### UNITED ST A TES ENVIRONMENT AL PROT ECT IO N AGENCY

WASHINGTON, D.C. 20460

OFFICE OF
C HEMI CAL SAFETY AND
POLLUTION PREVENTION

MEMORANDUM

Date: September 15

, 2015



### SUBJECT : Ortho s ulfamuron. Draft Human Health Risk Assessment in Support of Registration Review.

P C Code: 108209

D ecis i o n No.:499854
Petition No.: NA DP Barcode: 0 425534 Registration No.: NA Regulatory Act ion: Regi stration R ev iew

Case No.: N / A Ri s k Assessment Type: S in g le Chem ical Aggregate

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

MRID No.: NA 40 CFR: .6 25



### FROM:

THROUGH:

TO: Karl y n Middleton

, M.S

.. Ri s k Assessorffoxicologist
Zaida Figueroa, M.S., In dustrial Hy gien ist**~ ~** **~** Michael A. D oherty

, Ph .D

., Chemist 

# fv A,.....,_ 

### Je1i(nv
Ri sk Assessment Branch II ,- - 

## 0

He alth Effects Division (7509P)

C hri stina Swartz

, Branch Ch i ef

# ~A-­ Ri sk Assessment Branch II

He a l th Effects Divi sion (7509P)

Khue Nguyen

, C h emica l R eview Manager
Risk Mana ge ment and Impl e m entatio n Branch I (RMIB I)

Pesticide R e-Evaluation Divi sion (7508P)

As part of registration review, 

### HED has examined the toxicological and expos ur e 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. Baile y, 

### 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 assessmen t 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 r esu lt

, previously identified deficiencies related to the goat metabolism

and multiresidue method data have been re solved. 5) A high-end drinking water exposure va lue was used to assess scree ning-level dietary

exposu r e / risk estimates.

Page 1 of 31Table of Co ntent s

1 .0 E xecutiv e S un1m ary

. .. ... . .. . ....... . ........................................... .. ......................... ......... . .. ....... 3

2.0 H E D Recommendation s

..................................................................................................... 4


### 2.1 Tolerance Considerations

... .. .. .... . .. . .. .. .. ... . .. .. .. . ....... .. . ........ .. .. .......... .. . .. .......... . ............ .. .. . 4
2.2 L a b e l Considerations

. .. ...... .. .. . .................................. ..................................... .. ......... .. ..... 5

3. 0 Intr o ducti o n

.. ....... .. ... ... ..................... ... .. . .... .. ..... .... . .. ... . .. . ... .. .. .. . ... . . .. ... . ...... . ... . ................. . . 5


### 3.1 Che mical I dentity and Physical/Chemical Characteristics

.. ... .................. ... .. ..... . .. ... .... .. .. 5


### 3.2 P esticide Use Pattern and Anticipated Exposure Pathways

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

### 5

3.3 Consideration of Environmental Justice

.......................................... . ......................... ... . .. 6

4

. 0 Hazard ld e ntific a tionff oxicology

.. . ..... .. ......... . .............. .. ...... .. .. . ...... .. .. ...... . .......... .. . ... .. . .. 6

4. 

### l Summary of T ox i co l og ical Effects

.. .. .......... .. . .. .. .......... .. ... . ........ .. .. ... . ..... .. ... . ..... .. .. .. .......... .. 7



### 4.2 

### Safety Factor 

### for In fants and Children (FQ P A Safety Factor)

........................... ... ....... ... ... .. 8

4.3 

### Toxicity Endpo int and P oint of Departure Selections

.................................................. .. ...... 8

4.4 

### Endocrine Disruptor Screeni n g Program

... ......................... ........ ... .. .. .. .. .... ... .. ........ .. ....... 9

5. 0 Dietary Ex po s ur e and Ri s k Assess m e nt

. ... . .. ... ..... .. .. ...................................................... 10


### 5.1 Water R esidue Profile

... . ... . ................................................................... . .. .. .......... . .. .. ..... I 0

5.2 Food R es idue Profil e

.... .. .. . . ................ . ............... .. .......... .. .. .. .. .. . ... . .. ... . ..... . .... . ................ 11
5.3 Dietar y Exposure and Ri sk Est imat es

. . . ... .......... .. ... .. ......... .. .. ......... .. ... .......................... 11

6.0 Residential (No n

- Occup a tion a l ) Ex p os ure / Risk C h a r ac terizati o n

...... ... ... . .......... .. ..... 12


### 6.1 

### Spray Drift

. ... ..... . .... . .......... . ............................................................................................ 1 2

