs does not 

present any risk estimates of concern at this time. 

Table 3.3. Summary of Toxicological Doses and Endpoints for Imazosulfuron for Use in 

Dietary, Non-Occupational and Occupational Human Health Risk Assessments 

Uncertainty/ RfD, Level of 

Exposure/ Point of Safety Concern for Study and Toxicological Effects Scenario Departure Factors Risk 

Assessment 

Acute neurotoxicity screening battery (rat; 

Acute Dietary MRJD 47305319). 

Acute RID = LOA EL = 2000 mg/kg/day based on the (General NOAEL = UFA= IOX 4 mg/kg/day following clinical signs: abnormal gait, Population, 400 UFH = !OX decreased activity, piloerection and upward including mg/kg/day FQPA SF = aPAD = 4 curvature of the spine; and incidents of irregu tar Infants and IX 

Children) mg/kg/day breathing, reduced righting reflex, tremors, 

decreased visual placement response in males 

and increased response to sound in one female. 

Acute Dietary An acute reference dose was not identified for females age 13-49 because there was no prenatal (Females 13- or fetal toxicity observed in developmental or reproductive animal studies following a single 49 years of 

oral dose. 

age) 

Chronic RID 

Chronic NOAEL = UFA= !OX = 0.75 Chronic toxicity (dog; MRlD 47305305) 

Dietary (All 75 UFH = IOX mg/kg/day LOAEL = 150 mg/kg/day based on moderate 

Populations) mg/kg/day FQPA SF = thyroid hypertrophy (males at mid- and highIX cPAD = 0.75 dose: mild hypertrophy in females at high-dose). 

mg/kg/day 

Reproduction, 2 generation (rat; MRJD 

47305304) 

Incidental NOAEL= 88 mg/kg/day 

Oral Short- NOAEL = UFA= IOX LOA EL = 777 mg/kg/day based on increased 

Term (1 -30 266 UFH = !OX LOC for MOE pup mortality (decrease pup viability) and 

days) and mg/kg/day FQPA SF = = 100 deceased body weights. 

lntennediate- (MRID IX Tenn ( 1-6 47305232) 90-day oral toxicity (rat; MRJD 47305232). 

months) NOA EL = 266 mg/kg/day 

LOAEL = 956 mg/kg/day based on decreased 

body weight gains and food efficiency 

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IMAZOSULFURON Human Health Risk Assessment DP No. D427999 

Table 3.3. Summary of Toxicological Doses and Endpoints for Imazosulfuron for Use in 

Dietary, Non-Occupational and Occupational Human Health Risk Assessments 

Exposure/ 

Scenario 

Denna I 

Short-Term 

(1-30 days) 

and 

lntennediateTenn (I-6 

months) 

Inhalation 

Short- Term 

(1-30 days) 

and 

lntem1ed iateTenn (1 -6 

months) 

Cancer (oral, 

dennal, 

inhalation) 

Point of 

Departure 

Uncertainty/ 

Safety 

Factors 

RID, Level of 

Concern for 

Risk 

Assessment 

Study and Toxicological Effects 

No systemic toxicity occurred at the limit dose and the primary toxic effects of concern (liver, 

eye) were adequately assessed in a 2 1-day dermal toxicity study (MRJD 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. 

NOAEL = 

266 

mg/kg/day 

UFA= IOX 

UFH = IOX 

FQPA SF= 

IX 

LOC for MOE 

= 100 

Reproduction, 2 generation (rat; MRID 

47305304) 

NOAEL= 88 mg/kg/day 

LOAEL = 777 mg/kg/day based on parental 

effects: increased mortality, decreased body 

weights, & food consumption. 

90-day oral toxicity (rat; MRJD 47305232). 

NOA EL = 266 mg/kg/day 

LOAEL = 956 mg/kg/day based on decreased 

body weights and food efficiency 

Classification: "Not likely to be Carcinogenic to Humans" based on the absence of significant 

tumor increases in two adequate rodent carcinogenicity studies (MRJD 47305307, mouse; 

MRJD 47305306, rat). 

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

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

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

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFu = potential variation in 

sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of 

concern. 

