### Tebuthiuron Human Health Risk Assessment DP No. D414218

Page 2 of 57 1.0 Executive Summary

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

2.0 HED Recommendations

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

2.1 Data Deficiencies

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

2.2 Tolerance Considerations

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

2.2.1 Enforcement Analytical Method

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

2.2.2 Established Tolerances

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

2.2.3 International Harmonization

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

2.3 Label Recommendations

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

2.3.1 Recommendations from Occupational Assessment

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

3.0 Introduction

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

3.1 Chemical Identity and Physical/Chemical Characteristics

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

3.2 Pesticide Use Pattern

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

3.3 Anticipated Exposure Pathways

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

3.4 Consideration of Environmental Justice

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

3.5 Incident Reports

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

4.0 Hazard Characterization and Dose

- Response Assessment

................................ ................ 13

4.1 Toxicology Studies Available for Analysis

................................ ................................ ... 13

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

................................ ... 13

4.3 Toxicological Effects

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

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

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

4.4.1 Completeness of the Toxicology Database

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

4.4.2 Evidence of Neurotoxicity

................................ ................................ .......................... 15

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

............. 15

4.4.4 Residual Uncertainty in the Exposure Database

................................ ......................... 15

4.5 Toxicity Endpoint and Point of Departure Selections

................................ .................... 15

4.5.1 Dose

- Response Assessment

................................ ................................ ....................... 15

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

........... 17

4.5.3 Cancer Classification and Risk Assessment Recommendation

................................ .. 17

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk

Assessment

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

4.6 Endocrine Disruption

................................ ................................ ................................ .. 19

5.0 Dietary Exposure and Risk Assessment

................................ ................................ ............ 19

5.1 Summary of Plant and Animal Metabolism Studies

................................ ...................... 19

5.1.1 Summary of Environmental Degradation

................................ ................................ ... 20

5.1.2 Residues of Concern Summary and Rationale

................................ ........................... 20

5.2 Food Residue Profile

................................ ................................ ................................ ...... 21

5.3 Water Residue Profile

................................ ................................ ................................ .... 21

5. 4 Dietary Risk Assessment

................................ ................................ ................................ 22

5.4.1 Description of Residue Data Used in Dietary Assessment

................................ ......... 22

5.4.2 Percent Crop Treated Used in Dietary Assessment

................................ .................... 22

5.4.3 Acute Dietary Risk Assessment

................................ ................................ ................. 22

5.4.4 Chronic Dietary Risk Assessment

................................ ................................ .............. 22

5.4.5 Summary Table

................................ ................................ ................................ ........... 22

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

................................ .... 23

6.1 Residential Bystander Post

- application Inhalation Exposure

................................ ........ 23

### Tebuthiuron Human Health Risk Assessment DP No. D414218

Page 3 of 57 6.2 Spray Drift

................................ ................................ ................................ ...................... 23

6.2.1 Combined Risk Estimates from Lawn Deposition Adjacent to Applications

......... 25

7.0 Aggregate Exposure/Risk Characterization

................................ ................................ ... 26

8.0 Cumulative Exposure/Risk Characterization

................................ ................................ . 26

9.0 Occupational Exposure/Risk Characterization

................................ ............................... 26

9.1 Short

- /Intermediate Handler Risk

................................ ................................ .................. 26

9.2 Short

- /Intermediate

- term Post

- Application Risk

................................ ........................... 28

9.2.1 Dermal Post

- application Risk

................................ ................................ ..................... 28

9.2.2 Inhalation Post

- application Risk

................................ ................................ ................. 29

10.0 References

................................ ................................ ................................ .......................... 30 Appendix A. Toxicology Profile and Executive Summaries

................................ ....................... 32

A.1 Toxicology Data Requirements

................................ ................................ ...................... 32

A.3 Hazard Identification and Endpoint Selection

................................ ............................... 35

A.4 Executive Summaries

................................ ................................ ................................ ..... 37 Appendix B. Physical/Chemical Properties