6.1.1 Combined Risk Est imat es from L awn Deposition Adjacent to Applications

.............. l 2

6.2 Residential Bystander Post-Application Inhalation Exposure

............................ . .......... 1 3

7.0 Aggregate Ex p os ur e /Ri s k C h a ra c t e riz at ion

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

### 1 3

8 .0 C umul a ti v e Ex p os ur e/R i sk C haracterization

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

### 13

9.0 Occu p at ion a l Expos ur e/ Ri s k C haract erizati on

................................................... .... ...... 14


### 9. 

### l Occupat i onal Handler Exposure/Risk Es timat es

...... .. .. .... .... . .............. . ..................... .. .. . 14


### 9.2 Occupational Post-application Expos ure/Risk Estimates

.. . ... .. ..... . ... ..... . .. ... .. .... .. ......... . ..... 16

9.2 .1 Occupational Post-application I nhalation Exposure / Risk Estimates

........................... 1 6



### 9.2.2 Occupational Po st

- application Dermal Exposure/Risk Estimates

......................... .... .. 16

l 0.0 Public Health and Pesticide Ep idemiolo gy Data

....... ...... ...... . ....... . ... ............................ 1 7


### 11 .0 Lite ratur e Ref ere nce s

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

### 1 7

12.0 Reference s

............................................................................................. .... .. .. . ...... . ............ 18

A ppendix A. Toxicolo gy D ata Requirements a nd T ox icolo gy Profile

.. .... . ... . ........................ 1 9 Appe ndi x B

. R evie \v of Human Re s earch

............................................ . ................................... 25 Ap p e ndix 

### C. Occupational Non-cancer H a ndl e r Algorithm s

.. .. ...... .. .. ........ .. ... .... ............. .. ... 27 Appendix E. No menclatur e and Physical/Chemical P roperti es

... . .. .... . .................................. 29 Appendix F. S pr ay Drift Detailed Description

.. .. ...... .. .. ...... . ... . ..................... ... .. . ...... .... ......... .. 30



### P age 

### 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 require d 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 dat a 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 reso lved (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 asses sment in order to a ssess 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 u pdates 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 screening

level 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 assessme nt 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. Therefo re, a quantitative residential exposure assessment was not performed. However, o rthosulfamuron 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, i ncidental 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 (margin s of exposure (MOE s) ≥ 340 ,000 with a LOC =100)

. T here were no ri sks 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 occup ational 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/lo ading 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 p ersonal protective e quipment ( 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

acu te toxicity of orthosulfamuron and is adequate to protect agricultural workers from post

application exposures

.

HED has no t identified any risk concerns associated with the registered uses of orthosulfamuron

. Ther e 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 chemis try 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, HE D 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. Complian ce 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 La bel C onsiderations

There are no label recommendations for registered products containing orthosulfamuron.

3.0 Introduction

3.1 Chemical Identity and Physical/Chemical Characteristics

O rthosulfamuron { 2

- [[[[[(4,6

- dimethoxy

- 2

- pyrimidinyl)amino]carbonyl]amino]sulfonyl]amino]

- N,N dimethylbenzamide } is a systemic he rbicide 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 consta nts, 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/che mical 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 product s 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 whic h 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 i ntermediate

- term ( i.e., 1 to 6 months) ; long

- term exposures (greater than 6 months) are not anticipated. The PPE statement s 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 r estricted 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

,

1 0% ai

, [71711

- 4 6 ] 0.06 6 lbs
ai/A 1 app/season 0.06 6 lb ai /A Do not apply by any irrigation system. Apply to young emerging and actively gro wing weeds, between 2

- 4 leaves. For dry

- seeded rice, apply from early post

- emergence to pre

flood. Strada PRO Herbicide WDG

, 42.05 % ai

, [71711

- 4 7 ]

Strada Herbicide WDG,
50% ai

, [71711

- 44] 0.067 lb
ai/A 0.067 lb ai/A

Strada GR Granular,
0. 50% ai

, [71711

- 4 5 ] Apply to young emer ging 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 p olicy, 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 sub groups 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. When ever 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 subgroup s.

4.0 Hazard Identification/Toxicology

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

I mmunotoxicity, neurotoxicity, and inhalation studies are no t available for orthosulfamuron, as required in accordance with the current Part 158 Guidelines (40 CFR Part 158 ). However,

neuro toxicity studies are not needed, since there are several toxicity studies available

### Page 7 of 31

( reprod uction and subchronic/chronic toxicity ) that include neurotoxic measures that adequately characterize the potential neurotoxicity of th e chemical

. T he 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 sulfony lurea chemicals (TXR#0056723). N o new toxicity
and/or metabolism data have been received since the last risk assessment ( D319264 , K. Bailey)



### . The toxicological endpoints and points of de parture (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 App endix 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. Li ver 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, l esions, 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 orth osulfamuron 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 res ult 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 exposu re to orthosulfamuron. N o 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 effe cts 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.