3.4 Endocrine Disruption 

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse 

outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and 

chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, 

reproductive, and general or systemic toxicity. These studies include endpoints which may be 

susceptible to endocrine influence, including effects on endocrine target organ histopathology, 

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, 

and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and 

chronic studies that assess growth, developmental and reproductive effects in different 

taxonomic groups. As part of its most recent registration decision for metsulfuron-methyl, EPA 

reviewed these data and selected the most sensitive endpoints for relevant risk assessment 

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IMAZOSULFURON Human Health Risk Assessment DP No. 0427999 

scenarios from the existing hazard database. However, as required by FFDCA section 408(p ), 

metsulfuron-methyl is subject to the endocrine screening part of the Endocrine Disruptor 

Screening Program (EDSP). 

EPA has developed the EDSP to determine whether certain substances (including pesticide 

active and other ingredients) may have an effect in hwnans or wildlife similar to an effect 

produced by a "naturally occurring estrogen, or other such endocrine effects as the Administrator 

may designate. " The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier I consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. chemicals that go through Tier I screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine-related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect. 

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between 

October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of 

chemicals identified for EDSP screening was published on June 14, 2013 1 and includes some 

pesticides scheduled for Registration Review and chemicals found in water. Neither of these 

lists should be construed as a list of known or likely endocrine disruptors. 

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

chemicals, future lists, the test guidelines and the Tier I screening battery, please visit our 

website.2 

4.0 Residue Chemistry 

An adequate high performance liquid chromatography 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. 

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. The 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 metabolite UDPM, expressed as equivalents of 

imazosulfuron. The residue of concern for tolerance enforcement in livestock is imazosulfuron 

1 See http://www.rcgulations.gov/#! documentDetail;D=EPA-HO-OPPT-2009-0477-0074 for the final second list of 

chemicals. 2 http://www.epa.gov/endo/ 

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IMAZOSULFURON Human Health Risk Assessment DP No. D427999 

and the residue of concern for dietary risk assessment in livestock is the sum of imazosulfuron 

and the metabolite IPSN, expressed as equivalents of imazosulfuron. 

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

established for imazosulfuron. 

Based on a risk assessment from 20 I 0, there are three conditions ofregistration that were 

pending resolution: (I) storage stability data, (2) confined accumulation in rotational crops data, 

and (3) field accumulation in rotational crops data (DP362653, S. Healy, 11 /03/2010). These 

data have all been submitted and, based on a preliminary review, HED believes the submissions 

are sufficient. The existing imazosulfuron risk estimates and tolerances are not expected to 

change upon full review of these data. 

5.0 Dietary Risk Assessment 

The residue chemistry data and environmental fate data are adequate to assess human exposure. 

The previously conducted dietary exposure assessments are considered conservative and are 

based on re liable data which do not underestimate exposure/risk. Unrefined acute and chronic 

dietary assessments were conducted using assuming I 00% of the crops were treated and that all 

treated crops contained residues at tolerance levels. Default processing factors were assumed for 

the registered crop uses. The highest estimated drinking water concentration (EDWC) of 278.9 

μg/L was incorporated into both acute and chronic assessments. This recommended EDWC 

resulted from the Tier I Rice model, and is based on aerial spray application of 0.30 lb ai/ A per 

year for rice. 

Acute 

Risk estimates for all population subgroups did not exceed HED's level of concern at the 95'11 

percentile of exposure for food and drinking water. The U.S. population resulted in < 1.0% of the 

acute population-adjusted dose (aP AD), while the most highly exposed population subgroup, all 

infants(< I year old), resulted in 1.2% of the a PAD. 

Chronic 

Risk estimates for all population subgroups did not exceed HED's level of concern for dietary 

exposure from food and drinking water. The U.S. population resulted in < l % of the chronic 

population-adjusted dose (cPAD), while the most highly exposed population subgroup, all 

infants (< 1 year old), resulted in 2.0% of the cPAD. 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization 

There are existing residential uses that have been previously assessed according to HED's 2012 

Residential SOPs3 along with policy changes for body weight assumptions (DP403362, C. Walls, 

0I/ 18/2013). Residential handler scenarios resulted in margins of exposure (MO Es) greater than 

the level of concern (i.e. the LOC is an MOE < l 00) and therefore are not of concern to HED. 

