Iodosulfuron-Methyl-Sodium Human-Health Assessment Scoping Document D404948 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: 

Subject: 

From: 

Tbru: 

To: 

7-March-2013 

lodosulfuron-Metbyl-Sodium. Human-Health Assessment Scoping Document in 

Support of Registration Review. 

PC Code: 122021 DP Barcode: 0404948 

Decision No.: 469137 Registration Nos.: N/A 

Petition No.: N/A Regulatory Action: Registration Review Scoping Document 

Risk Assessment Type: Scoping Document Case No.: 7253 

TXRNo.: N/A CAS No.: 144550-36-7 

MRID No.: none 40CFR: 180.580 

Tom 

Chester 

Bloem, 

E. Rodriguez, 

Chemist, 

Ph.D.

Risk Assessment 

, Pharmacologist, 

Branch 

RABl 

1 (RA~k "...(, ~7. 

Matthew Crowley, Biologist, Chemistry and Exposure Branch EB) f/./~ Health Effects Division (HED, 7509P) /-· 

Dana Vogel, Associate HED Director and RAB 1 Branch Chief 

George F. Kramer, Ph.D., Senior hemist~ .PI(• • 

RABl/HED (7509P) 

Katherine StClair, Chemical Review Manager 

Eric Miederhoff, Acting Team Leader 

Kevin Costello, Branch Chief 

Risk Management & Implementation Branch 4 

Pesticide Reevaluation Division (PRD, 7508P) 

Attached is HED's human-health risk assessment scoping document for iodosulfuron-methylsodium submitted in support of Registration Review. 

Page I of23 
lodosulfuron-Methyl-Sodium Human-Health Assessment Scoping Document 0404948 

EXECUTIVE SUMMARY 

Background: Iodosulfuron-methyl-sodium is a sulfonylurea herbicide (Group 2) which 

interferes with branched-chain amino acid biosynthesis through inhibition of acetolactate 

synthase (ALS) in susceptible plants (annual/perennial grass and broadleafweeds). 

lodosulfuron-methyl-sodium is currently registered for foliar application to wheat, triticale, field 

corn, and turf (commercial/industrial, sod farms, ornamental, golf course, recreational, 

residential) and for preplant burndown application for cereal grains, soybean, and cotton. 

Several products are registered all of which are water-dispersible granules (WDG). The 

maximum seasonal application rate is 0.0089 lb ai/acre. The most recent HED human-health risk 

assessment was conducted in 2008 (D350046, S. Levy et al., 12-Nov-2008). 

HED evaluated the iodosulfuron-methyl-sodium human-health risk assessments to determine 

whether sufficient data are available and whether any updates are needed to support Registration 

Review. HED has considered all registered uses for iodosulfuron-methyl-sodium with respect to 

its toxicity, exposure, and usage databases, and the most updated Agency science policy and risk 

assessment methodologies to determine the scope of work necessary to support Registration 

Review. HED notes that iodosulfuron-methyl-sodium is applied in combination with the 

safeners isoxadifen-ethyl or mefenpyr-diethyl. In addition, metsulfuron-methyl, a registered 

active ingredient (PC code 122010), is a residue of concern in drinking water following 

application of iodosulfuron-methyl-sodium. The current document pertains only to the 

Registration Review ~ata requirements for iodosulfuron-methyl-sodium. 

It is noted that at the time the first human-health risk assessment for iodosulfuron-methyl-sodium 

was being conducted, a full review of the metsulfuron-methyl toxicological database had not yet 

been conducted and the assessment assumed that the doses and endpoints for iodosulfuron-methylsodium were applicable to metsulfuron-methyl (D267577, T. Bloem, 30-Jan-2002). Since that 

time, the metsulfuron-methyl toxicological database has undergone a full review by the HED 

Hazard Identification Assessment Review Committee (HIARC; 14-Mar-2002; HED Doc. No. 

0050569). As a result of this review, it was concluded that metsulfuron-methyl and iodosulfuronmethyl-sodium are not toxicologically identical and exposures do not need to be combined. 

Hazard Identiftcation!Toxicology: The toxicity database for iodosulfuron-methyl-sodium is 

adequate to support current registration requirements; currently, no additional toxicological 

studies are required. It is noted that as part of Registration Review, the iodosulfuron-methylsodium points of departure (PODs) will be reevaluated along with reevaluation of the of the 

toxicological and exposure databases in terms of assigning a Food Quality Protection Act Safety 

Factor (FQPA SF). The following paragraphs are a summary of the toxicological profile for 

iodosulfuron-methyl-sodium. 

Iodosulfuron-methyl-sodium was classified as having low acute toxicity via the oral (Category 

Ill), dermal (Category III), and inhalation (Category IV) routes of exposure. It was not irritating 

to the eye and not considered a dermal sensitizer. The subchronic and chronic oral toxicity 

studies indicated that the target organs include the liver and hematopoietic system. The most 

sensitive species tested was the dog. In a subchronic toxicity study with dogs, the reported toxic 

effects were changes in hematology (decreased hemoglobin and hematocrit), microscopic 

pathology of the bone marrow (hemopoietic hyperplasia, preponderance of immature 

granulocytes, and reduced number of erythroblasts), and liver effects (macroscopic changes 

including coloration differences and an accentuated lobular pattern). In addition to 

Page 2 of23 
Iodosulfuron-Methyl-Sodium Human-Health Assessment Scoping Document D404948

Page 3 of 23

histopathological changes in the hematopoietic system, the chronic dog study also reported 

peripheral swelling of the spleen. In the mouse, only liver effects were reported in both chronic 

and subchronic studies (increased weight and histopathological changes). In the rat subchronic 

and chronic studies, the only effects reported were body-weight decrements (including decreased 

body-weight gain) and decreased food efficiency. The immunotoxicity study indicated that the 

immune system is not a direct target of iodosulfuron-methyl-sodium toxicity. Iodosulfuronmethyl-sodium was non-mutagenic in various assays. The HIARC classified iodosulfuron as 

“not likely to be carcinogenic to humans” based on the lack of evidence for carcinogenicity in 

mice and rats (TXR # 0052286).

In a prenatal developmental toxicity study in rats, there was evidence of increased qualitative 

prenatal susceptibility based on delayed ossification in the fetuses of dams that exhibited 

minimal toxicity (salivation). Similarly, there was also evidence of quantitative increased 

susceptibility based on the multi-generation rat reproduction study where there was decreased 

pup viability on postnatal days 0 and 4 in the absence of parental effects at the highest dose 

tested. Susceptibility was not observed in the developmental toxicity study in the rabbit; no 

effects (maternal or developmental) were identified.

The acute neurotoxicity (ACN) study revealed decreased motor and locomotor activity at 

relatively high dose levels (lowest-observed adverse-effect level (LOAEL) =500 mg/kg bw). 

The HED Hazard and Science Policy Council (HASPOC) met on October 9th, 2012 (TXR 

#.0052381) to determine if a subchronic neurotoxicity study for iodosulfuron-methyl-sodium 

was necessary. Based on the following considerations, the Committee decided to not require a 

subchronic neurotoxicity study: (1) the lack of evidence in the available toxicology studies for 

the nervous system being a target of iodosulfuron-methyl-sodium toxicity; (2) effects on the liver 

and hematopoietic system are the primary toxic effects in the most sensitive species (dog) and 

provides the most sensitive POD for risk assessment; and (3) the low concern for neurotoxicity 

in other members of this class of chemicals (i.e., sulfonylureas) for which evidence for 

neurotoxicity among this group occurred at high doses or near the limit dose. 

The HASPOC also considered the need for a repeated exposure inhalation toxicity study. The 

committee decided to not require an inhalation study at this time on the basis of the following 

considerations: (1) the physical/chemical properties and low volatility (6.7 x 10-9Pa at 25 C) of 

iodosulfuron-methyl-sodium; (2) the low acute inhalation toxicity of iodosulfuron-methylsodium; (3) the use of an oral POD that results in occupational inhalation margins of exposure 

(MOEs) greater than 6700; and (4) the low concern for inhalation toxicity in other members of 

this class of chemicals (i.e., sulfonylureas). 