O rthosulfamuron is rapidly and well absorbed following oral dosing in rats, regardless of sex, dose, or number of doses

. T he time to maximum plasma levels (t max 

### ) 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 recommend ed that the required 10X Food Quality Protection Act ( FQPA S afety F actor (SF) be reduced to 1 x for orthosulfamuron. The toxicology database is complete, there is no evidence of increased susceptibility

, no concerns/ residual uncertainties with regard to pre

- and/or

p ostnatal 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 t oxicological d oses a nd e ndpoints used in the
orthosulfamuron human health risk a ssessments 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 Asses sments

. 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 UF A = 10x

UF H =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 (short

term) NOAEL=

88.6 mg/kg/day UF A =10x

UF H =10x Residential LOC

for MOE = 100 2

- Generation Reproduction

- Ra t

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 th e 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 toxic ity, including carcinogenicity that could result from exposure to orthosulfamuron.

NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty
factor. UF A = extrapolation from animal to human (interspecies). UF H = 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 i n 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 UF A =10x

UF H =10x Occupational LOC

for MOE = 100 2

- Generation Reproduction

– Ra t

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 c ancer 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. UF A = extrapolation from animal to human (interspecies). UF H = 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, EP A 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, a nd 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, r eproductive 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 registrat ion 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 e ndocrine 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 effe ct 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 as says to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal
systems. C hemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal s ystems 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 che micals identified for EDSP screening was published on June 14, 2013 1 

### and includes some pesticides s che duled for Registration Review and che micals 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 list s of
che micals, 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 pr ovided coarse

screen 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 conce rn, 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 ( D 427429, G. Orrick ).

The acute and chronic dietary as sessments 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 Sulfonylureas 1

.

Modeled Scenario K d or K OC Initial Application Dates (days post

emergence) Max. Daily Conc.

(μg/L) Mean

Breakthrough Time (yrs) Post

breakthrough Mean (μg/L)

WI corn K d 7 449 11.5 415

K OC 7 504 6.9 425

DMV corn K d 7 489 5.3 369

K OC 7 560 3.3 378

FL citrus K d 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://w ww.epa.gov/endo/

### Page 11 of 31

Table 5.1. PRZM

- GW Coarse

- Screen EDWCs for Sulfonylureas 1

.

Modeled Scenario K d or K OC Initial Application Dates (days post

emergence) Max. Daily Conc.

(μg/L) Mean

Breakthrough Time (yrs) Post

breakthrough Mean (μg/L)

K OC 7 467 2.3 349

FL potato K d 7 375 2.6 272

K OC 7 407 2.2 275

GA peanut K d 7 197 5.2 156

K OC 7 206 3.9 158

NC cotton K d 7 640 8.7 492

K d 37 641 8.7 491

K d 67 637 8.7 490

K OC 7 742 5.7 484

K OC 37 751 5.7 483

K OC 67 744 5.7 482

1 Maximum values are bold ed.


### 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
resi dues 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

conce rned 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 conse rvative 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 t o 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 O rthosulfam uron. 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. 0 103 1 21

All Infants (< 1 year old) 0. 0 266 1 53

Children 1

- 2 years old 0. 0 14 8 9 30

Children 3

- 5 years old 0. 0 125 4 25

### Page 12 of 31

Table 5 .3

. Summary of dietary exposure and risk estimates for O rthosulfam uron. Acute Estimates Chronic Estimates

Population Group Exposure, mg/kg bw Risk, % aPAD Exposure, mg/kg bw/day Risk, % cPAD

Children 6

- 1 2 years old 0. 00 90 4 18

Youth 13

- 19 years old 0. 00 7 5 2 15

Adults 20

- 49 years old 0. 0 10 29 21

Adults 50

- 99 years old 0. 0 10 17 20

Female 13

- 49 years old 0. 0 102 5 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. Therefo re, a quantitative residential exposure assessment was not performed.

6.1 Spray Drif

t

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 applicati ons 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 dri ft

a ssessment 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 (margin s of exposure (MOEs) ≥ 34 0,000

, 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) TTR 1 (ug/cm 2 ) 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, Fu ngicide, 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 develope d 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 ot her 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 Cumulati ve 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

- screening

analysis.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) 4 

### and conducting cumulative risk assessments (CRA) 5



### . The Agency has utilized
this framework to evaluate the SUs of which or thosulfamuron 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 th at 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 i ntermediate

- 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. L ong

- term

exposu res ( 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 descri ption.

Body Weight & Absorption Factor : The standard body weight (80 kg) was used in this risk assessment since the endpoint selected w as 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 surroga te 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 predicti ng handler exposure that are used in this assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate
Reference Table 6



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

sour ces, can be found at the Agency website 7



### .

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

- Ca ncer 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 o f 9,800 is associated with mix ing /load ing 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 r egistered labels.