The residential short-term post-application incidental oral scenario for children resulted in an 

3 A vai I able: hrtp://www.epa.gov/pest ic ides/science/residential-exposure-sop. htm I 

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IMAZOSULFURON Human Health Risk Assessment DP No. 0427999 

MOE greater than the LOC of 100 and therefore is not of concern to HED (MO Es ranged from 

2, l 00 to 9,300,000). 

Spray Drift 

Off-target movement of pesticides can occur via many types of pathways and it is governed by a 

variety of factors. Sprays that are released and do not deposit in the application area end up offtarget and can lead to exposures to those it may directly contact. They can also deposit on 

surfaces where contact with residues can eventually lead to indirect exposures (e.g. children 

playing on lawns where residues have deposited next to treated fields). The potential risk 

estimates from these residues can be calculated using drift modeling coupled with methods 

employed for residential risk assessments for turf products. 

The approach to be used for quantitatively incorporating spray drift into risk assessment is based 

on a premise of compliant applications which, by definition, should not result in direct exposures 

to individuals because of existing label language and other regulatory requirements intended to 

prevent them.4 Direct exposures would include inhalation of the spray plume or being sprayed 

directly. Rather, the exposures addressed here are thought to occur indirectly through contact 

with impacted areas, such as residential lawns, when compliant applications are conducted. 

Given this premise, exposures for children (1 to 2 years old) and adults who have contact with 

turf where residues are assumed to have deposited via spray drift thus resulting in an indirect 

exposure are the focus of this analysis analogous to how exposures to turf products are 

considered in risk assessment. 

EPA Reg. No. 59639-155 is an existing label for use on turf, thus it was evaluated to determine 

whether the risk assessment for that use may be considered protective of any type of exposure 

that would be associated with spray drift. If the maximum application rate on crops, adjusted by 

the amount of drift expected, is less than or equal to existing turf application rates, the existing 

turf assessment is considered protective of spray drift exposure. For imazosulfuron, the 

registered residential uses on turf result in estimated exposure levels that are greater than the 

potential exposure from spray drift; therefore, no new residential assessment needs to be 

completed. The currently registered maximum single application rate of imazosulfuron for all 

registered crops is 0.30 lb ail A The highest degree of spray drift noted for any application 

method immediately adjacent to a treated field (Tier 1 output from the aerial application using 

fine to medium spray quality) results in a deposition fraction of 0.26 of the application rate. A 

quantitative spray drift assessment for imazosulfuron is not required because the maximum 

application rate to a crop/target site multiplied by the adjustment factor for drift of 0.26 is less 

than the maximum direct spray residential turf application rate 0.75 lb ai/A5 for any 

imazosulfuron products. The turf post-application MOEs have been previously assessed and are 

based on the 2012 Residential SOPs. 

7.0 Aggregate Exposure/Risk Characterization 

Aggregate acute risk is equivalent to acute dietary risk via food and drinking water exposure 

4 This approach is consistent with the requ irements of the EPA's Worker Protection Standard which, 

when included on all labels. precludes direct exposure pathways. 

5 0.30 lb ai/A x 0.26 ::; 0.75 lb ai/A 

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IMAZOSULFURON Human Health Risk Assessment DP No. 0 427999 

pathways and comprises 1.2% of the aP AD 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 < l year old. 

Short- and Intem1ediate Term 

There is potential short- and intermediate-term exposw-e to imazosulfuron via the dietary 

pathway (which is considered background exposure) and the residential pathway (which is 

considered the primary pathway). For adults, since a dermal hazard was not identified, the 

exposure pathways include only the dietary and inhalation (residential handler) routes. For 

children, the exposure pathway includes the dietary exposure and the incidental oral postappli cation residential pathway. All aggregate MOEs are greater than 100; therefore, aggregate 

exposure to irnazosulfuron is not of risk concern. 