Residue Chemistry and Dietary Exposure: Adequate metabolism (crops, livestock, and 

rotational crops) and magnitude of the residue data are available to support the registered uses. 

Based on these data and the low application rates and low livestock dietary burdens, HED 

concluded that the residue of concern in cereal grains, rotational crops, and livestock, for 

purposes of tolerance enforcement and risk assessment, is only iodosulfuron-methyl-sodium 

(note that HED determined that the preplant application to cotton and soybean scenario did not 

require a tolerance). Adequate methods are available for enforcement of the currently 

established tolerances. No additional residue chemistry data are needed to support the currently 

registered uses. As part of Registration Review, a revised dietary risk assessment may be 

necessary to reflect potential revised estimated drinking water concentrations (EDWCs), the 

most recent dietary exposure models, and/or revised toxicological PODs.
Iodosulfuron-Methyl-Sodium Human-Health Assessment Scoping Document D404948

Page 4 of 23

Residential Exposure: The residential exposure database is adequate to support the Registration 

Review process. Based upon revisions to HED’s Residential Standard Operating Procedures 

(SOPs) and/or potential changes to the toxicological PODs, residential handler exposure 

estimates and updated post-application exposure assessments may be required under Registration 

Review. Based on existing and anticipated residential post-application risk estimates and the 

current toxicological PODs, a turf-transferable residue (TTR) study is unnecessary. 

Aggregate Risk Assessment: As part of Registration Review, updated aggregate risk 

assessments may be necessary to reflect revised residential exposure estimates, dietary exposure 

estimates, and/or toxicological PODs. 

Occupational Exposure: The occupational exposure database is adequate to support the 

Registration Review process. Based upon revisions to the Agency’s scenario-specific surrogate 

handler-exposure data, updated occupational handler exposure assessments may be required 

under Registration Review. Reviewers should incorporate new exposure monitoring data, as 

necessary, during Registration Review. Updated occupational post-application exposure 

assessments may be required under Registration Review based upon revisions to the Agency’s 

post-application exposure data. Revised occupational handler and post-application assessments 

may also be needed if toxicological endpoints change or other new data are received by the 

Agency that impact exposure estimates. Based on existing and anticipated residential postapplication risk estimates and the current toxicological PODs, it appears that TTR and/or 

dislodgeable-foliar residue (DFR) studies are unnecessary. 

Summary - Risk Assessment Updates, Data Deficiencies, and Label Revisions: The risk 

assessment updates that may be required under Registration Review. Based on the current use 

patterns, there are no data deficiencies.

Risk Assessment Updates: 

●The current PODs will be reevaluated along with evaluation of the toxicological and exposure 

databases in terms of assigning a FQPA SF. 

●Revised dietary risk assessment may be necessary to reflect revised EDWCs, dietary exposure 

models, and/or toxicological PODs.

●Revised residential risk assessment may be necessary to incorporate guidance from the updated 

Residential SOPs and/or toxicological PODs. 

●Revised aggregate risk assessment may be necessary to reflect revised residential exposure 

estimates, dietary exposure estimates, and/or toxicological PODs. 

●Revised occupational risk assessment may be necessary to reflect the most recent HED policies

and/or toxicological PODs. 

HED notes that based on the assumptions and resulting risks associated with the currently 

registered uses, it is highly unlikely that revised risk assessments conducted in support of 

registration review will yield exposure greater than HED’s level of concern. 
Iodosulfuron-Methyl-Sodium Human-Health Assessment Scoping Document D404948

Page 5 of 23

DETAILED CONSIDERATIONS

Registered Use Patterns

Iodosulfuron-methyl sodium is currently registered for foliar application to wheat, triticale, field 

corn, and turf (commercial/industrial, sod farms, ornamental, golf course, recreational, 

residential) and for preplant burndown application for cereal grains, soybean, and cotton. 

Several products are registered all of which are WDG formulations. The maximum seasonal 

application rate is 0.0089 lb ai/acre. See Attachment E for a summary of the registered end-use 

products and application scenarios. 

Hazard Identification/Toxicology

Iodosulfuron-methyl-sodium is a sulfonylurea herbicide that acts as an inhibitor of ALS which is 

involved in the synthesis of amino acids critical for plant growth. In mammals, the function of ALS 

has not been firmly established, and thus it remains unclear if mammalian toxicity is due to a 

similar mode of action. See Attachment C and D for a summary of the iodosulfuron-methyl-sodium 

toxicological profile and PODs used in the most recent human-health risk assessment (D350046, S. 

Levy et al., 12-Nov-2008). 

Following oral administration of radiolabeled iodosulfuron-methyl-sodium in rats and dogs, 

absorption was rapid in both species with a time to maximum plasma levels (tmax) of 3-6 hours. 

A prolonged tmax was noted in rats only at a very high dose (500 mg/kg bw). Elimination of 

radioactivity was mainly via the urine in both species. In dogs, renal excretion accounted for 64-

74% while the contribution of fecal radioactivity was estimated at 14-17%. Most of the dose 

was excreted within 24 hours at the low dose tested of 6 (dogs) and 10 (rats) mg/kg bw. 

Elimination of radioactivity from the blood in rats was biphasic and similar for both sexes, 

though elimination was slightly more rapid in females. For the first phase of elimination, the 

plasma half-life was estimated at 2.6-3.2 hours for the oral low-dose group and at 3.6-4.6 hours 

for the high-dose group. A comparison of the dose-corrected AUC (area under the curve) values 

for the oral and an intravenous (IV)-tested low-dose groups indicates that bioavailability was 

higher for males (83%) than females (63%). 

In acute toxicity studies in mammals, iodosulfuron-methyl-sodium was classified as having low 

acute toxicity via the oral (Category III), dermal (Category III), and inhalation (Category IV) 

routes of exposure. It was not irritating to the eye and not considered a dermal sensitizer.

The subchronic and chronic oral toxicity studies indicated that the target organs include the liver 

and hematopoietic system. The most sensitive species tested was the dog. In a subchronic 

toxicity study with dogs, the reported toxic effects were changes in hematology (decreased 

hemoglobin and hematocrit), microscopic pathology of the bone marrow (hemopoietic 

hyperplasia, preponderance of immature granulocytes, and reduced number of erythroblasts), and 

liver effects (macroscopic changes including coloration differences and an accentuated lobular 

pattern). In addition to histopathological changes in the hematopoietic system, the chronic dog 

study also reported peripheral swelling of the spleen. 

In the mouse, only liver effects were reported in both chronic and subchronic studies. The 

effects consisted of increased weight and histopathological changes (centrilobular hepatocyte 

enlargement, fat deposits in the periportal centrilobular regions, and focal necrosis).
Iodosulfuron-Methyl-Sodium Human-Health Assessment Scoping Document D404948

Page 6 of 23

In the rat subchronic and chronic studies, there were no effects reported to the liver or hemapoietic 

system; the only effects reported were body-weight decrements (including decreased body-weight

gain) and decreased food efficiency.

In a prenatal developmental toxicity study in rats, there was evidence of increased qualitative 

prenatal susceptibility based on delayed ossification in the fetuses of dams that exhibited minimal

toxicity (salivation). Similarly, there was also evidence of quantitative increased susceptibility 

based on the multi-generation rat reproduction study where there was decreased pup viability on 

postnatal days 0 and 4 in the absence of parental effects at the highest dose tested. Susceptibility 

was not observed in the developmental toxicity study in the rabbit; no effects (maternal or 

developmental) were identified.

In the most recent risk assessment (D350046, S. Levy et al., 12-Nov-2008), potential neurotoxicity 

could not be evaluated because neurotoxicity (acute and subchronic) studies were lacking in the 

toxicity database. Since then, an ACN study has been submitted by the Registrant and reviewed by 

the Agency. The rat ACN study revealed decreased motor and locomotor activity at relatively high 

dose levels (LOAEL =500 mg/kg bw). The HASPOC met on October 9th, 2012 (TXR #.0052381)

to decide on the need for a subchronic neurotoxicity study for iodosulfuron-methyl-sodium. Based 

on the following considerations, the committee decided to not require a subchronic neurotoxicity 

study: (1) the lack of evidence in the available toxicology studies for the nervous system being a 

target of iodosulfuron-methyl-sodium toxicity; (2) effects on the liver and hematopoietic system are 

the primary toxic effects in the most sensitive species (dog) and provides the most sensitive POD 

for risk assessment; and (3) the low concern for neurotoxicity in other members of this class of 

chemicals (i.e., sulfonylureas) for which evidence for neurotoxicity among this group occurred at 

high doses or near the limit dose. 