Table 9.1. Short

- term Handler Exposure and Risk Estimates for Orthosulfamuron

. Exposure Scenario Mitigation
Level a Inhalation

Unit Exposure b (mg/lb ai) Application

Rate c (lb ai/A) Area

Treated d Inhalation

Dose e (mg/kg/day) Total MOE f

Mixer/Loader & Loader

Gra nules for Aerial Application (Loading only) Baseline 0.0017 0.067 1

, 200 A/day 0.00171 0 52,000

Granules for Tractor

drawn Spreader Application (Loading only) 0.0017 0.067 200 A/day 0.000285 310,000

Dry Flowable (WG)
for Aerial Appl ication 0.00896 0.067 1

, 200 A/day 0.009 0 9,800

Dry Flowabl e 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 Appli cation 0.0013 0.067 1

, 200 A/day 0.00131 68,000

Spray s for
Groundboom Application Baseline 0.00034 0.067 200 A/day 0.000057 1,600,000

Granules for Tractor

drawn 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 App lication 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 Su rrogate 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

- ter

m Inhalation Dose (mg/kg/day) = [Rate (lb ai/A) x UE (mg /lb ai) x Acres Treated (A/day)]/BW (8 0 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 t he 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

- HQ

OPP

- 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 or thosulfamuron.

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, sub sequently, 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 assessme nt 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 estimat es 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 p ost

- 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 label s is based on the acute toxicity o f 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 considere d 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 inc idents (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 Notifica tion 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

- 201 1 , 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 prov iding 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 inclu ded 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

1 2 .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 ---

--- yes a

yes a

---

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 requ ired 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 LD 50 = > 5000 mg/kg/bw (both sexes) IV

870.1200 Acute dermal

- Rat 46219020 LD 50 = > 5000 mg/kg/bw (both sexes) IV

870.1300 Acute inhalation

Rat 46219021 LC 50 = > 2.19mg/L (both sexes) IV

870.2400 Acute eye irritation

Rat 46219022 Conjunctivitis,
moderate irritant III

870.2500 Acute dermal

irritation

- Rabbit 46260101 Non

- irritant IV

870.2600 Skin sensitization

Guinea Pig 46219024 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=

F 0 M: 0, 22.2, 88.6,
354.5

F 0 F: 0, 25.6, 102.2,
408.9

F 1 M: 0, 24.3, 97.0,
388.1

F 1 F: 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/k g/day, based on kidney lesions (tubular
mineralization and urothelial hyperplasia) in F 0 and F 1 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 F 1 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 (Metabolite

IR7863)

BACTERIAL
REVERSE
MUTATION
ASSAY (Metabolite

IR8181)

BACTERIAL
REVERSE
MUTATION
ASSAY (Metabolite

IR8181) 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 (Metabolite

IR7863)

IN VITRO
MAMMALIAN
CELL GENE
MUTATION TEST (Metabolite

IR8181)

IN VITRO
MAMMALIAN
CELL GENE
MUTATION TEST (Metabolite

IR7825 46219036

46578920

46578925

46578914 ---

---

---

--- Negative

Negative

Negative

Negative

870. 5375 IN VITRO

CHROMOSOME
ABERRATION TEST ( Technical IR5878)

IN VITRO
CHROMOSOME
ABERRATION TEST (Metabolite

IR7863)

IN VITRO
CHROMOSOME
ABERRATION TEST (Metabolite

IR8181)

IN VITRO
CHROMOSOME
ABERRATION TEST (Metabolite

IR7825) 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
(Metabolite

IR8181) 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. T
max 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.
Followi ng a single 5 mg/kg dose of [ 14 C

- 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), wi th the exception of the females treated with a single 5 mg/kg dose of [ 14 C

5

- pyrimidinyl] IR5878 (16.7 h).

Non

Guideline Thyroid 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 ethi cs 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 = e xposure (mg ai/day),

UE = u nit e xposure (μg ai/lb ai),

AR = m aximum appl ication rate according to registered label s (lb ai / A), and

A = a rea 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 = e xposure (mg ai/day),

AF = absorption fa ctor (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 a re 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

- 0 8

- 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 fact or #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 0.00752 1 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 C 16 H 20 N 6 O 6 S

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

com munication, 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 partitio n coefficient, Log(K OW ) 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 off

target and can lead to exposures to those the chemical may di rectly contact. Sprays can also deposit on surfaces where individuals come into contact with residues on these surfaces, lead ing 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 re quirements intended to prevent them 8



### . [ 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 t he 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 resident ial 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: Conside ration 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 (S OPs)

.

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 available 9 10 

### . 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 opt ions 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
estim ates represent plausible options for pesticide labels

.