UNITED ST A TES ENVIRONMENT AL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: September 15, 2015 

SUBJECT: Orthosulfamuron. Draft Human Health Risk Assessment in Support of 

Registration Review. 

PC Code: 108209 

Decision No.:499854 

Petition No.: NA 

DP Barcode: 0 425534 

Registration No.: NA 

Regulatory Action: Registration Review 

Risk Assessment Type: Single Chemical Aggregate Case No.: N/ A 

TXRNo.: NA CAS No.: 213464-77-8 

MRID No.: NA 40 CFR: .625 

FROM: 

THROUGH: 

TO: 

Karlyn Middleton, M.S .. Risk Assessorffoxicologist 

Zaida Figueroa, M.S., Industrial Hygienist ~ ~ ~ 

Michael A. Doherty, Ph.D., Chemist fv A,.....,_ Je1i(nv 

Risk Assessment Branch II ,-- 0 

Health Effects Division (7509P) 

Christina Swartz, Branch Chief ~A-­ Risk Assessment Branch II 

Health Effects Division (7509P) 

Khue Nguyen, Chemical Review Manager 

Risk Management and Implementation Branch I (RMIB I) 

Pesticide Re-Evaluation Division (7508P) 

As part of registration review, HED has examined the toxicological and exposure databases for 

assessing human health risks associated with orthosulfamuron and conducted a new risk 

assessment following current practices and policies. Significant changes relative to the last risk 

assessment (0319264, K. Bailey, 2007) include: 

I) The immunotoxicity and inhalation toxicity study requirements have been waived. 

2) Endpoints and points of departure have been selected for incidental oral to assess spray 

drift exposure/risk estimates. 

3) The occupational risk assessment has been updated to incorporate new science policies. 

4) Analytical chemistry and residue data have been submitted as a part of conditional 

registration. As a result, previously identified deficiencies related to the goat metabolism 

and multiresidue method data have been resolved. 

5) A high-end drinking water exposure value was used to assess screening-level dietary 

exposure/risk estimates. 

Page 1 of 31 
Table of Contents 

1.0 Executive Sun1mary ........................................................................................................... 3 

2.0 H ED Recommendations ..................................................................................................... 4 

2.1 Tolerance Considerations .................................................................. ... ........................... . 4 

2.2 Label Considerations ... ........ ............................................................................................ 5 

3.0 Introduction ........................................................................................................................ 5 

3.1 Chemical Identity and Physical/Chemical Characteristics ............................................... 5 

3.2 Pesticide Use Pattern and Anticipated Exposure Pathways ....................... ...................... 5 

3.3 Consideration of Environmental Justice .......................................................................... 6 

4.0 Hazard ldentifica tionff oxicology ..................................................................................... 6 

4. l Summary of Toxicological Effects ..................... ............................ ........... ........... .... ............ 7 

4.2 Safety Factor for Infants and Children (FQPA Safety Factor) ............................................. 8 

4.3 Toxicity Endpoint and Point of Departure Selections .......................................................... 8 

4.4 Endocrine Disruptor Screening Program ......................................................................... 9 

5.0 Dietary Exposure and Risk Assessment ......................................................................... 10 

5.1 Water Residue Profile .................................................................................................... I 0 

5.2 Food Residue Profile ............................................ ............ .... .... .... ... ............................... 11 

5.3 Dietary Exposure and Risk Estimates ...... ............................ .......................................... 11 

6.0 Residential (Non-Occupationa l) Exposure/Risk Cha racterization .............................. 12 

6.1 Spray Drift ...................................................................................................................... 12 

6.1.1 Combined Risk Estimates from Lawn Deposition Adjacent to Applications .............. l 2 

6.2 Residential Bystander Post-Application Inhalation Exposure ....................................... 13 

7.0 Aggregate Exposure/Risk Cha racterization .................................................................. 13 

8.0 Cumulative Exposure/Risk Characterization ................................................................ 13 

9.0 Occupationa l Exposure/Risk Characterization ............................................................. 14 

9. l Occupational Handler Exposure/Risk Estimates ........ ................................................. ... 14 

9.2 Occupational Post-application Exposure/Risk Estimates ................................................... 16 

9.2.1 Occupational Post-application Inhalation Exposure/Risk Estimates ........................... 16 

9.2.2 Occupational Post-application Dermal Exposure/Risk Estimates ............................... 16 

l 0.0 Public Health and Pesticide Epidemiology Data ........................................................... 17 

11.0 Literature References ....................................................................................................... 17 

12.0 References ......................................................................................................................... 18 

Appendix A. Toxicology Data Requirements and Toxicology Profile ................................... 19 

Appendix B. Revie\v of Human Research ................................................................................ 25 

Appendix C. Occupational Non-cancer Handler Algorithms ................................................. 27 

Appendix E. Nomenclature and Physical/Chemical Properties ............................................. 29 

Appendix F. Spray Drift Detailed Description ......................................................................... 30 

Page 2 of 31 
Page 3 of 31

1.0 Executive Summary

Orthosulfamuron, 1-(4,6-dimethoxypyrimidin-2-yl)-3-[2-(dimethylcarbamoyl)phenylsulfamoyl]

urea, is an herbicide of the sulfamoylurea class that is currently used on rice for the control of 

annual and perennial broadleaf weeds, sedges, and barnyard grass. Its mode of action is through 

inhibition of the plant enzyme acetolactate synthase, which is also known as acetohydroxy acid 

synthase. Inhibition of this enzyme blocks branch-chain amino acid biosynthesis of valine, 

leucine, and isoleucine (involved in plant growth) processes and leads to death of the plant. 

A human health scoping document was completed for orthosulfamuron in 2011 (D390069, D. 

Dotson); immunotoxicity and inhalation toxicity studies were identified as data gaps. However, 

the immunotoxicity study requirement has since been waived for the entire class of sulfonylurea 

chemicals (TXR#0056723). Additionally, HED’s Hazard and Science Policy Council 

(HASPOC) determined that the inhalation toxicity study is not required for orthosulfamuron

(TXR# 0050009). Guideline neurotoxicity studies are unavailable for orthosulfamuron, but are 

not required since there are several toxicity studies available (with neurotoxic parameters 

evaluated) that adequately characterize the potential neurotoxicity of the chemical. The 

toxicology database for orthosulfamuron is considered complete and adequate for risk 

assessment. The last human health risk assessment for orthosulfamuron was completed in 2007

(D319264, K. Bailey). Since then, no new toxicity and/or metabolism data have been received. 

However, in 2014, analytical chemistry and residue data were submitted as a part of conditional 

registration. As a result, previously identified deficiencies related to the goat metabolism and 

multiresidue method data have been resolved (D416922, W. Drew). The existing tolerances (40 

CFR 180.625) are supported by adequate residue chemistry data. For this assessment, the 

toxicological endpoints and points of departure (PODs) have been updated to include an 

incidental oral risk assessment in order to assess exposure from spray drift; dermal risks are not 

anticipated. All other endpoints/PODs selected for risk assessment remain the same as in the 

previous assessments. This draft risk assessment incorporates all new data and includes updates 

to hazard and exposure assessments, science policies, and procedures. 

For dietary exposure, HED has conducted a screening-level chronic dietary risk assessment for 

orthosulfamuron using tolerance-level residues in foods and a sulfonylurea-class-wide screeninglevel estimate of residues in drinking water. Dietary risk estimates range from 5 to 17% of the 

chronic population adjusted dose (cPAD) and are below HED’s level of concern (LOC). HED 

did not conduct an acute dietary exposure/risk assessment due to the lack of an appropriate 

endpoint for acute dietary assessment.