The HASPOC also considered the need for a repeated exposure inhalation toxicity study. The 

Committee decided to not require an inhalation study at this time on the basis of the following 

considerations: (1) the physical/chemical properties and low volatility (6.7 x 10-9Pa at 25 C) of 

iodosulfuron-methyl-sodium; (2) the low acute inhalation toxicity of iodosulfuron-methyl-sodium; 

(3) the use of an oral POD that results in occupational inhalation MOEs greater than 6700; and (4) 

the low concern for inhalation toxicity in other members of this class of chemicals (i.e., 

sulfonylureas). 

In the last risk assessment, an immunotoxicity study was noted as missing from the database. Since 

then, such a study has been submitted by the Registrant and reviewed by the Agency. The results of 

the study do not indicate that the immune system is a direct target of iodosulfuron-methyl-sodium

toxicity. Iodosulfuron-methyl-sodium was non-mutagenic in various assays and there is no

evidence of carcinogenicity based on studies carried out with rats and mice. The HIARC classified 

iodosulfuron-methyl-sodiumas “not likely to be carcinogenic to humans” based on the lack of 

evidence for carcinogenicity in mice and rats (TXR # 0052286).

Conclusions: The toxicity database for iodosulfuron-methyl sodium is adequate to support current 

registration requirements (no additional toxicological studies are currently required). However, as 

part of Registration Review, the iodosulfuron-methyl-sodium PODs will be reevaluated along with 

reevaluation of the toxicological and exposure databases in terms of assigning a FQPA SF. 
Iodosulfuron-Methyl-Sodium Human-Health Assessment Scoping Document D404948

Page 7 of 23

Residue Chemistry and Tolerance Assessment

Iodosulfuron-methyl-sodium is registered for postemergence application to field corn, wheat, and 

triticale and for preplant application to soybean, cereal grains, and cotton. Tolerances are 

established for residues of iodosulfuron-methyl-sodium per se in/on field corn and wheat 

commodities at 0.02-0.10 ppm (40 CFR § 180.580). Based on the preplant application scenario, 

HED concluded that tolerances in/on soybean, cotton, and the remaining cereal grains were 

unnecessary. 

Adequate wheat (triazinyl or phenyl labeled), dairy cow (phenyl labeled), and hen (phenyl 

labeled) metabolism studies, as well as adequate confined rotational crop studies (triazinyl 

labeled), are available to support the registered agricultural uses. Based on these data and the 

low application rates and low livestock dietary burdens, HED concluded that the residue of 

concern in cereal grains, rotational crops, and livestock, for purposes of tolerance enforcement 

and risk assessment, is only iodosulfuron-methyl-sodium (HED Metabolism Assessment Review 

Committee (MARC) decision memorandum – D278092, T. Bloem, 25-Oct-2001; D350509, S. 

Levy, 29-Oct-2008). It was noted that, depending on the proposed crop(s), application rates,

and/or livestock dietary burdens associated with future petitions, these conclusions may be 

revisited and/or additional metabolism (plant and/or livestock) and confined rotational crop 

studies may be required. HED advised that any future plant metabolism or confined rotational 

crop studies be conducted with the intended safener and correct active ingredient to safener ratio. 

Metsulfuron-methyl, a registered active ingredient (PC code 122010), was identified in the wheat 

and ruminant metabolism studies and in the confined rotational crop study but was not included 

as a residue of concern as, based on the application scenarios, residues were expected to be 

negligible. 

Adequate crop field trial and processing data are available for all registered crops. There are no 

outstanding issues related to the use directions and/or tolerances. Adequate methods are 

available for enforcement of the currently established corn and wheat tolerances (D282138, T. 

Bloem, 11-Apr-2002; D363433, S. Levy, 1-Apr-2009). In addition, data have been submitted 

which indicate that iodosulfuron-methyl-sodium is not recoverable through the FDA 

Multiresidue Method (MRM) protocols (MRID 45108716). 

Conclusions: The current residue chemistry database is sufficient to support the registered uses; 

No additional residue chemistry data are required.
Iodosulfuron-Methyl-Sodium Human-Health Assessment Scoping Document D404948

Page 8 of 23

EDWCs

Laboratory studies indicated that iodosulfuron-methyl-sodium is not persistent (half-life of 2-8 

days) and degrades via either dehalogenation, cleavage of the sulfonylurea bridge, and/or 

demethoxyfication of the triazine ring. Several degradates were found, including metsulfuronmethyl (registered active ingredient; PC code 122010), which forms relatively rapid from 

iodosulfuron-methyl-sodium in soils under both aerobic and anaerobic conditions. Metsulfuronmethyl does not form under abiotic conditions. Both iodosulfuron-methyl-sodium and 

metsulfuron-methyl are very mobile in soils. 

The MARC reviewed the environmental fate data for iodosulfuron-methyl-sodium and 

concluded that the residues of concern in drinking water are iodosulfuron-methyl-sodium and 

metsulfuron-methyl (D278092, T. Bloem, 25-Oct-2001). Based on the registered application 

rates, residues of metsulfuron-methyl resulting from application of iodosulfuron-methyl-sodium 

are expected to be insignificant when compared to residues resulting from application of 

metsulfuron-methyl. 

EFED has provided surface water and groundwater EDWCs for iodosulfuron-methyl-sodium

resulting from the registered uses (D350049, J. Wolf, 29-Aug-2008; D315491, S. Termes, 12-

Jan-2006). The highest acute and chronic EDWCs were generated from the turf (0.60 ppb; 

FQPA Index Reservoir Screening Tool (FIRST)) and wheat (0.067 ppb; Pesticide Root Zone 

Model/Exposure Analysis Modeling System (PRZM/EXAMS)) scenarios, respectively. These 

estimates were incorporated into the most recent dietary exposure analyses (see below). 

Conclusions: As part of Registration Review, EFED anticipates generating revised EDWCs to 

reflect current practices/models. 

Dietary Exposure

HED has conducted acute and chronic dietary exposure analyses which considered all currently 

registered uses (D355405, S. Levy, 5-Nov-2008). The analyses were conducted using the 

Dietary Exposure Evaluation Model – Food Consumption Intake Database (DEEM-FCIDTM, ver. 

2.03) which incorporates the food consumption data from the United States Department of 

Agriculture (USDA) Continuing Surveys of Food Intakes by Individuals (CSFII; 1994-1996 and 

1998) and assumed tolerance level residues and 100% crop treated. The resulting acute (<1% 

aPAD) and chronic (<3.1% cPAD) exposure estimates were less than HED’s level of concern

(LOC). 

Conclusions: As part of Registration Review, revised acute and chronic dietary exposure 

analyses may be required to reflect the most recent dietary exposure models, revised EDWCs, 

and/or changes to the toxicological PODs.
Iodosulfuron-Methyl-Sodium Human-Health Assessment Scoping Document D404948

Page 9 of 23

Residential Exposure

Iodosulfuron-methyl-sodium is currently registered for residential/public area uses on 

ornamental turf, including residential and commercial lawns, golf courses, sports fields, 

cemeteries, parks, campsites and other recreational areas, and schools. The initial registration for 

these uses was for Iodosulfuron Turf Herbicide (EPA Reg. #432-1404), a 10% ai waterdispersible granule (WDG). The 2005 assessment for this use (D318061, M. Dow, 8-Jun-2005) 

included residential post-application only (dermal and non-dietary incidental ingestion) and no 

risks of concern were identified (MOEs ≥47,000). The assessment noted that the product was 

intended for professional applicators only, so residential handler exposure was not assessed. 

Since the product is not a restricted-use pesticide (RUP) and the use sites can potentially allow 

for homeowner applications, a residential handler assessment is required during Registration 

Review. In addition, post-application exposures will need to be reassessed during Registration 

Review to reflect current HED SOPs. 