Table 7.0. Short- and Intermediate-Term A22regate Risk Calculations 

Population LOC for Dietary MOE Residential MOEc Aggregate MOE 

Aggregate Risk3 (food + drinking water)b (food and residential)d 

Adults 100 43,000 NIA 140,000 33,000 

Children 100 27,000 21,000 NIA 12,000 (I to 2 years old) 

a Adults and Children Level of Concern = 100 (based on inter- and intra- species uncenainty factors, each at I OX). 

b Dietary MOE = NOAEL + chronic dietary exposure. NOAEL = 235 mg/kg/day. Adult chronic dietary exposure = 

0.005957 mg/kg/day (General U.S. population). Children dietary exposure = 0.008712 mg/kg/day (Children 1-2 

years old). 

c Residential MOE based on residential handler exposure and post-application exposure from application to 

residential lawns. 

d Aggregate MOE = I + [(I/dietary MOE) -r (I/residential MOE)]. 

8.0 Cumulative Exposure/Risk Characterization 

In 2015, EPA's Office of Pesticide Programs released a guidance document entitled, Peslicide 

Cumulative Risk Assessment: Framework for Screening Analysis 

[http://www.epa.gov/oppfead l/cb/csb _page/updates/2015/framework-for-screeningana lysis.html]. This document provides guidance on how to screen groups of pesticides for 

cumulative evaluation using a two-step approach beginning with the evaluation of available 

toxicological infonnation and if necessary, followed by a risk-based screening approach. This 

framework supplements the existing guidance documents for establishing common mechanism 

groups (CMGs)lll and conducting cumulative risk assessments (CRA)l2

1. The Agency has 

utilized this framework to evaluate the SUs of which imazosulfuron is a member (DP428798, J. 

D. Agostino, 0910912015). Although the SUs share some chemical and toxicological 

characteristics, the toxicological database does not support a testable hypothesis for a common 

mechanism of action. No further mechanistic data are required and no further cumulative 

evaluation is necessary. 

fll Guidance For Identifying Pes1icide Chemicals and Other Substances That Have a Common 

Mechanism of Toxicity (USEPA, 1999) 

r

21 Guidance on Cumulative Risk Assessment of Pesticide Chemicals That Have a Common 

Mechanism of Toxicity (USEP A, 2002) 

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IMAZOSULFURON Human Health Risk Assessment DP No. 0427999 

9.0 Occupational Exposure/Risk Characterization 

Dermal exposure during handling activities was not considered because systemic toxicity was 

not 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., MO Es 2: 100) at baseline (no respirator) attire (DP403362, C. Walls, 

01/ 18/2013). The lowest MOE of 6,600 represents the most protective worst-case occupational 

scenario: mixing/loading dry flowables (water-dispersible granules) to support aerial applications 

to high acreage crops (i.e. rice). These risk estimates are not of concern to HED. 

Dermal exposure during post-application activities was not considered because no systemic 

toxicity was observed at the limit dose in the dermal 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 need for a quantitative occupational post-application inhalation exposure 

assessment for irnazosulfuron. 

10.0 References 

Healy, S., 02/ 15/201 3, DP409228, lmazosulfuron: Human Health Risk Assessment f or Proposed 

Uses on Melon (Crop Subgroup 9A) and Tuberous and Corm Vegetables (Crop Subgroup IC). 

Healy, S., 11/03/20 I 0, DP362653, lmazosulfuron: Human Health Risk Assessment for Proposed 

Uses on Rice. Peppers and Tomatoes. 

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IMAZOSULFURON Human Health Risk Assessment DP No. 0427999 

Appendix A. Toxicology Profile for lmazosulfuron 

Technical 

Table A.1. Toxicology Data Requirements Required Submitted 

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

870.1200 Acute Dennal Toxicity .................................................. yes yes 

870. 1300 Acute Inhalation Toxicity .............................................. yes yes 

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

870.2500 Primary Dennal Irritation .............................................. yes yes 

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

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

870.3 150 Oral Subchronic (non-rodent) ........................................ yes yes 

870.3200 2 1-0ay Den11al .............................................................. yes yes 

870.3250 90-Day Dennal .............................................................. no no 