There are no registered residential uses or uses resulting in direct residential exposure associated 

with orthosulfamuron. Therefore, a quantitative residential exposure assessment was not 

performed. However, orthosulfamuron can be applied via groundboom and aerial equipment

and, therefore, there is the potential for indirect exposure to orthosulfamuron related to spray 

drift. As a result, incidental oral risk estimates for children 1 to <2 years old were calculated. 

The highest exposure resulted from drift following orthosulfamuron applications using aerial 

equipment for children 1 to <2 years old (margins of exposure (MOEs) ≥ 340,000 with a LOC 

=100). There were no risks of concern. 
Page 4 of 31

In the case of orthosulfamuron, aggregate exposure and risk estimates are equivalent to the 

dietary exposure and risk estimates do not exceed HED’s level of concern.

No chemical-specific handler exposure data were submitted in support of this draft risk 

assessment; therefore, HED relied on the best available data to assess handler exposure. Default 

assumptions established by HED’s Science Advisory Council for Exposure (ExpoSAC) were 

used for parameters such as body weight and amount handled. Since dermal risks are not 

anticipated due to the absence of dermal toxicity/endpoint, the occupational handler assessment 

is based on inhalation exposures only and a dermal occupational post-application assessment was 

not conducted. All occupational handler scenarios for the registered uses resulted in MOEs 

greater than the level of concern (LOC) of 100 and are not of concern. The lowest MOE of 

9,800 is associated with mixing/loading a dry flowable formulation applied aerially up to 1,200 

acres. All other MOEs were significantly higher, ranging from 52,000 to 18,000,000. No 

additional personal protective equipment (PPE) recommendations are needed on the registered

labels. 

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

inhalation exposure assessment was not performed for orthosulfamuron. If new policies or 

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

post-application inhalation exposure assessment for orthosulfamuron. 

The restricted entry interval (REI) of 12 hours specified on the registered labels is based on the 

acute toxicity of orthosulfamuron and is adequate to protect agricultural workers from postapplication exposures. 

HED has not identified any risk concerns associated with the registered uses of orthosulfamuron. 

There are no data gaps that would require submission of additional toxicity, residue chemistry, or 

exposure data.

2.0 HED Recommendations

2.1 Tolerance Considerations

The existing tolerances (40 CFR 180.625) are supported by the available residue chemistry data. 

At this time, there are no Codex or Canadian MRLs; therefore, international harmonization is not 

a consideration for orthosulfamuron during registration review. 

HED notes that “rice, straw” is no longer considered to be a significant livestock feed item and 

that a tolerance for residues in/on that commodity is not necessary. Therefore, the tolerance 

listing for rice, straw at 0.05 ppm should be deleted from 40 CFR 180.625; the listing for rice, 

grain at 0.05 ppm should remain.

Furthermore, HED notes that the tolerance expression for orthosulfamuron requires revision to 

state the following:
Page 5 of 31

Tolerances are established for residues of orthosulfamuron, including its metabolites and 

degradates, in or on the commodities in the table below. Compliance with the tolerance 

levels specified below is to be determined by measuring only orthosulfamuron, 1-(4,6-

dimethoxypyrimidin-2-yl)-3-[2-(dimethylcarbamoyl)- phenylsulfamoyl] urea.

2.2 Label Considerations

There are no label recommendations for registered products containing orthosulfamuron.

3.0 Introduction

3.1 Chemical Identity and Physical/Chemical Characteristics

Orthosulfamuron {2-[[[[[(4,6-dimethoxy-2-pyrimidinyl)amino]carbonyl]amino]sulfonyl]amino]-

N,N dimethylbenzamide} is a systemic herbicide belonging to the pyrimidinylsulfonylurea class 

of chemicals. The chemical properties of orthosulfamuron do not suggest that there are any 

particular exposure issues that warrant special consideration. The compound has multiple 

dissociation constants, making its water solubility dependent on pH, with lower solubility under 

more acidic conditions. The potential for orthosulfamuron to partition into fatty matrices is also, 

by extension, pH dependent; however, based on the octanol/water partitioning coefficients, such 

partitioning is unlikely to occur. Orthosulfamuron has a relatively low vapor pressure, indicating 

that inhalation of vapors is unlikely to be a significant source of exposure under ambient 

conditions. The nomenclature and physical/chemical properties of orthosulfamuron are provided 

in Appendix E.

3.2 Pesticide Use Pattern and Anticipated Exposure Pathways

Orthosulfamuron is currently used on rice for the control of annual and perennial broadleaf 

weeds, sedges, and barnyard grass. There are 4 registered end-use products formulated as a

water dispersible granular (WG) or granular (GR) for use on rice. The registered application 

methods for orthosulfamuron include the use of aerial and ground equipment.

Based on the use pattern which allows only one application per season, the duration of exposure

for occupational handlers in conjunction with the registered uses is expected to be short-term

(i.e., 1 to 30 days) and intermediate-term (i.e., 1 to 6 months); long-term exposures (greater than 

6 months) are not anticipated. The PPE statements on registered labels require applicators, 

flaggers and other handlers to wear the following: long sleeved shirt, long pants, shoes plus 

socks, chemical-resistant gloves and protective eyewear. The restricted entry interval (REI) on 

all labels is 12 hours.

Exposure Pathways

Individuals may be exposed to orthosulfamuron via their diet (food and drinking water). There 

are no registered uses for orthosulfamuron that will result in direct non-dietary (i.e., residential) 

exposures. However, there is the potential for indirect exposure (incidental oral and dermal) to 
Page 6 of 31

orthosulfamuron related to spray drift. Agricultural workers may be exposed (dermal and 

inhalation) to orthosulfamuron during mixing, loading, and/or applying the herbicide as well as 

during post-application activities.

Table 3.2. Summary of Directions for Registered Use of Orthosulfamuron.

Applic. 

Timing, Type, 

and Equip.

Formulation and Products

[EPA Reg No.]

Applic. 

Rate

(lb ai/A)

Max. No. 

Applic. per 

Season

Max. Seasonal 

Applic. Rate 

(lb ai/A)

Use Directions and Limitations

Rice

Ground, Aerial; 

Broadcast 

Spray

Strada XT2 Herbicide WDG, 

10% ai, [71711-46]

0.066 lbs 

ai/A

1 app/season 0.066 lb ai/A Do not apply by any irrigation system. Apply 

to young emerging and actively growing 

weeds, between 2-4 leaves. For dry-seeded 

rice, apply from early post-emergence to preflood.

Strada PRO Herbicide WDG, 

42.05% ai, [71711-47]

Strada Herbicide WDG,

50% ai, [71711-44]

0.067 lb 

ai/A

0.067 lb ai/A

Strada GR Granular,

0.50% ai, [71711-45]

Apply to young emerging weeds, between 1-2 

leaves.

3.3 Consideration of Environmental Justice

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

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

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

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf). As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the USDA under the Continuing 

Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all 

registered food uses of a pesticide. These data are analyzed and categorized by subgroups based 

on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to 

assess dietary exposure to smaller, specialized subgroups and exposure assessments are 

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

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

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

evaluated. Further considerations are currently in development as OPP has committed resources 

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

bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific 

subgroups.

4.0 Hazard Identification/Toxicology

The toxicology database for orthosulfamuron is complete and adequate for risk assessment. 

Immunotoxicity, neurotoxicity, and inhalation studies are not available for orthosulfamuron, as 

required in accordance with the current Part 158 Guidelines (40 CFR Part 158). However, 

neurotoxicity studies are not needed, since there are several toxicity studies available
Page 7 of 31

(reproduction and subchronic/chronic toxicity) that include neurotoxic measures that adequately 

characterize the potential neurotoxicity of the chemical. The Hazard and Science Policy Council 

(HASPOC) determined that the subchronic inhalation toxicity study is not required for 

orthosulfamuron (TXR# 0050009). The HASPOC also waived the immunotoxicity study 

requirement for the entire class of sulfonylurea chemicals (TXR#0056723). No new toxicity 

and/or metabolism data have been received since the last risk assessment (D319264, K. Bailey). 