In accordance with the updated Part 158 data requirements (2007), a turf transferable residue 

(TTR) study is required for all residential turf uses. As part of the recent revision to the Health 

Effects Division’s 2012 Standard Operating Procedures for Residential Pesticide Exposure 

Assessment, HED analyzed all of the available TTR data and selected new liquid and granular 

default values for the fraction of the application rate available for transfer after a turf application 

(FAR). This default is 1% for formulations applied as liquids. Of the available TTR studies 

submitted to the Agency, the maximum FAR value seen using a liquid product was 6.1% or 6.1 

times higher than the default residue transfer value. Therefore, HED has decided that a 

calculated MOE of approximately 10 times higher than the LOC (e.g., an MOE >1,000 if the 

LOC = 100) using the default residue transfer values would provide an adequate margin of safety 

for any potentially higher residues seen in a chemical-specific TTR study (ExpoSAC Memo, 

6/7/12, “Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable 

Foliar Residue (DFR) Studies”). Based on the existing uses, previous assessments, and 

toxicology of iodosulfuron-methyl-sodium, a TTR study will not be required for Registration 

Review since estimated dermal MOEs for residential post-application scenarios are greater than 

1000 (MOE ≥ 360,000). If the use pattern and/or toxicological PODs change in the future, this 

requirement may be revisited.

Residential exposures resulting from off-site transport (e.g., spray drift or volatilization) may 

occur as a result of applications of iodosulfuron-methyl-sodium. The Agency is in the process of 

evaluating these types of exposures and will examine the need for spray drift and volatilization 

assessments for iodosulfuron-methyl-sodium during registration review.

Conclusions: The residential exposure database is adequate to support the Registration Review 

process. Based upon revisions to HED’s Residential SOPs and/or potential changes to the 

toxicological PODs, residential handler exposure estimates and updated post-application 

exposure assessments may be required under Registration Review. Based on existing and 

anticipated residential post-application risk estimates and the current toxicological PODs, a TTR 

study is unnecessary. 
Iodosulfuron-Methyl-Sodium Human-Health Assessment Scoping Document D404948

Page 10 of 23

Aggregate Risk Assessment

As part of the most recent iodosulfuron-methyl-sodium human-health risk assessment, HED 

conducted aggregate exposure assessment which considered all registered iodosulfuron-methylsodium uses (D350046, S. Levy et al., 12-Nov-2008). The resulting acute (food and water; <1% 

aPAD), short-term (food, water, and residential; MOEs ≥110,000), intermediate-term (food, 

water, and residential; MOEs ≥21,000), and chronic (food and water; <3.1% cPAD) exposure 

estimates were less than HED’s LOC. 

Conclusions: As part of Registration Review, revised aggregate exposure assessments may be 

necessary to reflect revised dietary exposure estimates, residential exposure estimates, and/or 

changes to the toxicological PODs.

Occupational Exposure

Iodosulfuron-methyl-sodium is registered for control of annual/perennial grass and broadleaf 

weeds in field corn and for post-harvest/pre-plant burndown uses on corn (field, pop, sweet, 

grown for seed), wheat, triticale, cereals, grain or forage sorghum, and soybean. All products are 

water-dispersible granules ranging from 0.6% to 10% iodosulfuron-methyl-sodium. There are 

also products registered for use on ornamental turf, including residential and commercial lawns, 

golf courses, sports fields, cemeteries, parks, campsites and other recreational areas, roadsides, 

schools, and sod farms. 

Previous assessments (D280164, D. Vogel, 10-Jan-2001; D318061, M. Dow, 8-Jun-2005; 

D318364/D318367, M. Dow, 15-Mar-2006; D350596, M. Clock-Rust, 12-Nov-2008) estimated 

exposure for various occupational handler scenarios and found no risks of concern. Based on 

existing registrations, the previous assessments identified the anticipated occupational handler 

exposure scenarios, so no additional scenarios need to be included in Registration Review. 

Additionally, since the previous reviews, there have been several updates to HED’s exposure 

policies, including updates to default exposure data used for handler scenarios and assumptions 

for body weights (Registration Review will need to consider these updates).

Based on existing registrations and the use pattern of iodosulfuron-methyl-sodium, the previous 

assessments also identified the anticipated major occupational post-application exposure 

scenarios. Additionally, since the previous reviews, there have been several updates to HED’s 

exposure policies, including updates to post-application transfer coefficients, transferable residue 

assumptions, and assumptions for body weights (Registration Review will need to consider these 

updates). 

In accordance with the updated Part 158 data requirements (2007), a TTR study is required for 

all occupational turf uses (e.g., sod farms). As part of the recent revision to the Health Effects 

Division’s 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment, 

HED analyzed all of the available TTR data and selected new liquid and granular default values 

for the fraction of the application rate available for transfer after a turf application (FAR). This 

default is 1% for formulations applied as liquids. Of the available TTR studies submitted to the 

Agency, the maximum FAR value seen using a liquid product was 6.1% or 6.1 times higher than 

the default residue transfer value. Therefore, HED has decided that a calculated MOE of 
Iodosulfuron-Methyl-Sodium Human-Health Assessment Scoping Document D404948

Page 11 of 23

approximately 10 times higher than the LOC (e.g., an MOE >1,000 if the LOC = 100) using the 

default residue transfer values would provide an adequate margin of safety for any potentially 

higher residues seen in a chemical-specific TTR study (ExpoSAC Memo, 6/7/12, “Guidance for 

Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable Foliar Residue (DFR) 

Studies”). For the current uses of iodosulfuron-methyl-sodium, a TTR study will not be required 

for Registration Review since estimated dermal MOEs for occupational workers exposed to 

treated sod and golf courses are greater than 1000 (estimated MOEs are ≥ 4,400). If the use 

pattern and/or toxicological PODs change in the future, this requirement may be revisited.

Also in accordance with the updated Part 158 data requirements (2007), one or more DFR 

studies are required when a pesticide has occupational uses that could result in post-application 

dermal exposure. HED analyzed a number of DFR studies and selected a new default value for 

the fraction of the application rate available to be dislodged after a foliar application (FAR). This 

default value is 25%. Of the analyzed DFR studies, the maximum FAR value seen was 89% or 

3.6 times higher than the default residue transfer value. Therefore, a calculated MOE of 

approximately 4 times higher than the LOC (i.e., an MOE >400 if the LOC = 100) using the 

default dislodged residue value would provide an adequate margin of safety for any potentially 

higher residues seen in a chemical-specific DFR study (ExpoSAC Memo, 6/7/12, “Guidance for 

Requiring/Waiving TTR and DFR Studies: A DFR study for iodosulfuron-methyl-sodium is not 

required since estimated dermal MOEs for occupational workers exposed to treated foliage are 

greater than 400 (estimated MOEs are ≥ 150,000). If the use pattern and/or toxicological PODs 

change in the future, this requirement may be revisited.

Conclusions: The occupational exposure database is adequate to support the Registration 

Review process. Based upon revisions to the Agency’s scenario-specific surrogate handlerexposure data, updated occupational handler exposure assessments may be required under 

Registration Review. Reviewers should incorporate new exposure monitoring data, as necessary, 

during Registration Review. Updated occupational post-application exposure assessments may 

be required under Registration Review based upon revisions to the Agency’s post-application 

exposure data. Revised occupational handler and post-application assessments may also be 

needed if toxicological endpoints change or other new data are received by the Agency that 

impact exposure estimates. Based on existing and anticipated residential post-application risk 

estimates and the current toxicological PODs, it appears that TTR and/or DFR studies are 

unnecessary. 
Iodosulfuron-Methyl-Sodium Human-Health Assessment Scoping Document D404948

Page 12 of 23

Public Health, Pesticide Epidemiology, and Human Incidence Data

The following databases were consulted to identify potential patterns in the frequency and 

severity of the health effects attributed to iodosulfuron-methyl-sodium exposure (i.e. incident 

data): OPP Incident Data System (IDS) and the Centers for Disease Control and 

Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event 

Notification System for Occupational Risk-Pesticides (SENSOR). HED notes that iodosulfuronmethyl-sodium is not included in the Agricultural Health Study (AHS). 