870.3465 90-Day Inhalation .......................................................... cR• waivedb 

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

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

870.3800 Reproduction ................................................................. yes yes 

870.4 lOOa Chronic Toxicity (rodent) .............................................. n/a - 870.4 IOOb Chronic Toxicity (non-rodent) ....................................... yes yes 

870.4200a Oncogen icity (rat) .......................................................... n/ a - 870.4200b Oncogenicity (mouse) ................................................... yes yes 

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

870.5100 Mutagenicity-Gene Mutation - bacterial ..................... yes yes 

870.5300 Mutagenicity-Gene Mutation - mammalian ................ yes yes 

870.5375 Mutagenicity-Structural Chromosomal Aberrations ... yes yes 

870.5395 Mutagenicity- Other Genotoxic Effects ....................... yes yes 

870.6100a Acute Delayed Neurotoxicity (hen) ............................... no no 

870.6100b 90-Day Neurotoxicity (hen) ........................................... no no 

870.6200a Acute Neurotoxicity Screening Battery (rat) ................. yes yes 

870.6200b 90-Day Neurotoxicity Screening Battery (rat) ............... yes yes 

870.6300 Develop. Neuro .................................................... .......... no no 

870.7485 General Metabolism ...................................................... no yes 

870.7600 Denna! Penetration ........................................................ no no 

870.7800 lrnmunotoxicity ............................................................. yes yes 

a CR = conditionally required. 

b The Hazard and Science Policy Counc il (HASPOC) detem1ined that a subchronic inhalation study is not required 

at this time for imazosulfuron (TXR#0056566, 02/20/2013). 

Table A.2. Acute Toxicity Profile - Test Substance 

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

870.1100 Acute oral - rat 47305221 LDso > 5000 mg/kg IV 

870.1200 Acute dennal - rat 47305227 LDso > 2000 mg/kg Ill 

870.1300 Acute inhalation - rat 47305228 LCso > 2.12 mg/L IV 

870.2400 Acute eye irritation - rabbit 47305229 Non-irritating IV 

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IMAZOSULFURON Human Health Risk Assessment DP No. 0427999 

870.2500 Acute dermal irritation - rabbit 47305230 Non-irritating IV 

870.2600 Skin sensitization - guinea pig 4730523 1 Negative NI A 

Metabolites 

870.1100 IHOA 47305222 LDso > 5000 mg/kg IV 

870.1100 UDPM 47305223 LDso = 677 mg/kg Ill 

870.1100 IPSN 47305224 LDso = 4 15 mg/kg, males; II 445 mg/kg. fema les 

870.1100 M-1 47305225 LDso > 5000 mg/kg IV 

870. 1100 ADPM 47305226 LDso = 836 mg/kg I II 

Page 12 of 15 
IMAZOSULFURON Human Health Risk Assessment DP No. D427999 

Table A.3 Subchronic, Chronic and Other Toxicity Profile of Imazosulfuron 

Guideline Study Type MRID Number (year)/ Results Number Classification/Doses 

47305232 ( 1991) NOA EL= 235/266 mg/kg/day (MJF) 

90-Day oral Acceptable/Guideline LOAEL = 95611081 (M/F) based on 870.3100 

toxicity (rat) 0. 2500. I 0000. 45000 ppm: reduced mean body weights and food M: 0, 234.7. 956.3. 4577.2 mg/kg/day: 

F: 0. 265.7. 1081.4. 5135.7 mg/k!!lday efficiency. 

47305233 ( 1991 ) NOA EL= I 820/2727 mg/kg/day (M/F) 

90-Day oral Acceptable/Guideline LOAEL = 9776/ 12695 mg/kg/day 

870.3 JOO toxicity (mouse) 0, 2500. I 0000. 45000 ppm: (M/F) based on central lobular 

M: 0, 456, I 820, 9776 mg/kg/day; hepatocyte hypertrophy and increased 

F: 0, 692, 2727, 12695 mg/kg/day liver weie.hts. 

870.3 I 50 90-Day oral No available toxicity (dog) 

2 1128-Day 4 7305236 (2006) 

870.3200 dermal toxicity Acceptable/Guideline NOAEL = 1000 mg/kg/day (HOT). 