The toxicological endpoints and points of departure (PODs) have been updated to include an 

incidental oral risk assessment for the purpose of assessing exposure from spray drift. All other 

endpoints/PODs selected for risk assessment remain the same as those used in the previous 

assessment. See Appendix A.2 for the orthosulfamuron toxicological profile. 

4.1 Summary of Toxicological Effects

The target organs for orthosulfamuron are the liver, kidneys, and the thyroid gland. Subchronic 

exposure to orthosulfamuron leads to hepatotoxicity in dogs, but not in mice and rats. Chronic 

exposure results in hepatotoxicity in dogs, rats, and mice. Liver effects observed include 

increases in liver enzymes and weights, gross pathology and histopathology (hypertrophy, 

vacuolation, pigmented Kupffer cells, etc.). Evidence of nephrotoxicity was seen only in rats, in 

the form of increased kidney weights, lesions, and nephropathy. Additionally in rats, long-term 

exposure led to thyroid hypertrophy, enlarged thyroids, and thyroid follicular cell adenomas. 

Based on the thyroid follicular adenomas, the Cancer Assessment Review Committee (CARC) 

classified orthosulfamuron as having “Suggestive Evidence of Carcinogenicity.” The CARC 

determined that the quantification of cancer risk using a non-linear approach (i.e., RfD) would 

adequately account for all chronic toxicity, including carcinogenicity, that could result from 

exposure to orthosulfamuron. There is no mutagenicity concern for orthosulfamuron.

There is no concern for increased quantitative or qualitative susceptibility of the young following 

in utero and pre-and post-natal exposure to orthosulfamuron. No treatment-related effects were 

observed in maternal animals or fetuses in developmental toxicity studies in rats or rabbits. In 

the reproduction study, effects in offspring animals (decreased motor activity) were seen in the 

presence of comparable effects in adult animals (kidney effects). 

In acute lethality studies, orthosulfamuron has low toxicity via the oral, dermal, and inhalation 

routes of exposure (Category IV). It is non-irritating to the skin (Category IV), and it is not a 

skin sensitizer. It is slightly irritating to the eye (Category III). The acute toxicity of 

orthosulfamuron is presented in Appendix A.2.

Orthosulfamuron is rapidly and well absorbed following oral dosing in rats, regardless of sex, 

dose, or number of doses. The time to maximum plasma levels (tmax) ranged from 12 min up to 

4hrs depending on the dose. At 72 h post-dose, overall recovery of the radioactive dose from 

both sexes was 92-100%. The majority of the dose was recovered in the feces (43-73%); 18-

46% of the dose was found in the urine; and cage wash accounted for 1-5% dose. Minimal 

radioactivity was detected in the carcass and GI tract. 
Page 8 of 31

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

HED has recommended that the required 10X Food Quality Protection Act (FQPA Safety Factor

(SF) be reduced to 1x for orthosulfamuron. The toxicology database is complete, there is no 

evidence of increased susceptibility, no concerns/residual uncertainties with regard to pre- and/or 

postnatal toxicity, and no concern for neurotoxicity. In addition, HED has not underestimated 

the potential for exposure through food and water, using conservative assumptions regarding 

residues in food and modeled drinking water estimates.

4.3 Toxicity Endpoint and Point of Departure Selections

The toxicological endpoints/PODs have been updated to include an incidental oral risk 

assessment. All other endpoints/PODs selected for risk assessment remain the same as in 

previous assessments. A summary of toxicological doses and endpoints used in the 

orthosulfamuron human health risk assessments is presented below.

Table 4.3.1.a. Summary of Toxicological Doses and Endpoints for Orthosulfamuron for Use in Dietary and 

Non-Occupational Human Health Risk Assessments.

Exposure/

Scenario

Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

RfD, PAD, Level 

of Concern for 

Risk Assessment

Study and Toxicological Effects

Acute 

Dietary (all 

populations)

No appropriate endpoint attributable to a single dose was identified in the toxicity database.

Chronic 

Dietary (All 

Populations)

NOAEL= 5 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF=1x

Total UF=100x

Chronic RfD =0.05 

mg/kg/day

cPAD

= 0.05mg/kg/day

Combined 

Chronic/Carcinogenicity-Rat

LOAEL (mg/kg/day): 500, based 

on decreased body weight gains, 

hepatotoxicity and nephrotoxicity 

in both sexes. 

Incidental 

oral (shortterm)

NOAEL=

88.6 mg/kg/day

UFA=10x

UFH=10x

Residential LOC 

for MOE = 100

2-Generation Reproduction -Rat

LOAEL (mg/kg/day): 354.5 based 

on increased kidney weights and 

lesions (tubular mineralization and 

urothelial hyperplasia) in parental 

animals.

Dermal (all 

exposures) 

N/A N/A N/A No dermal endpoint was selected 

based on a lack of systemic 

toxicity in the dermal study and no 

concern for susceptibility.

Cancer (oral, 

dermal, 

inhalation)

Classification: “Suggestive Evidence of Carcinogenicity.” Quantification of cancer risk using a 

non-linear approach (i.e., RfD) would adequately account for all chronic toxicity, including 

carcinogenicity that could result from exposure to orthosulfamuron. 

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

factor. UFA = extrapolation from animal to human (interspecies). UFH = variation in sensitivity among members of 

the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, 

c = chronic). RfD = reference dose. N/A = not applicable. LOC = level of concern.
Page 9 of 31

Table 4.3.1.b. Summary of Toxicological Doses and Endpoints for Orthosulfamuron for Use in 

Occupational Human Health Risk Assessments.

Exposure/

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

Dermal (all 

exposures) 

N/A N/A N/A No dermal endpoint was selected 

based on a lack of systemic 

toxicity in the dermal study and 

no concern for susceptibility.

Inhalation 

Short-Term 

(1-30 days) 

NOAEL=

88.6 mg/kg/day

UFA=10x

UFH=10x

Occupational LOC 

for MOE = 100

2-Generation Reproduction –Rat

LOAEL (mg/kg/day): 354.5 based 

on increased kidney weights and 

lesions (tubular mineralization 

and urothelial hyperplasia) in 

parental animals.

Cancer 

(oral, 

dermal, 

inhalation)

Classification: “Suggestive Evidence of Carcinogenicity.” Quantification of cancer risk using a 

non-linear approach (i.e., RfD) would adequately account for all chronic toxicity, including 

carcinogenicity that could result from exposure to orthosulfamuron. 

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

factor. UFA = extrapolation from animal to human (interspecies). UFH = variation in sensitivity among members of 

the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

N/A = not applicable.

4.4 Endocrine Disruptor Screening Program

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

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

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

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

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

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

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

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

taxonomic groups. As part of its most recent registration decision for orthosulfamuron, 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), 

orthosulfamuron 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 
Page 10 of 31

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

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

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

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

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

of chemicals identified for EDSP screening was published on June 14, 20131and includes some 

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

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

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

chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our 

website.2

5.0 Dietary Exposure and Risk Assessment 

5.1 Water Residue Profile

Screening groundwater-sourced drinking water exposure estimates were generated with the 

Pesticide Root Zone Model for GroundWater (PRZM-GW; v.1.07) for use in the sulfonylurea 

(SU) dietary risk assessments. Rather than produce chemical-specific estimated drinking water 

concentrations (EDWCs) following the usual assessment procedures, EFED provided coarsescreen estimates that should exceed upper-bound, chemical-specific EDWCs for any SU. This 

was achieved by using model inputs that represent the use pattern of highest exposure from any 

SU, the highest soil mobility of any SU residue of concern, and the highest persistence to any 

route of degradation over time. The resulting coarse-screen EDWCs from PRZM-GW were used 

as conservative estimates of exposure and are summarized in Table 5.1 (D427429, G. Orrick). 