................................ ................................ ................. 47 Appendix C. Residue Summary Table

................................ ................................ ......................... 50 Appendix D. Spray Drift Estimate Tables

................................ ................................ ................... 5 1 Appendix E. Occupational Exposures and Risk Estimates Table

................................ ................ 5 3

### Tebuthiuron Human Health Risk Assessment DP No. D414218

Page 4 of 57 1.0 Executive Summary

Introduction The Health Effects Division (HED) of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides. The HED Tebuthiuron Registration Review Team has evaluated the current databases to support the R egistration

R eview of the active ingredient (ai), tebuthiuron

. Tebuthiuron is a relatively nonselective

substituted urea herbici de that acts by inhibiting photosynthesis. It is used to control broadleaf, grassy weeds, and woody plants. Use sites include pastureland, rangeland, and a variety of non

food sites including airports/landing fields, outdoor industrial areas, non

- agricul tural rights

- of

way, fencerows, hedgerows, uncultivated areas/soils, and under paved roads and sidewalks in areas where no future landscaping is planned. Tebuthiuron is not registered for agricultural

crop s or for residential use

. End use products are fo rmulated as dry flowable (DF) , water dispersible granulars (WDG)

, pellets (P) , and granulars (G) . Applications are conducted by aerial, ground, and handheld equipment

.

Updated points of departure (POD) and safety factors (SF) were used for the dietary and occupational exposure risk assessments , as well as for the spray drift assessment

. No change s to
the current tolerance s for meat and milk are recommended at this time. Tebuthiuron is not registered for residential uses ; however reside ntial bystander exposure may be possible through spray drift . T herefore, HED has conducted a spray drift assessment and there are risks of

concern identified from exposures to both adults (dermal only) and children 1 to < 2 years old (dermal and incidenta l oral)

. Ther e are no dietary (food and drinking water) or aggregate risks of

concern associated with tebuthiuron. There are several occupational dermal and inhalation risks

of concern for scenarios including mixing/loading for aerial application

, and ground application

, and mixing/loading/applying using handheld equipment.

Hazard Identification The most consistent toxicological effect across the tebuthiuron database is decreased body weight, occurring in rats, rabbits and dogs. No evidence of reprod uctive, neurological or immunological toxicity were identified in the database. No evidence of qualitative/quantitative susceptibility was observed in the rabbit or rat database. D ecreased fetal body weights and increased number of litters with early res orption s in the rabbit developmental study were observed at the same dose

. In rats, decreases in pup body weights were observed on post natal day (PND) 21 in the first and second (F1 and F2) generation pups occurred in the presence of maternal toxicity (d ecreases in F1female adult bodyweights).

The acute toxicity studies indicate th at tebuthiuron is more toxic following oral ( Toxicity Category II) exposure than either dermal ( Toxicity Category IV) or inha lation ( Toxicity Category III) exposure. Tebuthiur on is not an eye or skin irritant and not a skin sensitizer. In the 2002 Preliminary Human Health Risk Assessment ( P. Deschamp , D274580

, April 22, 2002 ) tebuthiuron was classified as a Group D compound “not classifiable as to human carcinogenicity .”

Dose Response Assessment

### Tebuthiuron Human Health Risk Assessment DP No. D414218

Page 5 of 57 Acute Dietary No appropriate acute toxicological endpoint attributable to a single exposure was identified for the general population. An acute reference dose (aRfD) was selected for females 13

– 49 years old based on an increase in early resorptions at the lowest observed adverse effect level (LOAEL) of 25 mg/kg/day in the developmental toxicity study in rabbits with a no adverse effect

level (NOAEL) of 10 mg/kg/day.

Chronic Dietary

The chronic reference dose (cRfD ) was selected f rom the 2

- generation reproductive toxicity study in rats based on decreased body weights in parents and pups at the LOAEL of 2 6 mg/kg/day

. The study NOAEL was 14 mg/kg/day.