Based on the low frequency and severity of incident cases reported for iodosulfuron-methylsodium, there does not appear to be a concern at this time that would warrant further 

investigation (D405837, S. Recore, 17-Oct-2012). The Agency will continue to monitor the 

incident information and if a concern is triggered, additional analysis will be included in the risk 

assessment.

International Harmonization

There are no Codex or Mexican maximum residue limits (MRLs) in/on the registered crops (see 

Attachment F). However, there is a Canadian MRL for residues of iodosulfuron-methyl-sodium 

per se in/on field corn grain of 0.025 ppm (US tolerance is 0.03 ppm). Therefore, the US and 

Canadian corn grain tolerance/MRL is not harmonized. Generally, HED does not recommend 

that tolerances be set to the thousandths of a “ppm” and the ability of the current enforcement 

method to accurately quantify residues to the thousandths of a “ppm” is unknown. Therefore, 

HED concludes that the current tolerance is appropriate. In accordance with the most recent 

guidance concerning tolerance expressions, HED recommends that the tolerance expression for 

180.580(a) be changed as follows: 

180.580(a) General. Tolerances are established for residues of the herbicide iodosulfuron-methylsodium, including its metabolites and degradates, in or on the commodities listed below. Compliance 

with the following tolerance levels is to be determined by measuring only iodosulfuron-methylsodium (sodium salt of methyl 4-iodo-2-[[[[(4-methoxy-6-methyl-1,3,5-triazin-2-

yl)amino]carbonyl]amino]sulfonyl]benzoate), in or on the following commodities:
Iodosulfuron-Methyl-Sodium Human-Health Assessment Scoping Document D404948

Page 13 of 23

Endocrine Disruption

As required by the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal 

Food, Drug, and Cosmetic Act (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 the most recent registration decision for iodosulfuronmethyl-sodium, EPA reviewed these data and selected the most sensitive endpoints for relevant 

risk assessment scenarios from the existing hazard database. However, as required by FFDCA 

section 408(p), iodosulfuron-methyl-sodium 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 humans or wildlife similar to an effect 

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

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

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

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

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

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

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

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

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

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. Iodosulfuronmethyl-sodium is not among the group of 58 pesticide active ingredients on the initial list to be 

screened under the EDSP. Accordingly, as part of Registration Review, EPA will issue future 

EDSP orders/data call-ins, requiring the submission of EDSP screening assays for iodosulfuronmethyl-sodium. For further information on the status of the EDSP, the policies and procedures, 

the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please 

visit our website: http://www.epa.gov/endo/.
Iodosulfuron-Methyl-Sodium Human-Health Assessment Scoping Document D404948

Page 14 of 23

Cumulative 

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding for 

iodosulfuron-methyl-sodium and any other substances. It is noted that the iodosulfuron-methylsodium fate/metabolism studies did result in the identification of metsulfuron-methyl, a 

registered active ingredient. However, based on these data and the application scenarios for each 

of the active ingredients, residues of metsulfuron methyl from iodosulfuron-methyl-sodium 

application are expected to be negligible when compared to residues resulting from application

of metsulfuron-methyl. Therefore, for the purposes of this and previous actions, EPA has 

assumed that iodosulfuron-methyl-sodium does not have a common mechanism of toxicity with 

other substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

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

Human Studies 

Past iodosulfuron-methyl-sodium risk assessments relied in part on data from studies in which 

adult human subjects were intentionally exposed to a pesticide to determine their dermal and 

inhalation exposure. Many such studies, involving exposure to many different pesticides, 

comprise generic pesticide exposure databases such as the Pesticide Handlers Exposure Database 

(PHED), the Agricultural Reentry Task Force (ARTF) Database, and the Outdoor Residential 

Exposure Task Force (ORETF) Database. EPA has reviewed all the studies supporting these 

multi-pesticide generic exposure databases, and has found no clear and convincing evidence that 

the conduct of any of them was either fundamentally unethical or significantly deficient relative 

to the ethical standards prevailing at the time the research was conducted. All applicable 

requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) 

have been satisfied, and there is no regulatory barrier to continued reliance on these studies.

Environmental Justice

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

most recent iodosulfuron-methyl-sodium human-health risk assessment, in accordance with U.S. 

Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority 

Populations and Low-Income Populations,” 

(http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf). The OPP typically 

considers the highest potential exposures from the legal use of a pesticide when conducting 

human-health risk assessments, including, but not limited to, people who obtain drinking water 

from sources near agricultural areas, the variability of diets within the U.S., and people who may 

be exposed when harvesting crops. Should these highest exposures indicate potential risks of 

concern, OPP further refines the risk assessments to ensure that the risk estimates are based on the 

best available information.
Iodosulfuron-Methyl-Sodium Human-Health Assessment Scoping Document D404948

Page 15 of 23

Risk Assessment Updates and Data Deficiencies

The risk assessment updates that may be required under Registration Review are summarized 

below. Based on the current use patterns, there are no data deficiencies.

Risk Assessment Updates: 

●The current PODs will be reevaluated along with evaluation of the toxicological and exposure 

databases in terms of assigning a FQPA SF. 

●Revised dietary risk assessment may be necessary to reflect the most recent EDWCs, dietary 

exposure models, and/or toxicological PODs.

●Revised residential risk assessment may be necessary to incorporate guidance from the updated 

Residential SOPs and/or toxicological PODs. 

●Revised aggregate risk assessment may be necessary to reflect revised residential exposure 

estimates, dietary exposure estimates, and/or toxicological PODs. 

●Revised occupational risk assessment may be necessary to reflect the most recent HED policies

and/or toxicological PODs. 

HED notes that based on the assumptions and resulting risks associated with the currently 

registered uses, it is highly unlikely that revised risk assessments conducted in support of 

registration review will yield exposure greater than HED’s level of concern. 

Attachment A: References

Attachment B: Chemical Identity and Physicochemical Properties

Attachment C: Hazard Profile Tables

Attachment D: Toxicological Endpoint Selection Table 

Attachment E: Registered Application Scenarios and Rates

Attachment F: International Residue Limits

RDI: RAB1 and J. Rowland/D. Vogel (November-2012); PRD (Feb-2013)

T. Bloem:Potomac Yard 1:703-605-0217:S10945P
Iodosulfuron-Methyl-Sodium Human-Health Assessment Scoping Document D404948

Page 16 of 23

Attachment A: References

Memoranda Relevant to Registration Review

Author DP# Barcode/

TXR #

Date Title

HED – Toxicological Documents

P. Shah 0052286 5-Jan-2004 Iodosulfuron - 2

nd

 - Report of the Hazard Identification Assessment 

Review Committee.

J. Van Alstine 0052381 28-Feb-2013

Iodosulfuron Methyl-Sodium: Summary of the Hazard and Science 

Policy Council (HASPOC) Meeting of October 4, 2012: Recommendations 

on the Need for a Subchronic Inhalation, Subchronic Neurotoxicity, and 

Developmental Neurotoxicity Studies.

HED – Residue Chemistry Documents

T. Bloem D278092 25-Oct-2011 Health Effects Division (HED) Metabolism Assessment Review Committee 

(MARC) Decision Document. 

T. Bloem D275418 7-Nov-2001 Iodosulfuron-Methyl-Sodium in/on Field Corn. Evaluation of Residue Data 

and Analytical Methods.

T. Bloem D282138 11-Apr-2002 Analytical Enforcement Method sent to FDA. 

T. Bloem D318365 13-Sep-2006 Preplant Application to Field Corn and Soybean. Evaluation of Residue 

Chemistry Data and Analytical Methods. 

T. Bloem D348071 17-Apr-2008 Label Amendment Application for Adding 90-Day Plantback Interval for 

Sweet Corn, Popcorn, and Corn Grown for Seed.

S. Levy D350509 29-Oct-2008 Application for Amended Section 3 Registration to Add Uses on Wheat. 

Summary of Analytical Chemistry and Residue Data. 

S. Levy D355405 5-Nov-2008 Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure 

and Risk Assessments for the Section 3 Registration Action on Wheat.