The acute and chronic dietary assessments for orthosulfamuron used the coarse-screen maximum 

daily concentration of 751 μg/L (0.751 ppm) and the post-breakthrough mean value of 492 μg/L

(0.492 ppm), respectively. 

Table 5.1. PRZM-GW Coarse-Screen EDWCs for Sulfonylureas1.

Modeled Scenario Kd or KOC

Initial Application 

Dates (days postemergence)

Max. Daily Conc. 

(μg/L)

Mean 

Breakthrough 

Time (yrs)

Postbreakthrough 

Mean (μg/L)

WI corn

Kd 7 449 11.5 415

KOC 7 504 6.9 425

DMV corn

Kd 7 489 5.3 369

KOC 7 560 3.3 378

FL citrus Kd 7 429 3.2 351

 

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

chemicals.

2 http://www.epa.gov/endo/
Page 11 of 31

Table 5.1. PRZM-GW Coarse-Screen EDWCs for Sulfonylureas1.

Modeled Scenario Kd or KOC

Initial Application 

Dates (days postemergence)

Max. Daily Conc. 

(μg/L)

Mean 

Breakthrough 

Time (yrs)

Postbreakthrough 

Mean (μg/L)

KOC 7 467 2.3 349

FL potato

Kd 7 375 2.6 272

KOC 7 407 2.2 275

GA peanut

Kd 7 197 5.2 156

KOC 7 206 3.9 158

NC cotton

Kd 7 640 8.7 492

Kd 37 641 8.7 491

Kd 67 637 8.7 490

KOC 7 742 5.7 484

KOC 37 751 5.7 483

KOC 67 744 5.7 482

1 Maximum values are bolded.

5.2 Food Residue Profile 

Orthosulfamuron is registered for use on rice and a tolerance has been established for residues in 

rice grain at 0.05 ppm. In conducting this assessment, HED has assumed tolerance-level 

residues in all rice grain and processed products and that 100 percent of rice is treated with 

orthosulfamuron.

5.3 Dietary Exposure and Risk Estimates

Exposure and risk estimates were obtained from the Dietary Exposure Evaluation Model using 

the Food Commodity Intake Database (DEEM-FCID; version 3.18). The model uses food 

consumption data from the 2003-2008 NHANES/WWEIA database, coupled with recipe files 

and residues in foods, to derive estimates of dietary exposure and risk. Generally, HED is 

concerned when dietary exposure estimates exceed 100% of the population adjusted dose (PAD). 

In the case of orthosulfamuron, the dietary risk estimates (Table 5.3) range from 5 to 17% of the 

cPAD and are below HED’s level of concern. Because of the very conservative assumptions 

used in the analysis (tolerance level residues, 100 % crop treated, upper-bound modeled drinking 

water estimates), actual exposure and risk are expected to be much lower than those shown in 

Table 5. The listings of inputs and outputs to the assessment are included in Appendix D. HED 

did not conduct an acute dietary exposure/risk assessment due to the lack of an endpoint 

appropriate for acute dietary assessment.

Table 5.3. Summary of dietary exposure and risk estimates for Orthosulfamuron.

Acute Estimates Chronic Estimates

Population Group

Exposure, 

mg/kg bw Risk, % aPAD

Exposure, 

mg/kg bw/day Risk, % cPAD

Total US Population Not Applicable 0.01031 21

All Infants (< 1 year old) 0.02661 53

Children 1-2 years old 0.01489 30

Children 3-5 years old 0.01254 25
Page 12 of 31

Table 5.3. Summary of dietary exposure and risk estimates for Orthosulfamuron.

Acute Estimates Chronic Estimates

Population Group

Exposure, 

mg/kg bw Risk, % aPAD

Exposure, 

mg/kg bw/day Risk, % cPAD

Children 6-12 years old 0.00904 18

Youth 13-19 years old 0.00752 15

Adults 20-49 years old 0.01029 21

Adults 50-99 years old 0.01017 20

Female 13-49 years old 0.01025 21

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no registered residential uses or occupational uses resulting in residential exposure 

associated with orthosulfamuron. Therefore, a quantitative residential exposure assessment was 

not performed.

6.1 Spray Drift

A detailed description about HED’s spray drift policy and how to evaluate the drift potential and 

associated risks is available in Appendix F.

6.1.1 Combined Risk Estimates from Lawn Deposition Adjacent to Applications

The spray drift risk estimates are based on an estimated deposited residue concentration as a 

result of the screening level agricultural application scenarios. The potential risk estimates from 

these residues can be calculated using drift modeling onto 50 feet wide lawns coupled with 

methods employed for residential risk assessments for turf products. Orthosulfamuron is used on 

rice and can be applied via groundboom and aerial equipment. The recommended drift scenario 

screening level options are listed below: 

• Groundboom applications are based on the AgDrift option for high boom height and 

using very fine to fine spray type using the 90th percentile results. 

• Aerial applications are based on the use of AgDrift Tier 1 aerial option for a fine to 

medium spray type and a series of other parameters which will be described in more detail below 

(e.g., wind vector assumed to be 10 mph in a downwind direction for entire application/drift 

event). 

Since dermal risks are not anticipated due to the absence of dermal toxicity, the spray drift

assessment is based on incidental oral exposures only. The highest exposure resulted from drift 

following orthosulfamuron applications using aerial equipment, for children 1 to <2 years old

(margins of exposure (MOEs) ≥ 340,000, with a LOC =100). There are no risks of concern at 

the field’s edge (i.e., assuming a residential lawn is directly adjacent to a field where rice is 

grown and treated with aerial or ground equipment). See Table 6.1.1 for detailed results.
Page 13 of 31

Table 6.1.1. Children (1<2 years old) Risk Estimates (MOEs) Related to Indirect Exposure to Spray Drift for 

Orthosulfamuron for the Incidental Oral Route of Exposure.

Crop/Rate 

Group Spray Type/ Nozzle Configuration Appl. Rate (lb ai/A) TTR1

(ug/cm2) At Edge of the Field

Aerial Fine to Medium 0.067 0.00745 340,000

Groundboom High Boom Very fine to Fine 460,000

1 HED’s default assumption that 10% of the application is available for transfer on day 0 following the application 

and the residues dissipate at a rate of 10% each following day.

6.2 Residential Bystander Post-Application Inhalation Exposure

Volatilization of pesticides may be a source of post-application inhalation exposure to 

individuals nearby pesticide applications. The agency sought expert advice and input on issues 

related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

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

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

agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis.

3

 During Registration Review, the agency will 

utilize this analysis to determine if data (i.e., flux studies, route-specific inhalation toxicological 

studies) or further analysis is required for orthosulfamuron.

7.0 Aggregate Exposure/Risk Characterization

The Food Quality Protection Act of 1996 directs EPA to assess aggregate exposure to pesticide 

chemical residues, including all anticipated dietary exposures and all other exposures for which 

there is reliable information. In the case of orthosulfamuron, aggregate exposure and risk 

estimates are equivalent to the dietary exposure and risk estimates in Section 5, above, and are 

below HED’s level of concern.

8.0 Cumulative Exposure/Risk Characterization

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

Cumulative Risk Assessment: Framework for Screening Analysis 

[http://www.epa.gov/oppfead1/cb/csb_page/updates/2015/framework-for-screeninganalysis.html]. This document provides guidance on how to screen groups of pesticides for 

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

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

framework supplements the existing guidance documents for establishing common mechanism 

groups (CMGs)4and conducting cumulative risk assessments (CRA)5. The Agency has utilized 

this framework to evaluate the SUs of which orthosulfamuron is a member (J. D’Agostino; 

D428798; 9/9/15). Although the SUs share some chemical and toxicological characteristics, the 

 

3 Available at: http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219.

4 Guidance For Identifying Pesticide Chemicals and Other Substances that have a Common Mechanism of Toxicity 

(USEPA, 1999)

5 Guidance on Cumulative Risk Assessment of Pesticide Chemicals That Have a Common Mechanism of Toxicity 

(USEPA, 2002)
Page 14 of 31

toxicological database does not support a testable hypothesis for a common mechanism of action. 

