Iodosulfuron-Methyl-Sodium Human-Hea l th 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: 040 4948 Decision No.: 469137 Registration Nos.: N/A Petition No.: N/A Regulatory Action: Registration Review Scoping Document Risk Assessment T y pe: Scoping Document Case No. : 7253 TXRNo.: N / A CAS No.: 144550-36-7 MRID No.: none 40CFR: 180.580 

### Tom Bloem, Chemist, Risk Assessment Branch 1

# (RA**~k** Chester E. Rodriguez, Ph.D. , Pharmacologist, RABl "...(,**~7.** 

### Matthew Crowley, Biologist , Chemistry and Exposur e Branch EB)

## f/./~ Health Effects Division (HED, 7509P) /-· Dan a Vogel, Assoc iate HED Director and RAB 1 Branch Chief George F. Kramer, Ph.D. , Senior**hem ist** **~** 

### .PI(• • RABl/HED (7509P) Katherine StClair, Chemical Review Manager Eric Miederhoff, Acting Team Leader Kevin Coste llo , Branch Chief Risk Management & 

### Implemen tation Branch 4 Pesticide Reevaluation Division (PRD, 7508P)

Attached is HED's human -heal th risk assessment scoping document for i odosulfuron -me thy lsodium s ubmitted 

### in s upport of Registration Review.

Page I of23lodosulfuron-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 inhib i t ion of acetolactate synthase (ALS) in susceptible plants (annual /peren nial grass and broadleafweeds). lodosulfuron-methyl-sodium is currently registered for foliar application to wheat, tritica le, 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 iodo su lfuron-me thy l-sodium with respect to i ts toxicity, exposure, and usage databases, and the most updated Agency science policy and risk assessment methodologies to determine the scope of work nece ssary to support Regi st ration Review. HED notes that iodo s ulfuron -me thyl -sodium is applied in combination with the safeners isoxadifen-ethyl or mefenpyr-diethyl. 

### In addition, metsulfuron-methyl, a registered active ingredient (PC code 1220 10) , is a residue of concern in drinking water following application of io dosulfuron-methyl-so dium. The current document pertains only to th e Registration Review**~ata** 

### requirements for iodosulfuron-methyl-sodium. It 

### i s noted that at the time the first human-health risk assessment for iodosulfuron-methyl-sodium was being conducted, a full revie w of the metsulfuron-methyl to xicologica l 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 t ime, the metsulfuron-methyl toxicological database has undergone a full review by th e HED Hazard Identification Assessment Review Committee (HIARC; 14-Mar-2002; HED Doc. No. 0050569). As a result of this review, i t was concluded tha t 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-me t hyl-sodium is adequate to support current registration requirements; currently, no additional toxicological s tud ies are required. It 

### is noted that as part of Registration Review , the iodosulfuron-methylsodium points of departure (PODs) will be reevalu ated along with reevaluation of the of the toxicologica l and exposure databases in terms of assigning a Food Quality Protection Act Safety Factor (FQPA SF). The following paragraphs are a summary of the toxico logical profile for iodo su lfuron-m ethyl-sodium

. Iodosulfuron-methyl-sodium was classified as having low acute toxici ty via the oral (Category Ill), dermal (Catego r y 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 subc hronic 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 lobu lar pattern). In addition to Page 2 of23Iodosulfuron

- Methyl

- Sodium Human

- Health Assessment Scoping Document D 404948

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 l iver effects were reported in both chronic and subchronic studies ( increased weig ht and histopathological changes ). In the r at subchronic and chronic studies , the only effects reported were body

- weight decre ments (including decreased body

- weight gain) and decreased food efficiency . The immunotoxicity study indicated that the immune s ystem is not a direct target of iodosulfuron

- methyl

- sodium toxicity. Iodosulfuron

methyl

- 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 prenat al susceptibility based on delayed ossification in the fetuses of dams that exhibited minimal toxicity (salivation)