S. Levy D363431 25-Mar-2009 Iodosulfuron-Methyl-Sodium in/on Wheat; Revised Response to the Health 

Effects Division (HED) Review of 29-Oct-2008.

S. Levy D363433 1-Apr-2009 Analytical Enforcement Method sent to FDA. 

T. Bloem D368850 5-Nov-2009

Iodosulfuron-Methyl Sodium. Revised Rotational Crop Restrictions for 

Several Crops and Post-Harvest Burndown Application Prior to Planting 

Cereal Grain and Grain/Forage Sorghum. 

HED – ORE Documents

M. Dow D318061 8-Jun-2005 Exposure/Risk Assessment for the Proposed Use of Iodosulfuron-methylsodium on Ornamental Turfgrass.

D. Vogel D280164 10-Jan-2001 Iodosulfuron-methyl-sodium ORE Registration Action for the Proposed Use 

on Corn.

M. Clock-Rust D318364/D318367 12-Nov-2008 Iodosulfuron-methyl – Human Exposure/Risk Assessment for the Preplant 

Uses of Iodosulfuron-methyl on Corn and Soybean

HED – Risk Assessment Documents

P. Shah et al. D267577 30-Jan-2002 Iodosulfuron-Methyl-Sodium in/on Field Corn; Health Effects Division 

(HED) Risk Assessment. 

P. Shah D282333 5-Apr-2002 Addendum to the Iodosulfuron-Methyl-Sodium in/on Field Corn; Health 

Effects Division (HED) Risk Assessment. 

T. Bloem D318083 4-Jan-2007 Iodosulfuron-Methyl-Sodium. Preplant Application to Field Corn and 

Soybean. Risk Assessment Document. 

S. Levy et al. D350046 12-Nov-2008 Iodosulfuron-Methyl-Sodium; Human-Health Risk Assessment for 

Proposed Section 3 New Use on Wheat.

HED – Incidence Document

S. Recore D405837 17-Oct-2012 Iodosulfuron-methyl-sodium: Review of Human Incidents

EFED – EDWCs Documents

S. Termes D315491 12-Jan-2006 --

J. Wolf D350049 29-Aug-2008 --

RD Document

H. Podall D272474 16-May-2001 --
Iodosulfuron-Methyl-Sodium Human-Health Assessment Scoping Document D404948

Page 17 of 23

Attachment B: Chemical Identity and Physicochemical Properties

Iodosulfuron-Methyl-Sodium Nomenclature.

Chemical structure

Common name Iodosulfuron-methyl-sodium

Company experimental name AE F115008

IUPAC name Sodium ({[5-iodo-2-(methoxycarbonyl)phenyl]sulfonyl}carbamoyl)(4-methoxy-6-methyl1,3,5-triazin-2-yl)azanide

CAS name Sodium salt of methyl 4-iodo-2-[[[[(4-methoxy-6-methyl-1,3,5-triazin-2-

yl)amino]carbonyl]amino]sulfonyl]benzoate

CAS registry number 144550-36-7

End-use product (EP) Hussar® Herbicide (5% WDG; EPA File Symbol No. 264-IEN); Iodosulfuron Turf 

Herbicide®(10% WDG; EPA File Symbol No. 432-1404)

Physicochemical Properties of Iodosulfuron-Methyl-Sodium.

Parameter Value Reference

Melting point 152oC

RD Memorandum:

D272474, H. Podall,

16-May-2001

pH of 1% dispersion in water 6.7

Density 1.76 g/cm3

Water solubility pH Solubility at 20oC (g/L)

7.6 (unbuffered) 60.0

4 0.02

5 0.17

7 25.0

9 65.0

10 45.0

Solvent solubility Solvent Solubility at 20oC (g/L)

acetone >380.0

dichloromethane >500.0

ethyl acetate 23.0

n-hexane ~1.2 × 10-3

methanol 12.0

n-heptane ~1.1 × 10-3

2-propanol 4.4

toluene 2.1

ACN 52.0

dimethyl sulfoxide >500.0

polyethylene glycol 87.0

Vapor pressure 2.6 × 10-9Pa at 20oC; 6.7 × 10-9Pa at 25oC

Dissociation constant, pKa pKa = 3.22 ± 0.06 at 20 oC

Octanol/water partition coefficient, 

Log (KOW)

pH 4: 1.96; pH 5: 1.07; pH 6: 0.07; pH 7: -0.70; pH 9: 

-1.22; pH 10: -1.15 (all at 25oC)

Ultraviolet (UV)/visible absorption

spectrum

Solvent λmax (nm) ε [L/(mol × cm)]

MeOH 203 2.990 × 104

MeOH 238 3.184 × 104

MeOH + NaOH 239 3.170 × 104

(90/10, v/v); No observed absorption at λ 300–800 nm.

I S

N N

H

O

O

O

O

CH3

N

N

CH3

O

CH3

O

N

Na

+
Iodosulfuron-Methyl-Sodium Human-Health Assessment Scoping Document D404948

Page 18 of 23

Attachment C: Hazard Profile Tables

Acute Toxicity of Iodosulfuron-Methyl-Sodium Technical.

Guideline

No. Study Type MRID # Results Toxicity Category

870.1100 Acute Oral 45133404

LD50 mg/kg (calculated)

Males 2947 (2053-11146) 

Females 2448 (1632-5780) 

Combined 2678 (2175-4744)

III

870.1200 Acute Dermal 45133405 LD50 > 2,000 mg/kg (limit dose) III

870.1300 Acute Inhalation 45108805 LC50 > 2.81 mg/L IV

870.2400 Primary Eye Irritation 45133407 Not an ocular irritant III

870.2500 Primary Skin Irritation 45133406 Non-irritating IV

870.2600 Dermal Sensitization 45108806 Non sensitizer --

Toxicity Profile for Iodosulfuron-Methyl-Sodium Technical.

Guideline No./ Study 

Type

MRID No. (year)/

Classification /Doses Results

870.3100

90-Day oral toxicity 

rodents-rat

45133408 (1997)

Acceptable/guideline 

0, 200, 1,000, 5,000 or 10,000 ppm; 

0/0, 13.8/15.4, 67/74, 347/388 or 

686/790 M/F mg/kg/day

NOAEL = 67 mg/kg/day in males, 74 mg/kg/day in females.

LOAEL = 347 mg/kg/day in males, 388 mg/kg/day in females 

based on reduced body weight and overall body-weight gains in 

both sexes. 

870.3100

90-Day oral toxicity 

rodents - mouse

45108808 (1997)

Acceptable/guideline

0, 700, 2,100, or 7,000 ppm

0/0, 119/139, 332/401, or 1311/1332 

M/F mg/kg/day

NOAEL = 119 mg/kg/day in males, Not observed in females.

LOAEL = 332 mg/kg/day in males, 139 mg/kg/day in females 

based on hepatotoxicity.

870.3150

90-Day oral toxicity 

nonrodents - dog

45108809, 45108807 (1998)

Acceptable/guideline

0, 200, 1200, or 7200 ppm

0/0, 8.1/8.4, 49/51, or 301/317 M/F, 

mg/kg/day

NOAEL = 8.1 mg/kg/day in males, 8.4 mg/kg/day in females.

LOAEL = 49 mg/kg/day in males, 51 mg/kg/day in females 

based on changes in hematology, microscopic pathology of the 

bone marrow and spleen (females), clinical chemistry (males).

870.3700a

Prenatal 

developmental in 

rodents - rat

45108820, 45108819 (1996)

Acceptable/guideline

0, 100, 315 or 1,000 mg/kg/day 

Maternal: NOAEL = 315 mg/kg/day.

LOAEL = 1,000 mg/kg/day based on increased salivation.

Developmental: NOAEL = 315 mg/kg/day.

LOAEL =1000 mg/kg/day based on delayed ossification.

870.3700b Prenatal 

developmental in 

nonrodents - rabbit

45108901, 45108821 (1996)

Unacceptable/guideline (not 

upgradable)

0, 25, 100 or 400 mg/kg/day

Maternal: NOAEL = 400 mg/kg/day (HDT).

LOAEL = Not observed.

Developmental: NOAEL = 400 mg/kg/day (HDT).

LOAEL = Not observed.