(rat) 0, I 00, 300, I 000 mg/kg/day 

870.3465 90-Day Waived (TXR: 0056566; 212012013) inhalation study 

4 7305238 ( 1989) Maternal NOA EL = I 000 mg/kg/day 

Acceptable/Guideline (limit); 

Prenatal 0, 250, 500, I 000 mg/kg/day. Since LOAEL = 1500 mg/kg/day based on 

870.3700a developmental no maternal toxicity was observed in the decreased body weight gain and food 

(rat) original treatment groups. an additional consumption. 

treatment group of 1500 mg/kg/day was Developmental NOAEL = 1500 

added to the study. mg/kg/day 

{HOT; > limit dose) 

4 730530 I ( I 990) 

Maternal NOA EL = I 25 mg/kg/day Prenatal Acceptable/Non-Guideline• 

870.3700b developmental 0, 25, 50, 125 mg/kg/day (HDT) 

(rabbit) Developmental NOAEL = 125 

•tested under FIFRA S11bd1v1sio11 F mg/kg/day; 

flwdelines 

Parenta l NOA EL = 78/88 mg/kg/day 

(MIF) 

47305304 ( 1990); LOAEL = 777/869 mg/kg/day (M/F) 

Acceptable/Guideline based on mortality, clinical signs, 

Reproduction 0, 100, 1,000, 10,000 ppm: decreased body weights and food 

870.3800 and fenility Fo consumption. 

effects M: 0, 7.7, 77.8, 777.4 mg/kg/day; Reproductive NOAEL = 777/869 

{rat) F: 0, 8.93, 88.4, 868.5 mg/kg/day; mg/kg/day (M/F) (HOT) 

Offspring NOA EL = 78/88 mg/kg/day 

(M/F) LOAEL = 777/869 mg/kg/day 

(MJF) based on decreased pup viability 

and body weie.hts. 

NOA EL = 75 mg/kg/day 

Chronic toxicity 4 7305305 ( 1990) LOAEL = 150 mg/kg/day based on 

870.4 IOOb Acceptable/Guideline moderate thyroid hypertrophy (males at (dog) 0, 75, I 50, 300 mg/kg/day mid- and high-dose; mild hypertrophy 

in females at hi.e.h-dose). 

Page 13 of15 
IMAZOSULFURON Human Health Risk Assessment DP No. D427999 

Table A.3 Subchronic, Chronic and Other Toxicity Profile of lmazosulfuron 

Guideline Study Type MRID Number (year)/ Results Number Classification/Doses 

47305307 (1991) NOA EL = 73/87 mg/kg/day (M/F) Acceptable/Guideline 

Carcinogenicity 0,450,4500,45000ppm; LOAEL = 741 /870 mg/kg/day (M/F) 

870.4200b (mouse) M: 0, 72.7, 741.3, 7848.1 based on centrilobular swelling of 

mg/kg/day: hepatocytes. 

F: 86.8, 870.0, I 0303.5 mg/kg/day No evidence of carcinogenicity 

47305306 (199 1): NOA EL = I 061132 mg/kg/day (M/F) 

0, 200, 2000, 20000 ppm; 

LOA EL = 1124/1554 mg/kg/day (M/F) 

Chronic M: 0, 10.39, 106.10, 1123.99 based on increased mortality, decreased 

870.4300 toxicity/Carcinog mg/kg/day; 

body weight, and clinical ophthalmic 

en icity F: 0, 12.94, 132.46, 1554.35 observations (cataracts and retinal 

(rat) mg/kg/day. degeneration) and hepatotoxicity in 

females. Acceptable/Guideline No evidence of carcinogenicity 

Bacterial reverse 47305308 ( 1988) TH-913 Technical: Test article has no 

870.5100 reverse mutagenic potential under these mutation test Acceptable/Guideline experimental conditions 

Bacterial reverse 4 7305309 ( 1990) UDPM: Test article has no reverse 

870.5100 mutagenic potential under these mutation test Acceptable/Guideline experimental conditions 