. Similarly, there was also evidence of quantitati ve 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 high est dose tested. Susceptibility was not observed in the developmental to xicity 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 d etermine if a subchronic neuro toxicity study for iodosulfuron

- methyl

- sodium was necessary. Based on the following consideration s , t he C ommittee deci ded to not require a subchronic neurotoxicity stud y : ( 1) the lack of evidence in the available toxicology studies for the nervous system being a target of iodosulfuron

- methyl

- sodium toxicity ; ( 2) e ffects 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 e vidence 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 . T he 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 - 9 

### Pa 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 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 residu e 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 req uire 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 Re gistration Review, a r evised dietary risk a ssessment 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 D 404948

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### Residential Exposure: The residential exposure database is adequate to sup port the Registration Review process. B ased 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. A ggregate Risk Assessment : As part of Registration Review, updated aggregate risk assessment s may be necessary to reflect revised residential exposure estimates, dietary exposure estimates, and/or toxicological PODs

. Occupational Exposure: The occupati onal exposure database is adequate to support the Registration Review process. B ased upon revisions to the Agency’s scenario

- specific surrogate handler

- exposure data , u pdated occupational handler exposure assessments may be required under Registration Rev iew

. 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

- appli cation 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 reside ntial post

application 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 assessme nt 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 reeval uated 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. ●R evised residential risk assessment m ay be necessary to incorporate guidance from the updated Residential SOPs and/or toxicological PODs. ●R evised aggregate risk assessment may be necessary to reflect revised residential exposure estimates, dietary exposure estimates, and/or toxicological P ODs. ●R evised 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 unli kely 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 D 404948

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### DETAILED CONSIDERATIONS Registered U se Pattern s Iodo sulfuron

- 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 scenario s . Hazard Identification/Toxicology Iodosulfuron

- methyl

- sodium is a s ulfonylurea 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 t o 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 radiola beled iodosulfuron

- methyl

- sodium in rats and dogs, absorption was rapid in both species with a time to maximum plasma levels (t max 

### ) of 3

- 6 hours. A prolonged t max 

### was noted in rats only at a very high dose (500 mg/kg bw). Elimina tion of radioactivity was mainly via the urine in both species. In dogs, r enal 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 w as biphasic and similar for both sexes, t hough 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 hig her 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 subc hronic 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 r educed 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 t he spleen. In the mouse, only l iver 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 D 404948

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### In the r at subchronic and chronic studies , the re 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 ef ficiency

. In a prenatal developmental toxicity study in rats, there was evidence of increased qualitative prenat al susceptibility based on delayed ossification in the fetuses of dams that exhibited minimal toxicity (salivation)

. Similarly, there was also evidence of quantitati ve 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 to xicity 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 neurotox icity (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 neuro toxicity study for iodosulfuron

- methyl

- sodium. Based on the following consideration s , t he committee deci ded to not require a subchronic neurotoxicity stud y : ( 1) the lack of evidence in the available toxicology studies for the nervous system being a target of iodosulfuron

- methyl

- sodium toxicit y ; ( 2) e ffects 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 chem icals ( i.e ., sulfonylureas) for which e vidence 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 . T he C ommittee 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 - 9 

### Pa 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 a ssessment, 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 iod osulfuron

- 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

- sodium as “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 Re gistration Review , the iodos u lfuron

- methyl

- sodium PODs will be reevaluated along with re e valuation of the toxicological and exposure databases in terms of assigning a FQPA SF.Iodosulfuron

- Methyl

- Sodium Human

- Health Assessment Scoping Document D 404948

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### Residue Chemistry and Tolerance Assessment I odosulfuron

- methyl

- sodium is registered for postemergence application to fiel d 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) . B ased on the preplant application scenario , HED concluded that tolerances in/on soybean, cotton, and t he 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 t o 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 io dosulfuron

- 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 , d epen ding on the proposed crop(s), application rate s , 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 require d. 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 1 22010), 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 di rections and/or tolerances. Adequate method s 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 t hrough the FDA Multiresidue Method (MRM) protocols (MRID 451087 16)