No further mechanistic data are required and no further cumulative evaluation is necessary.

9.0 Occupational Exposure/Risk Characterization

9.1 Occupational Handler Exposure/Risk Estimates

Based on current labeling, types of equipment and techniques that can potentially be used, 

occupational handler exposure is expected from the registered use on rice. The quantitative 

exposure/risk assessment developed for occupational handlers is based on the scenarios listed in 

Table 9.1. Based on the use pattern (i.e., 1 application per season) and resistance management 

practices, occupational exposure from the registered food use is expected to be short-term (1-30 

days) and intermediate-term (i.e., 1-6 months) in duration. Since the same endpoint and point of 

departure were selected for short- and intermediate-term durations, short-term exposure and risk 

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

exposures (i.e., than 6 months) are not anticipated.

Occupational Handler Exposure, Assumptions and Risk Estimate Equations

Application Rate: The maximum single application rates are listed in Table 3.2. Refer to section 

3.0 for a complete use pattern description.

Body Weight & Absorption Factor: The standard body weight (80 kg) was used in this risk 

assessment since the endpoint selected was not developmental and/or based on fetal effects. 

Since no inhalation absorption data are available, toxicity by the inhalation route is considered to 

be equivalent to the estimated toxicity by the oral route of exposure.

Unit Exposures: It is the policy of HED to use the best available data to assess handler exposure. 

Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, 

include PHED 1.1, and the AHETF database. Some of these data are proprietary (e.g., AHETF 

data), and subject to the data protection provisions of FIFRA. The standard values recommended 

for use in predicting handler exposure that are used in this assessment, known as “unit 

exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate 

Reference Table6.” HED policy on use of surrogate data, including descriptions of the various 

sources, can be found at the Agency website7.

Area Treated: The area treated inputs were based on the Science Advisory Council for Exposure 

Policy 9.1: Standard Values for Daily Acres Treated in Agriculture (listed in Table 9.1).

Risk Estimate Equations: The algorithms used to estimate non-cancer exposure and dose for 

occupational handlers can be found in Appendix C.

Summary of Occupational Handler Non-Cancer Exposure and Risk Estimate

 

6 Available: http://www.epa.gov/opp00001/science/handler-exposure-table.pdf

7 Available: http://www.epa.gov/pesticides/science/handler-exposure-data.html
Page 15 of 31

All occupational handler scenarios for the registered uses resulted in MOEs greater than 100 at 

baseline level of risk mitigation (i.e., baseline attire with no gloves or respirator) or engineering 

control for aerial applications (i.e., enclosed cockpits) and, therefore, are not of concern. The 

lowest MOE of 9,800 is associated with mixing/loading a dry flowable formulation that is being 

applied aerially over up to 1,200 acres. All other MOEs were significantly higher, ranging from 

52,000 to 18,000,000. No additional PPE recommendations are needed on the registered labels. 

Table 9.1. Short-term Handler Exposure and Risk Estimates for Orthosulfamuron.

Exposure Scenario Mitigation 

Levela

Inhalation 

Unit 

Exposureb

(mg/lb ai)

Application 

Ratec

(lb ai/A)

Area

Treatedd

Inhalation 

Dosee

(mg/kg/day)

Total MOEf

Mixer/Loader & Loader

Granules for Aerial 

Application (Loading 

only)

Baseline 0.0017 0.067 1,200 A/day 0.001710 52,000

Granules for Tractordrawn Spreader

Application

(Loading only)

0.0017 0.067 200 A/day 0.000285 310,000

Dry Flowable (WG) 

for Aerial Application

0.00896 0.067 1,200 A/day 0.0090 9,800

Dry Flowable for 

Groundboom 

Application

0.00896 0.067 200 A/day 0.0015 590,000

Applicator

Sprays for 

Aerial Application

Engineering 

Controls 

(Enclosed 

Cockpit)

0.0049 0.067 1,200 A/day 4 x 10-6 18,000,000

Granules for Aerial 

Application

0.0013 0.067 1,200 A/day 0.00131 68,000

Sprays for 

Groundboom 

Application

Baseline 0.00034 0.067 200 A/day 0.000057 1,600,000

Granules for Tractordrawn Spreader 

Application

0.0012 0.067 200 A/day 0.000201 440,000

Flagger

Flagging Sprays for 

Aerial Application

Baseline 0.00035 0.067 350 A/day 0.000103 860,000

Flagging Granules for 

Aerial Application

0.00015 0.067 350 A/day 0.000044 2,000,000

a. Mitigation Level: “baseline” (i.e., single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no 

gloves, and no respirator); “engineering controls” (i.e., aerial applications enclosed cockpit).

b. Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (February, 2015).

c. Based on maximum single application rates on registered labels (Table 3.2).

d. Based on the Science Advisory Council for Exposure Policy 9.1: Standard Values for Daily Acres Treated in Agriculture.

e. Short-term Inhalation Dose (mg/kg/day) = [Rate (lb ai/A) x UE (mg /lb ai) x Acres Treated (A/day)]/BW (80 kg).

f. MOE = Short-term Inhalation NOAEL (88.6 mg/kg/day)/ Short-term Inhalation Dose (mg/kg/day). LOC=100.
Page 16 of 31

9.2 Occupational Post-application Exposure/Risk Estimates

9.2.1 Occupational Post-application Inhalation Exposure/Risk Estimates

There are multiple potential sources of post-application inhalation exposure to individuals 

performing post-application activities in previously treated fields. These potential sources 

include volatilization of pesticides and resuspension of dusts and/or particulates that contain 

pesticides. The agency sought expert advice and input on issues related to volatilization of 

pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel 

(SAP) in December 2009, and received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The agency has 

evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent 

Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQOPP-2014-0219). During Registration Review, the agency will utilize this analysis to determine 

if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is 

required for orthosulfamuron.

In addition, the Agency is continuing to evaluate the available post-application inhalation 

exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the 

Agency will continue to identify the need for and, subsequently, the way to incorporate 

occupational post-application inhalation exposure into the agency's risk assessments.

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational handlers. 

Handler exposure resulting from application of pesticides outdoors is likely to result in higher 

exposure than post-application exposure. Therefore, it is expected that these handler inhalation 

exposure estimates would be protective of most occupational post-application inhalation 

exposure scenarios.

9.2.2 Occupational Post-application Dermal Exposure/Risk Estimates

No post-application chemical-specific data were submitted in support of registration review. A

short-term dermal post-application exposure assessment is not required due to the absence of 

systemic and dermal toxicity in the dermal toxicity study.

Restricted Entry Interval

The REI specified on the registered labels is based on the acute toxicity of orthosulfamuron. 

Orthosulfamuron is classified as Toxicity Category IV via the dermal route and Toxicity 

Category IV for skin irritation potential. It is not a skin sensitizer. Under 40 CFR 156.208 (c) 

(2) (iii), ai’s classified as Acute III or IV for acute dermal, eye irritation and primary skin 

irritation are assigned a 12-hour REI. Therefore, the [156 subpart K] Worker Protection 

Statement REI of 12 hours is adequate to protect agricultural workers from post-application 

exposures to orthosulfamuron. 
Page 17 of 31

10.0 Public Health and Pesticide Epidemiology Data

For this evaluation, the OPP Incident Data System (IDS) was utilized for pesticide incident data 

on the active ingredient orthosulfamuron (D390658, S. Winfield). The purpose of the database 

search is to identify potential patterns in the frequency and severity of the health effects 

attributed to orthosulfamuron exposure. IDS records incidents resulting in higher severity 

outcomes in more detail, in a module called the Main IDS module. This system stores incident 

data for death, major and moderate incidents, and it includes more details about the location, date 

and nature of the incident. Main IDS incidents involving only one pesticide are considered to 

provide more certain information about the potential effects of exposure from the pesticide. The

less severe human incidents (minor, unknown, or no effects outcomes) are reported by registrants 

as counts called aggregate summaries and are recorded in a separate module called Aggregate 

IDS. 