Non

- Dietary Endpoints for Occupational and Spray Drift Analysis

Incidental Oral

The 2

- generation reproductive toxicity study in rats was selected with a NOAEL of 14 mg/kg/day for the short

- term (1

- 30 days) incidental oral endpoint. The LOAEL is 2 6 mg/kg/day based on decreased body weights in F1 females and decreased pup body weights on PND 21 in the F1 and F2 generation.

Dermal and Inhalation A dermal toxicity study is available for tebuthiuron, however, the short

- and intermediate

- term dermal endpoints were selected from the 2

- generation reproductive toxicity study in rats because

the dermal study conducted is not protective of the adverse outcome (resorptions) of concern for pregnant females

. Since the endpoint is derived from an oral study, HED would typically apply a dermal absorption factor, however because no dermal absorptio n data are available and the physical properties of the chemical support the potential for dermal absorption this risk assessment assumes 100% dermal absorption for tebuthiuron. There are no route

- specific

inhala tion studies available for tebuthiuron. Th e Hazard and Science Policy Council, ( HASPOC ) determined that a guideline 90

- day inhalation study is required for this route of exposure. In the absence of an inhalation study, HED has selected short

- and intermediate

- term endpoints from the 2

- generation rat study discussed above and has retained an additional 10X database uncertainty factor for the inhalation risk assessments to account for the missing data

. Long

- term exposures are not anticipated from the occupational use of tebuthiuron.

Uncertainty

/Safety Factors For acute and chronic dietary, incidental oral, and dermal risk assessment s , a 100X uncertainty factor is applied (interspecies factor of 10X and intraspecies factor of 10X). Acute and chronic risk estimates are expressed as a percent of the population adjusted dose (PAD) and risks which do not exceed 100% of the acute PAD (aPAD) or chronic PAD (cPAD) are not of concern.

I ncidental oral or dermal risk estimates resulting in MOEs greater than or equal to 10 0 do not

exceed HED’s level of co ncern ( LOC )

.

The total uncertainty/safety factor for the inhalation risk assessments is 1000 and includes a 10X for interspecies extrapolation, 10X for intraspecies variation, and a 10X database uncertainty

### Tebuthiuron Human Health Risk Assessment DP No. D414218

Page 6 of 57 factor to account for the missing inhalation s tudy. I nhalation risk estimates resulting in MOEs

greater than or equal to 1000 are not of concern.

There is no evidence of increased qualitative or quantitative susceptibility in the rat 2

- generation reproduction study or the rat and rabbit developmental studies

. Furthermore, t here is no evidence of neurotoxicity in any of the submitted studies for tebuthiuron and t here is no residual uncertainty in the exposure database. Therefore, the FQPA safety factor (for the protection of

infants and children) was reduced to 1X.

Residue Chemistry Considerations There are no outstanding residue chemistry data requirements for tebuthiuron. The nature and magnitude of the residue are well understood and adequate analytical methods exist to support

the existing tolerances. No changes to existing tolerances are required. There are no

harmonization issues associated with tebuthiuron.

Exposure/Risk Assessment and Risk Characterization

Dietary Risk Assessment Since there are no direct applications to agricultural crops, the only source of food exposure is the potential consumption of secondary residues in meat and milk from livestock fed

tebuthiuron

- treated grass forage and hay. Additionally, the potential exi sts for dietary exposure via the consumption of drinking water. A cute and chronic dietary risk assessment s were conducted for tebuthiuron which included tolerance level residues in animal commodities, and modelled estimates of drinking water concentrations , (EDWC) provided by the Environmental

Fate and Effects Division , (EFED)

. However, since water was the risk driver, a time series water

distribution was used. Pe rcent crop treated information were not relevant to these assessments

.