870.3800 

Reproduction and 

fertility effects - rat

45108818, 45108817 (1998)

Acceptable/guideline

0, 50, 500 or 5000 ppm

0/0, 3.43/3.90, 34.2/39.7 or 346/390.4 

M/F mg/kg/day

Parental/Systemic NOAEL = 346 mg/kg/day in males, 390 

mg/kg/day in females (HDT).

LOAEL = not established.

Reproductive NOAEL = 346 mg/kg/day in males, 390 mg/kg/day 

in females (HDT).

LOAEL = not established.

Offspring NOAEL = 34.2 mg/kg/day in males, 39.7 mg/kg/day in 

females.

LOAEL = 346 mg/kg/day in males, 390 mg/kg/day in females 

(HDT) based on pup mortality.
Iodosulfuron-Methyl-Sodium Human-Health Assessment Scoping Document D404948

Page 19 of 23

Toxicity Profile for Iodosulfuron-Methyl-Sodium Technical.

Guideline No./ Study 

Type

MRID No. (year)/

Classification /Doses Results

870.4100b Chronic 

toxicity - dog

45108810 (1998)

Acceptable/guideline

0, 30, 200 or 1200 ppm

0/0, 1.03/1.08, 7.37/7.25 or 41.8/43.7 

M/F mg/kg/day

NOAEL = 41.8 mg/kg/day in males, 7.25 mg/kg/day in females.

LOAEL = Not established in males, 43.7 mg/kg/day in females 

based on gross and histopathologic changes observed in the 

hematopoietic system.

870.4300 Chronic/

Carcinogenicity - rat

45108815, 45133408 (1998)

Acceptable/guideline

0, 70, 700, or 7,000 ppm

0/0, 2.96/3.91, 29.7/39.1, or 331/452 

M/F mg/kg/day

NOAEL = 29.7 mg/kg/day in males, 39.1 mg/kg/day in females. 

LOAEL = 331 mg/kg/day in males and 452 mg/kg/day in females

based on reduced body weight and body-weight gains in males and 

on reduced body weight, body-weight gains and food efficiency in 

females.

No evidence of carcinogenicity.

870.4300 

Carcinogenicity -

mouse

45108816 (1998)

Acceptable/guideline

0, 35, 350 or 1,750 ppm

0/0, 5.15/5.72, 54.2/57.6 or 279/277 

M/F

mg/kg/day

NOAEL = 54.2 mg/kg/day in males, 57.6 mg/kg/day in females.

LOAEL = 279 mg/kg/day in males, 277 mg/kg/day in females 

based on increased liver weights and histopathological changes in 

the liver. 

No evidence of carcinogenicity at doses tested.

870.5100 Gene 

Mutation

45133409 (1993)

Acceptable/guideline

4, 20, 100, 500, 2500 or 5000 

μg/plate

Non-mutagenic when tested up to 5000 ug/plate, in presence and 

absence of metabolic activation, in S. typhimurium strains TA98, 

TA100, TA1535 and TA1537 and E.coli strain WP2uvra.

870.5300 Gene 

Mutation

45108811 (1996)

Acceptable/guideline

5-7 doses ranging from 100 to 2649 

μg/mL

Negative for induction of forward mutation at the HPRT locus in 

Chinese hamster V79 lung fibroblasts, in the presence or absence 

of S9-activation at doses up to limit of solubility (2649 μg/mL).

870.5375 

Chromosome 

aberration

45108812 (1996)

Acceptable/guideline

0, 500, 1500, or 2649 μg/mL with S9 

activation and 0, 100, 250, or 500 

μg/mL without S9 activation

Did not induce structural chromosome aberration in Chinese 

hamster lung (V79) cell cultures in the presence and absence of 

activation up to cytotoxic concentrations.

870.5385 

Chromosomal 

aberration

45108814 (1996)

Acceptable/guideline

200, 1000 or 2000 mg/kg

Non-mutagenic in NMRI mouse bone marrow micronucleus 

chromosomal aberrations assay up to the limit dose (2000 mg/kg).

870.5550

Other Genotoxicity

45108813 (1996)

Acceptable/guideline

0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, 100, 

300, 1000, 3000, or 5000 μg/mL

No evidence that unscheduled DNA synthesis was induced by 

iodosulfuron-methyl-sodium, as determined by radioactive tracer 

procedures [nuclear silver grain counts]. Iodosulfuron-methylsodium was tested up to cytotoxic concentrations ( 3000 μg/mL). 

UDS activity was assessed at 0.01 to 1000 μg/mL. 
Iodosulfuron-Methyl-Sodium Human-Health Assessment Scoping Document D404948

Page 20 of 23

Toxicity Profile for Iodosulfuron-Methyl-Sodium Technical.

Guideline No./ Study 

Type

MRID No. (year)/

Classification /Doses Results

870.7485 Metabolism 

and pharmacokinetics -

rat

45108727-4510733 and 45108801-

45108803 (1996)

10 or 500 mg/kg single

100 mg/kg/day repeated dose for 7 

days

Total recovery of the administered dose was 95.9-102.4% for all 

treatment groups. No radioactivity was detected in exhaled air or 

organic volatiles. Elimination of radioactivity occurred primarily 

in the urine, mostly within 24 hours of dosing, and was essentially 

complete within 3 days of dosing. Overall urinary excretion 

accounted for 78.5% and 85.8% of the dose for males and females, 

respectively, and fecal elimination accounted for 19.2% and 10.1% 

of the dose, respectively. By 3 days post-dose, 0.5% of the dose 

remained in the blood and tissues of both sexes of rats from the 

low- and high-dose groups. Rats excreted the majority of the dose 

as unchanged parent via the urine (48.7-86.3% dose) or feces (1.1-

11.1% dose). Minor routes of metabolism for iodosulfuronmethyl-sodium included hydrolysis of the methylester to form 4-

iodo-2-[3-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)ureidosulfonyl] 

benzoic acid (AE F145740; 0.9-4.5% dose); O-demethylation of 

the triazine ring to form methyl 2-[3-(4-hydroxy-6-methyl-1,3,5-

triazin-2-yl)ureidosulfonyl]-4-iodobenzoate (AE F148741; 1.5-

8.2% dose); or hydroxylation of the methyl group on the triazine 

ring to form methyl 2-[3-(4-hydroxymethyl-6-methoxy-1,3,5-

triazin-2-yl)ureidosulfonyl]-4-iodobenzoate (AE F168532; 0.3-

6.6% dose). Each of these minor metabolites was present in both 

the urine and feces. The remaining metabolites each accounted for 

<3% of the dose.

870.7485 Metabolism 

and pharmacokinetics -

dog

45108804 (1998)

Acceptable/guideline

6 or 200 mg/kg single oral dose

Within 72 hours of oral dosing, 90-94% of the dosed radioactivity 

was recovered in the excrement and cage wash of both dose 

groups. Renal excretion accounted for 64-74% of the dose and 

elimination in the feces accounted for 14-17% of the radioactive 

dose. Most of the dose was excreted within 24 hours. 

Quantitative RP-HPLC analyses isolated up to 6 distinct 

radioactive components in urine and feces. The major isolated 

fraction was the parent: urine (54-61% dose) and feces (8-11%). 

In the rat, the major isolated fraction was also the parent, while the 

major metabolite was AE F145741. The metabolites identified in 

the dog were consistent with those identified in the rats.

870.7600

Dermal Penetration -

rat

45108915 (1998)

Unacceptable/guideline

0.023 or 0.376 mg/cm2

For both the low- and high-dose groups, dermal penetration of 

radioactivity was low (<2% dose) at exposure intervals up to 8 

hours. Absorption increased slightly with duration of exposure in 

the low-dose group, increasing from 0.019% of the dose (0.043 

μg/cm2) at 3 hours to 0.69% of the dose (0.159 μg/cm2) at 8 hours. 