In Aggregate IDS and Main IDS, from January 1, 2006 to June 6, 2011 there were no incidents 

involving orthosulfamuron. An updated incident evaluation was done in 2015 (D425815, S. 

Recore). An IDS analysis was conducted from June 2011 to February 25, 2015; no incidents 

(Aggregate or Main IDS) were reported for orthosulfamuron.

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) database was also consulted for pesticide incident data on the active ingredient 

orthosulfamuron. The SENSOR-Pesticides database covers 11 states from 1998-2011, although 

reporting varies from state to state. Cases of pesticide-related illnesses are ascertained from a 

variety of sources, including: reports from local Poison Control Centers, state Department of 

Labor workers’ compensation claims when reported by physicians, reports from State 

Departments of Agriculture, and physician reports to state Departments of Health. Although both 

occupational and non-occupational incidents are included in the database, SENSOR-Pesticides 

focuses on occupational pesticide incidents, and is of particular value in providing that 

information. A query of SENSOR-Pesticides from 1998-2011 identifies no cases involving 

orthosulfamuron.

The Agricultural Health Study (AHS) is a high quality, prospective epidemiology study 

evaluating the link between pesticide use and various health outcomes including cancer. The 

AHS includes private and commercial pesticide applicators and their spouses. The AHS includes 

information on use of 80 different pesticide active ingredients commonly used in agriculture. 

Orthosulfamuron is not included in the AHS, and therefore this study does not provide 

information for this document.

11.0 Literature References

A literature search was performed for orthosulfamuron. The search did not reveal information 

that would impact the current risk assessment. 
Page 18 of 31

12.0 References

Author Barcode Date Title

G. Orrick D427429 8/12/2015 Drinking Water Exposure Assessment for the Registration Review 

of 22 Sulfonylurea Herbicides 

S.Recore D425815 3/03/2015 Orthosulfamuron: Review of Human Incidents

D. Dotson,

K. Bailey,

Z. Figueroa

D390069 11/28/2011 Orthosulfamuron: Human Health Assessment Scoping Document in 

Support of Registration Review

S. Winfield D390658 8/31/2011 Orthosulfamuron: Review of Human Incidents

K. Bailey,

D. Dotson,

Z. Figueroa

D319264 2/14/2007 Orthosulfamuron: Human Health Risk Assessment for Proposed 

Use on Rice. 

D. Dotson D332295 2/14/2007 Orthosulfamuron: Chronic Dietary Exposure Assessment for the 

Section 3 Registration Action on Rice.

Z. Figueroa D333763 1/10/2007 Occupational Exposure Risk Assessment for Proposed Uses of 

Orthosulfamuron

G. Orrick D330828 10/31/2006 Orthosulfamuron (Section 3: Rice Use), Tier 1 Drinking Water 

Exposure Assessment for Orthosulfamuron on Rice

W. Drew D416922 9/19/2014 Orthosulfamuron. Review of Data Submitted as Condition of 

Registration for Use of the Herbicide on Rice. Summary of 

Analytical Chemistry and Residue Data.
Page 19 of 31

Appendix A. Toxicology Data Requirements and Toxicology Profile 

The toxicology requirements (40 CFR 158.340) for orthosulfamuron are presented below. 

Test Technical

Required Satisfied

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

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

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

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

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

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

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

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

870.3150 Oral Subchronic (nonrodent)........................................

870.3200 21/28-Day Dermal........................................................

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

870.3465 21/28-Day Inhalation....................................................

yes

yes

yes

no

no

yes

yes

yes

---

no*

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

870.3700b Developmental Toxicity (nonrodent) ...........................

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

yes

yes

yes

yes

yes

yes

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

870.4100b Chronic Toxicity (nonrodent).......................................

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

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

870.4300 Chronic/Oncogenicity ..................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

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

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

870.5375 Mutagenicity—Structural Chromosomal Aberrations..

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

yes

yes

yes

yes

yes

yes

yes

yes

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

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

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

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

870.6300 Develop. Neurotoxicity ................................................

no

no

yes

yes

no

---

---

yesa

yesa

---

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

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

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

yes

no

yes

yes

---

Waived*

Non guideline Thyroid MOA Investigation Study no ---

a Guideline acute and subchronic neurotoxicity studies are not available for orthosulfamuron. However, there are 

several toxicity studies available that adequately characterize the potential neurotoxicity of this chemical and 

additional studies are not required at this time. * The Hazard and Science Policy Council (HASPOC) determined 

that subchronic inhalation and immunotoxicity studies are not required (TXR 0050009).
Page 20 of 31

A.2. Toxicity Profiles

Table A.2.1. Acute Toxicity Profile – Orthosulfamuron (98%).

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

870.1100 Acute oral -Rat 46219019 LD50 = > 5000 

mg/kg/bw (both 

sexes)

IV

870.1200 Acute dermal-Rat 46219020 LD50 = > 5000 

mg/kg/bw (both 

sexes)

IV

870.1300 Acute inhalationRat46219021 LC50 = > 2.19mg/L 

(both sexes)

IV

870.2400 Acute eye irritationRat46219022 Conjunctivitis, 

moderate irritant

III

870.2500 Acute dermal 

irritation-Rabbit

46260101 Non-irritant IV

870.2600 Skin sensitizationGuinea Pig46219024 Not a sensitizer N/A
Page 21 of 31

Table A.2.2. Subchronic, Chronic and Other Toxicity Profile for Orthosulfamuron.

Guideline 

No. 

Study Type MRID No. 

(year)/ 

Classification 

Dose levels Results

870.3100 90-Day oral 

toxicity (rat)

46260103 

(2001)

Acceptable/

Guideline

ppm= 0, 250, 1500, 

9000

mg/kg/day=

M: 0, 19, 113, 706

F: 0, 22, 131, 773

NOAEL = 706 mg/kg/day

LOAEL = not determined

870.3100 90-Day oral 

toxicity (mouse)

46260102 

(2001)

Acceptable/

Guideline

ppm= 0, 250, 1250, 

6000

mg/kg/day=

M: 0, 36, 187, 865

F: 0, 47, 228, 1096

NOAEL = 865 mg/kg/day

LOAEL = not determined

870.3150 90-Day oral 

toxicity (dog)

46219027

(2001)

Acceptable/

Guideline

mg/kg/day= 

0, 150, 450, 1000

NOAEL = 450 mg/kg/day

LOAEL = 1000 mg/kg/day, based 

on increased alkaline phosphatase 

levels, increased absolute and 

relative liver weights

870.3200 21/28-Day dermal 

toxicity (rat)

46578911

( 2004)

Acceptable/

Guideline

mg/kg/day= 

0, 1000 

Systemic/Dermal NOAEL = 1000 

mg/kg/day

LOAEL = not determined

870.3700a Prenatal 

developmental in 

(rat)

46219031

(2001)

Acceptable/

Guideline

mg/kg/day= 

0, 100, 300, 1000

Maternal NOAEL = 1000 

mg/kg/day

LOAEL = not determined

Developmental NOAEL = 1000 

mg/kg/day

LOAEL = not determined

870.3700b Prenatal 

developmental in 

(rabbit)

46219029 

(2001)

Acceptable/

Guideline

mg/kg/day= 

0, 25, 75, 250

Maternal NOAEL = 250 mg/kg/day

LOAEL = not determined

Developmental NOAEL = 250 

mg/kg/day

LOAEL = not determined
Page 22 of 31

870.3800 Reproduction and 

fertility effects

(rat)

46219033

(2003)

Acceptable/

Guideline

ppm=(males/females)

0, 350/225, 

1400/900, 5600/3600

mg/kg/day= 

F0M: 0, 22.2, 88.6, 

354.5

F0F: 0, 25.6, 102.2, 

408.9

F1M: 0, 24.3, 97.0, 

388.1

F1F: 0, 27.8, 111.2, 

444.6

Parental/Systemic NOAEL = M=-

88.6-97.0/ F=102.2-111.2 

mg/kg/day

LOAEL = M=-354.5-

388.1/F=408.89-444.6 mg/kg/day, 

based on kidney lesions (tubular 

mineralization and urothelial 

hyperplasia) in F0 and F1 females.