. 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 D 404948

Page 8 of 23 

### E DWCs 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 metsulfuron

methyl (registered active ingredient ; PC code 122010 ), which forms relatively rapid from iodosulfuron

- methyl

- sodium in soils under both aerobic and anaerobic conditions. Metsulfuron

methyl does not form under abiotic conditions. Both iodosul furon

- methyl

- sodium and metsulfuron

- methyl are very mobile in soils. T he 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 metsulfuro n - 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 applica tion of metsulf u ron - methyl. EFED has provided surface water and groundwater EDWCs for iodosulfuron

- methyl

- sodium resulting from the registered uses ( D350049, J. Wolf, 29

- A ug - 2008; D3 1 549 1 , S. Termes, 12

- J an - 2006). The highest acute and chronic EDWC s w ere 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 in to the most re cent dietary exposure analyses (see below). Conclusions: As part of Registration Review, EFED anticipates generat ing revised EDWCs to reflect current practices/models. Dietary Exposure HE D has conducted a cute and chronic dietary exposure analyses which considered all currently registered uses ( D 355405 , S. Levy , 5

- Nov

- 2008 ). T he 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) expos ure 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 change s to the toxicological PODs

.Iodosulfuron

- Methyl

- Sodium Human

- Health Assessment Scoping Document D 404948

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 in itial registration for these uses was for Iodosulfuron Turf Herbicide (EPA Reg. #432

- 1404), a 10% ai water

dispersible 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 rest ricted

- 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 ap plication (F AR 

### ). This default is 1% for formulations applied as liquids. Of the available TTR studies submitted to the Agency, the maximum F AR 

### value seen using a liquid product was 6.1% or 6.1 times higher than the default residue transfer value. Theref ore, 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 require ment 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 a nd 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 revision s 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 residenti al post

- application risk estimates and the current toxicological PODs, a TTR study is unnecessary.Iodosulfuron

- Methyl

- Sodium Human

- Health Assessment Scoping Document D 404948

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

- methyl

sodium uses (D350046, S. Levy et al

. , 12

- Nov

- 2008). The resulting acute ( fo od 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 par t 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 ot her 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

- 20 06; 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, s ince 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 , s ince 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 cons ider 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 Proc edures 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 (F AR 

### ). This defau lt is 1% for formulations applied as liquids. Of the available TTR studies submitted to the Agency, the maximum F AR 

### 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 ofIodosulfuron

- Methyl

- Sodium Human

- Health Assessment Scoping Document D 404948

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 stu dy ( 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 accor dance 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 va lue for the fraction of the application rate available to be dislodged after a foliar application (F AR 

### ). This default value is 25%. Of the analyzed DFR studies, the maximum F AR 

### value seen was 89% or 3.6 times higher than the default residue transfer valu e. 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

- sp ecific DFR study ( ExpoSAC Memo, 6/7/12, “ Guidance for Requiring/Waiving TTR and DFR Studie s: A DFR study for iodosulfuron

- methyl

- sodium is not required since estimated dermal MOEs for occupational wor kers 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. B ased upon re visions to the Agency’s scenario

- specific surrogate handler

exposure data , u pdated occupational handler exposure assessments may be required under Registration Review

. Reviewers should incorporate new exposure monitoring data, as necessary, during Registr ation 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 D 404948

Page 12 of 23 

### Public Health , Pesticide Epidemiology , and Human Incidence Data The following database s 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 ) : O PP 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 Occupation al Risk

- Pesticides (SENSOR)

. HED notes that iodos u lfuron

methyl

- sodium is not included in the Agricultural Health Study ( AHS ). Based on the low frequency and severity of incident cases reported for iodosulfuron

- methyl

sodium , 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 pp m (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 accuratel y 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 f or 180.5 80 (a) be changed as follows: 180.580(a) General. Tolerances are established for residues of the herbicide iodosulfuron