The partially refined acute estimated dietary risk for females 13

- 49 years old is not of conc ern; the dietary risk is 93 % of the aPAD at the 95 th 

### percentile. The chronic estimated di etary risk s are not of conc ern; the dietary risk for the general U.S. population is 30 % of the cPAD and for the highest exposed population subgroup ( a ll i nfants) is 72 % of the cPAD. HED is concerned when

the estimated dietary risk exceeds 100% of the PAD

.

Residential Exposure and Risk Assessment

R esidential exposure was not assessed as there are no residential uses for tebuthiuron

.

Spray Drift Assessment

A non

- occupational spray drift assessment has been conducted for tebuthiuron based on the highest rate currently registered for aerial application on pastureland/rangeland and general non

cropland (6 lbs

. ai/acre )

. Spray drift occur s from the movement of tebuthiuron away from rangeland/pastureland application site s

. The dermal and incidental oral ri sk estimates calculated for adults and children ages 1 to <2 years old were combined since the toxicological effects for these exposure routes were similar

. The total applicable LOC is 100

, so MOEs less than 100 represent risk estimates of concern. Adult dermal risk estimates and children’s combined dermal

and incidental oral risk estimates from indirect exposure to tebuthiuron related to spray drift indicate that exposure above the LOC could occur at distances from 0 feet to greater than 150

### Tebuthiuron Human Health Risk Assessment DP No. D414218

Page 7 of 57 feet dependi ng on the nozzle type, droplet size , and application equipment

.

Occupational Handler and Post Application Exposure and Risk Assessments Occupational handler risks were assessed for the dermal and inhalation route s of exposure

. Since toxic effects are similar from the dermal and inhalation routes of exposure, but the LOC

values for dermal exposure (100) and inhalation exposure (1000) are different

, a total aggregated risk index (ARI) was used to estimate combined estimated handle r risks. The LOC ARI is 1; therefore, ARIs of less than 1 are potentially of concern to the Agency

. Several of the occupational handler scenarios resulted in ARIs < 1 with the personal protective equipment ( PPE ) currently required on the label and remain a concern d espite consideration of possible mitigation methods such as requiring doubler layer dermal PPE

, respirators

, and engineering

controls

.

Based on the Agency's current practices, a quantitative occupational post

- application inhalation exposure assessment was not performed for tebuthiuron at this time.

Use of Human Studies

This risk assessment relies, in part, on data from studies in whic h adult human subjects were intentionally exposed to a pesticide or other chemical s . These data, which include the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1) and the Agricultural Handler Exposure Task Force (AHETF) database

, are subject t o ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements. C ertain studies

within this assessment may have included review s by the Human Studies Review Board.

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

human health risk assessment.

2.0 HED Recommendations

2.1 Data Deficiencies

HED’s Hazard and Science Policy Council (HASPOC) determined that a guideline 90

- day inhalation study is required. (J. Leshin, TXR 0056925, May 27, 2014 )

. No other toxicology studies are required to support the registration review of tebuthiuron.

There are no residue chemistry or occupational/residential exposure data gaps for tebuthiuron.

2.2 Tolerance Co nsiderations

2.2.1 Enforcement Analytical Method

An adequate analytical method is available for the enforcement of plant and animal commodity

tolerances established for tebuthiuron. A gas

- liquid c hromatography ( GLC) method with flame photometric detecti on is designated as Method II in PAM Vol. II. Tebuthiuron and regulated metabolites 104 and 109 are thermally degraded on the GLC column and are determined as 5

- (1,

1

- dimethylethyl)

- N

- methyl

- 1,3,4

- thiadiazol

- 2

- amine; metabolite 103 (OH) is determined as 5

- (2

-

### Tebuthiuron Human Health Risk Assessment DP No. D414218

Page 8 of 57 hydroxy

- 1,1

- dimethylethyl)

- N

- methyl

- 1,3,4

- thiadiazol

- 2

- amine. The stated detection limits are 0.1 ppm for tebuthiuron and metabolites 104 and 109, and 0.2 ppm for metabolite 103(OH). The structures of these metabolites are shown in Appendix B Table B .4: Figure A

.