Reproductive NOAEL = M=-354.5-

388.1/F=408.89-444.6 mg/kg/day

LOAEL = not determined

Offspring NOAEL = M=-88.6-97.0/ 

F=102.2-111.2 mg/kg/day

LOAEL = M=-354.5-

388.1/F=408.89-444.6 mg/kg/day, 

based on decreased motor activity 

in F1 males at 6 weeks.

870.4100 Chronic toxicity 

(dog)

46578987 

(2001)

Acceptable/

Guideline

mg/kg/day=

0, 75, 300, 1000

NOAEL = 75 mg/kg/day

LOAEL = 300 mg/kg/day, based on 

changes observed in body weights, 

body weight gains, food 

consumption (females), hematology 

and clinical chemistry, increased 

liver weights, and histopathological 

changes in the liver, and bone 

marrow of the sternum

870.4200 Carcinogenicity

(rat)

46578913 

(2001)

Acceptable/

Guideline

mg/kg/day=

0, 1, 5, 500, 1000

NOAEL = 5 mg/kg/day

LOAEL = 500 mg/kg/day, based on 

decreased body weight gains, slight 

hepatotoxicity, slight 

nephrotoxicity in both sexes, and 

thyroid effects in males.

Evidence of carcinogenicity seen at 

500 and 1000 mg/kg/day in the 

form of thyroid follicular cell 

adenoma in males.

870.4300 Carcinogenicity

(mouse)

46578912 

(2003)

Acceptable/

Guideline

mg/kg/day=

0, 100, 500, 1000

NOAEL = 100 mg/kg/day

LOAEL = 500 mg/kg/day, based on 

increases in absolute and relative 

liver weights, centrilobular 

hepatocyte hypertrophy and 

centrilobular hepatocyte 

vacuolation in males. 

There was no evidence of 

carcinogenicity in mice.
Page 23 of 31

870.5100 BACTERIAL 

REVERSE 

MUTATION 

ASSAY (Technical 

IR5878)

BACTERIAL 

REVERSE 

MUTATION 

ASSAY 

(MetaboliteIR7863)

BACTERIAL 

REVERSE 

MUTATION 

ASSAY 

(MetaboliteIR8181)

BACTERIAL 

REVERSE 

MUTATION 

ASSAY 

(MetaboliteIR8181)

46219034

46578919

46578923

46578916

---

---

---

---

Negative

Negative

Negative

Negative
Page 24 of 31

870. 5300 IN VITRO 

MAMMALIAN 

CELL GENE 

MUTATION 

TEST (Technical 

IR5878)

IN VITRO 

MAMMALIAN 

CELL GENE 

MUTATION 

TEST (MetaboliteIR7863)

IN VITRO 

MAMMALIAN 

CELL GENE 

MUTATION 

TEST (MetaboliteIR8181)

IN VITRO 

MAMMALIAN 

CELL GENE 

MUTATION 

TEST (MetaboliteIR7825

46219036

46578920

46578925

46578914

---

---

---

---

Negative

Negative

Negative

Negative

870. 5375 IN VITRO

CHROMOSOME 

ABERRATION 

TEST (Technical 

IR5878)

IN VITRO

CHROMOSOME 

ABERRATION 

TEST (MetaboliteIR7863) 

IN VITRO

CHROMOSOME 

ABERRATION 

TEST (MetaboliteIR8181)

IN VITRO

CHROMOSOME 

ABERRATION 

TEST (MetaboliteIR7825)

46219035

46578921

46578924

46578917

---

---

---

---

Negative

Negative

There was evidence of chromosome 

aberrations induced over 

background in the absence and 

presence of S9 activation.

Negative
Page 25 of 31

870.5395 MAMMALIAN 

ERYTHROCYTE 

MICRONUCLEUS 

TEST (Technical 

IR5878)

MAMMALIAN 

ERYTHROCYTE 

MICRONUCLEUS 

TEST

(MetaboliteIR8181)

46219037

46578926

---

---

Negative

Negative

870.7485 Metabolism and 

pharmacokinetics

(species)

46578905-

46578910

mg/kg/day =

Low dose: 5

High dose: 1000

Repeated low dose = 

5

Absorption was rapid in all groups, 

regardless of sex, dose, or number 

of doses. Tmax values were 12 min 

for the 5 mg/kg repeated dose 

group, 24 min-1 h for the single 5 

mg/kg dose group, and 1-4 h for the 

single 1000 mg/kg dose group. 

Following a single 5 mg/kg dose of 

[

14C-U-phenyl] IR5878, 76-82% of 

the dose was absorbed and found in 

the urine/cage wash, bile, and 

carcass, indicating extensive 

absorption. The half-life was 

similar regardless of sex, dose, or 

number of doses (8.9-13.3 h), with 

the exception of the females treated 

with a single 5 mg/kg dose of [14C5-pyrimidinyl] IR5878 (16.7 h). 

NonGuidelineThyroid MOA 

Investigation Study

46578927 0, 5, and 1000 

mg/kg/day

Transient decreases in T3 at 5 and 

1000 mg/kg/day (D30), and no 

reductions in T4. In creased TSH 

levels at D 90 at 1000 mg/kg/day. 

TSH levels comparable to controls 

at all other doses and time points. 

Liver and thyroid histopathology, 

and enzyme changes,

Appendix B. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These data are subject to ethics review 

pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics 

requirements. For certain studies that review may have included review by the Human Studies 

Review Board. Descriptions of data sources as well as guidance on their use can be found at:

http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html.
Page 26 of 31
Page 27 of 31

Appendix C. Occupational Non-cancer Handler Algorithms

Potential daily exposures for occupational handlers are calculated using the following formulas:

E=UE * AR * A * 0.001 mg/ug

where:

E = exposure (mg ai/day),

UE = unit exposure (μg ai/lb ai),

AR = maximum application rate according to registered labels (lb ai/A), and

A = area treated or amount handled (e.g., A/day).

The daily doses are calculated using the following formula:

ADD= 

E * AF

BW

where:

ADD = average daily dose absorbed in a given scenario (mg ai/kg/day),

E = exposure (mg ai/day),

AF = absorption factor (inhalation), and

BW = body weight (kg).