- methyl

sodium , 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

- methyl

sodium (sodium salt of methyl 4

- iodo

- 2

- [[[[(4

- methoxy

- 6

- methyl

- 1,3,5

- triazin

- 2

- yl)amino]carbonyl]amino]sulfon yl]benzoate ) , in or on the following commodities:Iodosulfuron

- Methyl

- Sodium Human

- Health Assessment Scoping Document D 404948

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 potentia l 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 studi es 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 d ecision for iodosulfuron

methyl

- 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 sect ion 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 “natur ally 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 po tential 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

- res ponse 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. Iodosulfuron

methyl

- 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 iodosulfuron

methyl

- 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 D 404948

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 not ed that the io dosulfuron

- methyl

sodium fate/metabolism studies did result in the identification of metsulfuron

- methyl , a registered active ingredient. However, based on the se data and the application scenarios for each of the active ingredients , residues of metsulfuron methyl fr o m iodosul f uron - methyl

- sodium application are expected to be negligible when compared to resi d ues resulting from application of metsulfuron

- methyl. Therefore, for the purposes of this and previous action s , EPA has assumed that iodosul f

uron - 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 t he 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 iodosu l furon

- 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 d ermal and inhalation exposure. Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as the Pesticide Ha ndlers 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 funda mentally unethical or significantly deficient relative to the ethical standards prevailing at the time the research was conducted. A ll applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisf

ied , and t here 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 typi cally 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 informatio n.Iodosulfuron

- Methyl

- Sodium Human

- Health Assessment Scoping Document D 404948

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 curr ent PODs will be reeval uated 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 toxicologi cal PODs. ●R evised residential risk assessment may be necessary to incorporate guidance from the updated Residential SOPs and/or toxicological PODs. ●R evised aggregate risk assessment may be necessary to reflect revised residential exposure estimates, dietary exposure estimates, and/or toxicological PODs. ●R evised occupational risk assessment may be necessary to reflect the most recent HED policies and/or toxicological PODs. HED n otes 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

- 201 2 ) ; PRD ( Feb

- 201 3 ) T. Bloem:Potomac Yard 1:703

- 605

- 0217:S10945PIodosulfuron

- Methyl

- Sodium Human

- Health Assessment Scoping Document D 404948

Page 16 of 23 

### Attachment A: References Memoranda Relevant to Registration Review Author DP# Barcode /

TXR # Date Title
HED

– Toxicological Documents P. Sha h 0052286 5

- Jan

- 2004 I odosulfuron - 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 D 318365 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

- methyl

sodium 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 D 404948

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 S odium ({[5

- iodo

- 2

- (methoxycarbonyl)phenyl]sulfonyl}carbamoyl)(4

- methoxy

- 6

- methyl

1,3,5

- triazin

- 2

- yl)azanide CAS name S odium salt of methyl 4

- iodo

- 2

- [[[[(4

- methoxy

- 6

- methyl

- 1,3,5

- triazin

- 2

- yl)amino]carbonyl]amino]sulfonyl]benzoate CAS registry number 1445 50

- 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/cm 3 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 - 9 Pa at 20oC ; 6.7 × 10 - 9 Pa at 25oC Dissociation constant, pK a pK a = 3.22 ± 0.06 at 20 oC Octanol/water partition coefficient, Log (K OW ) 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) U ltraviolet (U V ) /visible absorption spectrum Solvent λmax (nm) ε [L/(mol × cm)] MeOH 203 2.990 × 10 4 MeOH 238 3.184 × 10 4 MeOH + NaOH 239 3.170 × 10 4 (90/10, v/v) ; No observed absorption at λ 300

– 800 nm.Iodosulfuron

- Methyl

- Sodium Human

- Health Assessment Scoping Document D 404948

Page 18 of 23 

### Attachment C : Hazard Profile Table s Acute Toxicity of Iodosulfuron - Methyl - Sodium Technical. Guideline No. Study Type MRID # Results Toxicity Category