2.2. 2 Established Tolerances

Tolerances are established for the herbicide tebuthiuron under 40 CFR: § 180.390 ; for Grass, ( forage and hay )

– 10 ppm; Cattle, ( fat and meat )

– 1.0 ppm; Goat ( fat and meat )

– 1.0 ppm; Horse, ( fat and meat )

– 1.0 ppm; Sheep ( fat and meat )

– 1.0 ppm; Cattle, Goat, Horse and Sheep, meat ( byproducts )

– 5.0 ppm and milk at 0.8 ppm

. These tolerances are adequate to support the currently established uses of tebuthiuron.

2.2. 3 International Harmonization

The re are no Codex , Canadian, or Mexican Maximum Residue Limits (MRLs) established for tebuthiuron; therefore issues of harmonization are not relevant to this risk assessment The International Residue Limit (IRL) Status sheet is attached as Appendix C

.

2.3 L abel Recommendations

2.3.1 Recommendations from Occupational Assessment

HED recommends PRD ensure that that worker protection standard (WPS) language appear s on all registered labels. Also if pastureland is intended for haying harvest, a re

- entry interv al (REI) of 12 hours based on the acute toxicity must be on the labels to protect workers from post

application exposures.

HED notes that the occupational assessment resulted in dermal and inhalation risk estimates of concern for several exposures scena rios (presented in section 9.1) with the current PPE on labels.

3.0 In troduction

Tebuthiuron is a relatively nonselective substituted urea herbicide that acts by inhibiting photosynthesis. It is used to control broadleaf, grassy weeds, and woody plants. Use sites include pastureland, rangeland, and a variety of non

- food sites and uncultivated areas/soils

. Tebuthiuron is not registered for agricultural crops or for residential use. The on ly source of dietary (food) exposure is the consumption of secondary residues in meat and milk from

livestock fed tebuthiuron

- treated grass forage and hay. Tebuthiuron primary environmental properties affect drinking water sources. The chemical is resist ant to biological and chemical degradation, and its principle route of dissipation in the environment appears to be off

- site

transport. Because of t ebuthiuron ’s environmental persistence and low adsorption t o soil it can be t ransport ed to ground water thr ough leaching and to surface water through run

- off and off

target spray drift

.

3.1 Chemical Identity and Physical/Chemical Characteristics

### Tebuthiuron Human Health Risk Assessment DP No. D414218

Page 9 of 57 Tebuthiuron is a solid at room temperature

. Any losses due to volatilization/sublimation are expected to be minimal due to the v apor p ressure ( 2 x 10

- 6 

### mm Hg at 25 °C )

. Tebuthiuron is stable to anaerobic soil metabolism and is likely to persist in an anaerobic soil environment. See

Table 3.1 and A ppendix B for a summary of tebuthiuron nomenclature and p hysical/chemical properties

.

Table 3.1

- Tebuthiuron Nomenclature

Chemical structure

Common Name Tebuthiuron Empirical Formula C 9 H 16 N 4 OS

IUPAC Name 1

- (5

- tert

- butyl

- 1,3,4

- thiadiazol

- 2

- yl)

- 1,3

- dimethylurea

CAS Name Urea, N

- [5

- (1,1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- yl]

- N,N'

- dimethyl CAS Registry Number 34014

- 18

- 1



### 3.2 Pesticide Use Pattern

Pastureland and rangeland appear to be the dominate use site in the western part of the United States ( US )

. The final biological assessment prepared by the Bureau of Land Management in 2007 estimated the number of public land acres treated with tebuthiuron at an average of 48,000 from the years 1997 to 2005. In a ddition

, registrant provided i nformation estimating a significant amount of tebuthiuron is applied aerially to pastureland/rangeland in western US

states. While tebuthiuron retreatment intervals (RTI) are once every 2 to 3 years and twice every

6 years
, large agribusiness and/or commercial applicators could apply tebuthiuron over a period

of week s for multiple clients within a region. In addition to pastureland /rangeland

, tebuthiuron can be applied aerially, by ground, and with handheld equipment on gen eral non

- crop land, wildlife clearings and rights

- of

- way

. Tebuthiuron e nd

- use formulations include dry flowable, water dispersible granular, pelleted/tablets , and granules. A summary of the existing use patterns

for tebuthiuron are shown in Tables 3.2.1 below

.