Bacterial reverse 47305310 (1993) THOA: Test article has no reverse 

870.5100 mutation test Acceptable/Guideline mutagenic potential under these 

experimental conditions 

Bacterial reverse M-1: Test article has no reverse 

870.5 100 mutation test; 473053 11 ( 1989) mutagenic potential under these 

870.5500 DNA repair test 

Acceptable/Guideline experimental conditions: negative with 

or without S9 metabolic activation 

Bacterial reverse 47305312 (1988) IPSN: Test artic le has no reverse 

870.5100 mutagenic potential under these mutation test Acceptable/Guideline experimental conditions 

Bacterial reverse 47305313 ( 1990) ADPM: Test article has no reverse 

870.5100 mutagenic potential under these mutation test Acceptable/Guideline experimental conditions 

In vitro 

870.5300 mammalian cell 473053 14 ( 1999) Test article is not mutagenic in test 

gene mutation Acceptable/Guideline system 

test 

Test article "was considered to induce 

no chromosomal aberration because the 

In vitro test substance showed a suspect 

870.5375 mammalian cell 47305315 (1988) positive by the direct method but the 

chromosome Acceptable/Guideline same results were not reproduced." 

aberration test Test article did not induce 

chromosomal aberrations at any 

concentration in presence of S9. 

Mammalian 4 73053 16 (2007) Test article has no potential to induce 

870.5395 erythrocyte Acceptable/Guideline micronuclei in mouse bone marrow 

micronucleus test cells under the conditions of this test 

Page 14 of 15 
lMAZOSULFURON Human Health Risk Assessment DP No. 0427999 

Table A.3 Subchronic, Chronic and Other Toxicity Profile of Imazosulfuron 

Guideline Study Type MRJD Number (year)/ Results Number Classification/Doses 

NOA EL = 400 mg/kg/day; 

Acute 4 7305319 (2007); LOA EL = 2000 mg/kg/day based on 

870.6200a neurotoxicity Acceptable/Guideline the clinical signs: abnonnal gait, 

screening battery 0, 80, 400, 2000 mg/kg decreased activity, piloerection and 

upward curvature of the spine and 

decreased motor activity in males. 

47305320 (2007) NOAEL = 169/201 mg/kg/day (M/F) 

870.6200b Subchronic Acceptable/Guideline LOAEL = 57 1/655 mg/kg/day (M/F) 

neurotoxicity 80~2500 8000ppm; based on decreased body weight and 

screening battery M: 0, 54.0, I 69.2, 571.3 mg/kg/day; food efficiency. 

F: 0, 6 1.9, 200.8, 655.3 mg/k!!/day No neurotoxicity was found. 

Parent and 5 metabolites were 

identified and quantified. Parent was 

detected on ly in feces and amounted to 

0.9% of the administered dose (AD). 

Metabolism and HMS, the predominant metabolite, was 

870.7485 pharmacokinetic 47305322 (2007) found in the urine at 6, 12 and 24 hours 

s Acceptable/Guideline amounting to 3 1.1 , 18.4 and 6.2 % of 

(rat) the dose, respectively, and in lesser 

amounts, in the feces (6.5). The lesser 

metabolites(< 5% AD), IHDU. HOS, 

IPSN and ACIS were identified in urine 

and feces. 

Metabolism and The absorption rate was estimated to be 

870.7485 phannacokinetic 47305323 (2007) - I 00%. Near complete elimination 

(66.4% urine, 34.0% bile, 2.4% feces) s Acceptable/Guideline within 24 hours after administration of (rat) radiolabeled compound was observed. 

Systemic NOA EL = 222 mg/kg/day 

Systemic LOAEL = 710 mg/kg/day 

based on decreased body weight, body 

weight gain, and relative thymus 

I mmunotoxicity 48691003 (2011) weights; and increased relative spleen 

870.7800 and adrenal weights (rat) Acceptable/Guideline lmmunotoxicity NOA EL = 222 

mg/kg/day) lmmunotoxicity LOAEL = 

710 mg/kg/day based on reduced 

thymus weights and decreased antiSRBC PFC response 

Page 15 of 15