870.1100 Acute Oral 45133404 LD 50 mg/kg (calculated) Males 2947 (2053

- 11146) Females 2448 (1632

- 5780) Combined 2678 (2175

- 4744) III
870.1200 Acute Dermal 45133405 LD 50 > 2,000 mg/kg (limit dose) III 870.1300 Acute Inhalation 45108805 LC 50 > 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 sexe s. 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 D 404948

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 e vidence 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

- methyl

sodium 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 D 404948

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, mos tly 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 iodosulfuron

methyl

- 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)ureidosu lfonyl]

- 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 t he 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 (5 4

- 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/cm 2 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/cm 2 ) at 3 hours to 0.69% of the dose (0.159 μg/cm 2 ) at 8 hours. However, a similar t rend 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/cm 2 ).Iodosulfuron

- Methyl

- Sodium Human

- Health Assessment Scoping Document D 404948

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 P OD Uncertainty/ FQPA SF FQPA SF and LOC for

Risk Assessment Study and Toxicological Effects Acute Dietary for general population NOAEL = 315

mg/kg/day UF A = 10X

UF H = 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 UF A = 10X

UF H = 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 UF A = 10X

UF H = 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, Intermediate

Term (1

- 6 months) Oral NOAEL = 8.1

mg/kg/day UF A = 10X

UF H = 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 termina tion

. Dermal Short

- Term (1

- 30 days) Oral NOAEL = 49

mg/kg/day dermal absorption factor 2% UF A = 10X

UF H = 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, Intermediate

Term (1

- 6 months) Oral NOAEL = 8.1

mg/kg/day dermal absorption factor 2% UF A = 10X

UF H = 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% UF A = 10X

UF H = 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, Intermediate

Term (1

- 6 months) Oral NOAEL = 8.1

mg/kg/day (inhalation absorption of 100% assumed) UF A = 10X

UF H = 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 D 404948

Page 22 of 23 

### Attachment E : Registered End - Use Products and Application Scenarios /R ates 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 App lication 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 T ribute S olo WG32 H erbicide (264

- 686) 2% post

- emergence broadcast/ground field corn Hussar Herbicide (264

- 820) 5% post

- emergence broadcast/ground wheat A utumn Super 51 WDG H erbicide (264

- 1134) 6% preplant burndown/ground field corn, soybeans I odosulfuron 10 WDG H erbicide (264

- 843) 10% preplant burndown/ground soybean I odosulfuron 10 WDG H erbicide (264

- 856) 10% preplant burndown/ground cereal grains, cotton, and soybean I odosulfuron Turf H erbicide (432

- 1404) 10% spot and broadcast/backpack and ground turf (commercial/industrial, sod farms, ornamental, golf course, recreational, residential) 12

- 24 hours C elsius 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 0.002 2

- 0.00 89 0.00 89 - N o 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) T ribute S olo WG32 H erbicide (264

- 686) V1

- V8 0.00 19 0.00 19

- PHIs: 70 days for grain and 45 days for forage. c ereal grains, cotton, and soybean (preplant burndown application) A utumn Super 51 WDG H erbicide (264

- 1134) ; I odosulfuron 10 WDG H erbicide (264

- 843 and 264

- 856) P replant 0.00 19 0.00 19 - 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) I odosulfuron Turf H erbicide (432

- 1404) ; C elsius WG (432

- 1507) b roadcast /spot postemergent 0.00 27

- 0.00 8 9 0.00 8 9 - 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 D 404948

Page 23 of 23 

### Attachment F : International Residue Limits Summary of US and International Tolerances and Maximum Residue Limits Residue Definition US Canada Mexico 2 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

- methyl

1,3,5

- triazin

- 2

- yl)amino]carbonyl] amino]sulfonyl]benzoic acid methyl ester, monosodium salt -- None Tolerance/Maximum Residue Limit (ppm)

Commodity 1 US Canada Mexico 2 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.