Margin of Exposure: Non-cancer risk estimates for each application handler scenario are 

calculated using a Margin of Exposure (MOE), which is a ratio of the toxicological endpoint to 

the daily dose of concern. The daily inhalation dose received by occupational handlers is

compared to the appropriate POD (i.e., NOAEL) to assess the risk to occupational handlers. All 

MOE values are calculated using the following formula:

MOE= 

POD

ADD

where:

MOE = margin of exposure: value used by HED to represent risk estimates (unitless),

POD = point of departure (mg/kg/day), and

ADD = average daily dose absorbed in a given scenario (mg ai/kg/day).
Page 28 of 31

Appendix D. Dietary Exposure/Risk Modeling Input and Output

Filename: Orthosulfamuron.R08

Chemical: Orthosulfamuron

RfD(Chronic): .05 mg/kg bw/day NOEL(Chronic): 0 mg/kg bw/day

RfD(Acute): 0 mg/kg bw/day NOEL(Acute): 0 mg/kg bw/day

Date created/last modified: 04-08-2015/11:10:59 Program ver. 3.16, 03-08-d

Comment: No acute endpoint identified

-----------------------------------------------------------------------------------

 EPA Crop Def Res Adj.Factors Comment

 Code Grp Commodity Name (ppm) #1 #2 

---------- ---- ------------------------------- ---------- ------ ------ -------

1500323000 15 Rice, white 0.050000 1.000 1.000 

1500323001 15 Rice, white-babyfood 0.050000 1.000 1.000 

1500324000 15 Rice, brown 0.050000 1.000 1.000 

1500324001 15 Rice, brown-babyfood 0.050000 1.000 1.000 

1500325000 15 Rice, flour 0.050000 1.000 1.000 

1500325001 15 Rice, flour-babyfood 0.050000 1.000 1.000 

1500326000 15 Rice, bran 0.050000 1.000 1.000 

1500326001 15 Rice, bran-babyfood 0.050000 1.000 1.000 

8601000000 86A Water, direct, all sources 0.751000 1.000 0.655 Fact. 2 = 492 / 751 

(chronic/acute H2O)

8602000000 86B Water, indirect, all sources 0.751000 1.000 0.655 Fact. 2 = 492 / 751 

(chronic/acute H2O)

US EPA Ver. 3.16, 03-08-d

DEEM-FCID Chronic analysis for ORTHOSULFAMURON NHANES 2003-2008 2-day

Residue file name: Orthosulfamuron.R08

 Adjustment factor #2 used.

Analysis Date 04-08-2015/11:47:05 Residue file dated: 04-08-2015/11:10:59

Reference dose (RfD, Chronic) = .05 mg/kg bw/day

COMMENT 1: No acute endpoint identified

===============================================================================

 Total exposure by population subgroup

-------------------------------------------------------------------------------

 Total Exposure

 -----------------------------------

 Population mg/kg Percent of 

 Subgroup body wt/day Rfd 

-------------------------------------- ------------- ----------------

Total US Population 0.010314 20.6%

Hispanic 0.009855 19.7%

Non-Hisp-White 0.010605 21.2%

Non-Hisp-Black 0.008513 17.0%

Non-Hisp-Other 0.011915 23.8%

Nursing Infants 0.009352 18.7%

Non-Nursing Infants 0.034321 68.6%

Female 13+ PREG 0.009711 19.4%

Children 1-6 0.013218 26.4%

Children 7-12 0.008602 17.2%

Male 13-19 0.007090 14.2%

Female 13-19/NP 0.007944 15.9%

Male 20+ 0.009612 19.2%

Female 20+/NP 0.010829 21.7%

Seniors 55+ 0.009967 19.9%

All Infants 0.026612 53.2%

Female 13-50 0.010262 20.5%

Children 1-2 0.014890 29.8%

Children 3-5 0.012543 25.1%

Children 6-12 0.009043 18.1%

Youth 13-19 0.007521 15.0%

Adults 20-49 0.010292 20.6%

Adults 50-99 0.010169 20.3%

Female 13-49 0.010250 20.5%

-------------------------------------------------------------------------------
Page 29 of 31

Appendix E. Nomenclature and Physical/Chemical Properties

Table E.1. Nomenclature.

Chemical Structure

Empirical Formula C16H20N6O6S

Common Name Orthosulfamuron

IUPAC Name 1-(4,6-dimethoxypyrimidin-2-yl)-3-[2-(dimethylcarbamoyl)phenylsulfamoyl]urea

CAS Name 2-[[[[[(4,6-dimethoxy-2-pyrimidinyl)amino]carbonyl]amino]sulfonyl]amino]-N,N

dimethylbenzamide

CAS Registry Number 213464-77-8

Chemical Class Sulfamoylurea

Table E.2. Physical/Chemical Properties.

Parameter Value Reference (MRID)

Color White 46219004

Physical State Fine Powder at 20°C 46219005

Odor Odorless 46219006

pH 4.35 at 25°C (1% aqueous dispersion) 46219013

Density 1.45 g/mL at 20°C 46219008

Water solubility at 20°C pH 4 buffer: 0.062 g/L

pH 7 buffer: 0.63 g/L

pH 8.5 buffer: 39 g/L

46219009

Solvent solubility at 20°C n-heptane: 0.23 mg/L

xylene: 130 mg/L

acetone: 20 g/L

ethyl acetate: 3.3 g/L

dichloromethane: 56 g/L

methanol: 8.3 g/L

Electronic 

communication, J. 

Messina to E. Kraft, 

9/6/2006

Vapor pressure 1.1 x 10-4 Pa (8.3 x 10-7 mm Hg) at 20°C 46219010

Dissociation constant, pKa The test material becomes increasingly less soluble 

in water as the pH is lowered and undergoes 

degradation (hydrolysis) at neutral to acidic pHs. The 

test material is predicted to have 5 overlapping 

dissociation constants.

46219011

Octanol/water partition 

coefficient, Log(KOW)

pH 4: 2.0

pH 7: 1.3

46219012

UV/visible absorption spectrum pH 6.9, A=0.49 and ε = 2.1 x 104 at 238 nm 46219001
Page 30 of 31

Appendix F. Spray Drift Detailed Description

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

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

deposit on surfaces where individuals come into contact with residues on these surfaces, leading

to indirect exposures (e.g., children playing on lawns where residues have deposited next to 

treated fields).

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

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

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

prevent them8. [Direct exposures would include inhalation of the spray plume or being sprayed 

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

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

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

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

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

considered in risk assessment. 

In order to evaluate the drift potential and associated risks, an approach based on drift modeling 

coupled with techniques used to evaluate residential uses of pesticides was utilized. Essentially, 

a residential turf assessment based on exposure to deposited residues has been completed to 

address drift from the agricultural applications of orthosulfamuron. In the spray drift scenario, 

the deposited residue value was determined based on the amount of spray drift that may occur at 

varying distances from the edge of the treated field using the AgDrift (v2.1.1) model and the 

Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of 

Spray Drift Policy. Once the deposited residue values were determined, the remainder of the 

spray drift assessment was based on the algorithms and input values specified in the 2012 

Standard Operating Procedures for Residential Risk Assessment (SOPs). 

A screening approach was developed based on the use of the AgDrift model in situations where 

specific label guidance that defines application parameters is not available910. AgDrift is 

appropriate for use only when applications are made by aircraft, airblast orchard sprayers, and 

groundboom sprayers. When AgDrift was developed, a series of screening values (i.e., the Tier 

1 option) were incorporated into the model and represent each equipment type and use under 

varied conditions. The screening options specifically recommended in this methodology were 

selected because they are plausible and represent a reasonable upper bound level of drift for 

common application methods in agriculture. These screening options are consistent with how 

spray drift is considered in a number of ecological risk assessments and in the process used to 

develop drinking water concentrations used for risk assessment. In all cases, each scenario is to 

 

7 Available: 

http://www.epa.gov/pestic

ides/science/handler-exposure-data.html

outlined in the screening approach represent actual use practice so risk assessors should be aware and characterize 

these appropriately.
Page 31 of 31

be evaluated unless it is not plausible based on the anticipated use pattern (e.g., herbicides are 

not typically applied to tree canopies) or specific label prohibitions (e.g., aerial applications are 

not allowed). Section 6.1.1 provides the screening level drift related risk estimates. 

In many cases, risks are of concern when the screening level estimates for spray drift are used as 

the basis for the analysis. In order to account for this issue and to provide additional risk 

management options additional spray drift deposition fractions were also considered. These drift 

estimates represent plausible options for pesticide labels.