However, a similar trend was not observed in the high-dose group, 

as the maximum absorption was observed at the 5-hour exposure 

(1.60% dose, 6.02 μg/cm2). 
Iodosulfuron-Methyl-Sodium Human-Health Assessment Scoping Document D404948

Page 21 of 23

Attachment D: Toxicological Endpoint Selection Table

Summary of Toxicological Doses and Endpoints for Iodosulfuron-Methyl Sodium used in the 2008 Human 

Risk Assessment.1

Exposure 

Scenario POD Uncertainty/FQPA SF

FQPA SF and LOC for 

Risk Assessment Study and Toxicological Effects

Acute Dietary 

for general 

population 

NOAEL = 315 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

aRfD = 3.15 mg/kg/day

aPAD = 3.15 mg/kg/day

Developmental Toxicity- rats Maternal 

LOAEL of 1000 mg/kg bw based on 

increased salivation seen in dams on day 

one and throughout the dosing period . 

Chronic Dietary 

all populations

NOAEL = 7.3 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

cRfD = 0.073 mg/kg/day 

cPAD = 0.073 mg/kg/day

Chronic Oral Toxicity– dog;

LOAEL of 1200 ppm (43.7 mg/kg/day) 

based on gross and histopathologic 

changes observed in the hematopoietic 

system 

Incidental Oral

Short-Term

(1-30 days)

NOAEL = 49

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

LOC for MOE < 100 

(residential)

Subchronic Oral Toxicity – dog;

LOAEL of 301 mg/kg/day based on 

alterations in hematological parameters 

and changes in clinical chemistry seen at 4 

week observation 

Incidental Oral, 

IntermediateTerm 

(1-6 months)

Oral NOAEL = 8.1

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

LOC for MOE < 100 

(residential)

Subchronic Oral Toxicity– dog;

LOAEL of 49 mg/kg/day based on 

changes in hematology (males and 

females), microscopic pathology of the 

bone marrow (males and females), and 

spleen (females), and clinical chemistry 

(males) seen at termination.

Dermal

Short-Term

(1-30 days)

Oral NOAEL = 49

mg/kg/day

dermal absorption 

factor 2%

UFA = 10X

UFH = 10X

FQPA SF = 1X

LOC for MOE < 100 

(residential)

LOC for MOE < 100 

(occupational)

Subchronic Oral Toxicity-dog;

LOAEL of 301 mg/kg/day based on 

alterations in hematological parameters 

and changes in clinical chemistry seen at 4 

week observation period.

Dermal, 

IntermediateTerm 

(1-6 months)

Oral NOAEL = 8.1

mg/kg/day

dermal absorption

factor 2%

UFA = 10X

UFH = 10X

FQPA SF = 1X

LOC for MOE < 100 

(residential)

LOC for MOE < 100 

(occupational)

Subchronic Oral Toxicity -dog;

LOAEL of 49 mg/kg/day based on 

changes in hematology (males and 

females), microscopic pathology of the 

bone marrow (males and females) and 

spleen (females), and clinical chemistry 

(males) seen at termination.

Inhalation, 

Short-Term

(1-30 days)

Oral NOAEL = 49

mg/kg/day

inhalation 

absorption

factor 100%

UFA = 10X

UFH = 10X

FQPA SF = 1X

LOC for MOE < 100 

(residential)

LOC for MOE < 100 

(occupational)

Subchronic Oral Toxicity-dog;

LOAEL of 301 mg/kg/day based on 

alterations in hematological parameters 

and changes in clinical chemistry seen at 4 

week observation period.

Inhalation, 

IntermediateTerm

(1-6 months)

Oral NOAEL = 8.1

mg/kg/day

(inhalation 

absorption

of 100% assumed)

UFA = 10X

UFH = 10X

FQPA SF = 1X

LOC for MOE < 100 

(residential)

LOC for MOE < 100 

(occupational)

Subchronic Oral Toxicity -dog;

LOAEL of 49 mg/kg/day based on 

changes in hematology (males and 

females), microscopic pathology of the 

bone marrow (males and females) and 

spleen (females), and clinical chemistry 

(males) seen at termination.

Cancer(oral, 

dermal, and 

inhalation)

Classified as “not likely to be carcinogenic to humans” based on the lack of

evidence for carcinogenicity in mice and rats (HIARC 2004)

NOAEL = no-observed adverse-effect level. LOAEL = lowest-observed adverse-effect level. UF = uncertainty factor. FQPA 

SF = FQPA Safety Factor. MOE = margin of exposure. LOC = level of concern.
Iodosulfuron-Methyl-Sodium Human-Health Assessment Scoping Document D404948

Page 22 of 23

Attachment E: Registered End-Use Products and Application Scenarios/Rates

The information in the following two tables is based on the LUIS reports. 

Summary of End-Use Products.

Product 

Type Trade Names (EPA Reg. No.) AI Concentration Application Type/Equipment Use Sites REI Target Pests

WDG

Atlantis Herbicide (264-1103) 0.6% post-emergence broadcast/ground triticale and wheat

12 hours annual/perennial 

grass and 

broadleaf weeds

Tribute Solo WG32 Herbicide (264-686) 2% post-emergence broadcast/ground field corn

Hussar Herbicide (264-820) 5% post-emergence broadcast/ground wheat

Autumn Super 51 WDG Herbicide (264-1134) 6% preplant burndown/ground field corn, soybeans

Iodosulfuron 10 WDG Herbicide (264-843) 10% preplant burndown/ground soybean

Iodosulfuron 10 WDG Herbicide (264-856) 10% preplant burndown/ground cereal grains, cotton, and soybean

Iodosulfuron Turf Herbicide (432-1404) 10% spot and broadcast/backpack and ground turf (commercial/industrial, sod farms, 

ornamental, golf course, recreational, residential) 12-24 hours Celsius WG (432-1507) 1.9%

Summary of Application Scenario.

Formulation

(EPA Reg. No.) App. Timing App. Rate(lb ai/acre)

Max. Seasonal 

App. Rate

(lb ai/acre)

Use Directions and Limitations

triticale and wheat (post emergence foliar application)

Atlantis Herbicide (264-1103); 

Hussar Herbicide (264-820)

3-leaf to 

jointing stage 0.0022-0.0089 0.0089 -No more than two applications permitted per year (RTI = 14 days).-PHIs: 21-30 days for forage and 50-60 days for hay, grain, and straw.

field corn (post emergence foliar application)

Tribute Solo WG32 Herbicide (264-686) V1 - V8 0.0019 0.0019 -PHIs: 70 days for grain and 45 days for forage.

cereal grains, cotton, and soybean (preplant burndown application)

Autumn Super 51 WDG Herbicide (264-1134);

Iodosulfuron 10 WDG Herbicide (264-843 and 264-856) Preplant 0.0019 0.0019 -Wait 60 days prior to planting soybean, sweet corn, popcorn, and corn grown for seed; wait 30 days prior to planting cotton, field corn, and remaining cereal grains. 

turf (commercial/industrial, sod farms, ornamental, golf course, recreational, residential)

Iodosulfuron Turf Herbicide (432-1404);

Celsius WG (432-1507)

broadcast/spot

postemergent 0.0027-0.0089 0.0089

-Do not apply aerially.

-Spot applications are to made using 0.057-0.113 ounces of product per gallon of 

spray solution (≤0.00013 lb ai/gal). 
Iodosulfuron-Methyl-Sodium Human-Health Assessment Scoping Document D404948

Page 23 of 23

Attachment F: International Residue Limits

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition

US Canada Mexico2 Codex

Iodosulfuron-Methyl-Sodium: methyl 4-iodo-2-[3-(4-

methoxy-6-methyl-1,3,5 triazin-2-yl)ureidosulfonyl] 

benzoate, sodium salt

4-iodo-2-[[[[(4-methoxy-6-methyl1,3,5-triazin-2-yl)amino]carbonyl] 

amino]sulfonyl]benzoic acid methyl 

ester, monosodium salt

-- None

Tolerance/Maximum Residue Limit (ppm)

Commodity1 US Canada Mexico2 Codex

Corn, field, forage 0.05 -- -- --

Corn, field, grain 0.03 0.025 -- --

Corn, field, stover 0.05 -- -- --

Wheat, forage 0.10 -- -- --

Wheat, grain 0.02 -- -- --

Wheat, hay 0.05 -- -- --

Wheat, straw 0.05 -- -- --

Completed: M. Negussie: 08/20/2012

1

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

proposed by the applicant.

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