### Tebuthiuron Human Health Risk Assessment DP No. D414218

Page 10 of 57 Table 3.2.1 Summary of Directions for Use of Tebuthiuron

Company Formulation

Name EPA Reg.

No. %

a.i Applic ation Equipment and Rate (lb ai/A) Max. No. Applic ation per Season Max. Seasonal

Applic ation Rate (lb ai/A) Use sites Use Directions and Limitations

Dry Flowable

Dow AgroSciences

LLC Spike 80DF

62719

- 107

80 Broadcast

Aerial and

Ground

Handheld for Spot

Treatment 4 lb ai/A aerial

pastureland,

and

6 lb ai/A ground

broadcast or 1.6 lb ai/gallon (spot treatment) 1 application

every year with up to 6 lb ai/acre in a 6 year period. . 4 lb ai/acre per

year for h aying

and

no more than

two treatments totaling 6 lb ai/A every 6

years Non

- cropland,

including rangeland,

permanent grass pastures, fencerows, and wildlife clearings PPE includes eye protection, long

- sleeved

shirt, long pants, shoe and socks, and chemical resistant gloves. Not r egistered

in Florida or Nassau and Suffolk NY. Not

for use in California. Not for residential use. Do not apply on field crops. Aerial by helicopter and wing fixed for herbicidal firebreaks on rangeland. Aerial application limited to helicopter for rights

of

- way. Alligare

LLC Tebuthiuron

80WG

81927

- 37

Pellet

Dow AgroSciences

LLC Spike 20P

62719

- 121 20

Aerial,

Ground, and

Handheld for Spot

Treatment 4 lb ai/A aerial

pastureland,

and

6 lb ai/A for ground

broadcast and

spot treatment 1 application /3

years 4 lb ai/acre per

year for h aying

and

no more than

two treatments totaling 6 lb ai/A every 6

years Rights

- of Way,

pastureland, rangeland, non

cropland, fence rows, firebreaks, industrial sites, wildlife clearings. No PPE listed. Dormant season

ap plication. Do not feed to livestock for 1 year after treatment. Do not apply to soil

that is frozen. Not used in Nassau and

Suffolk Counties in NY and restrictions in

Florida.

Spike 40P

62719

- 122 40 PPE includes long sleeved shirt and long

pants, shoes plus socks, waterproof gloves, protective eyewear. Dormant season application. Do not feed to livestock for1 year after treatment. Do not apply to soil that is frozen. Not used in

Nassau and Suffolk Counties in NY and

restrictions in Florida.

Alligare, LLC Tebuthiuron

20P

81927

- 41 20 No PPE listed. Dormant season application. Do not feed to livestock for 1 year after treatment. Do not apply to

frozen soil. Not used in Nassau and

Suffolk Counties in NY restrictions in

Florida.

Granular

Rainbow Technology Corporation Rainbow

Weed Killer

4037

13283

- 18 2 Ground and

handheld

spot

t reatment 6 lb ai/A

broadcast and

spot treatment 2 applications

per year with

retreatment 6 lb ai/A every 6

years Buried cable

closures, telephone booths, cross

- connect boxes, transformer PPE includes NIOSH filter respirator for

tractor drawn spreaders, and all loaders

. All handlers must wear lon g sleeved shirt, long pants shoes plus socks, and chemical

### Tebuthiuron Human Health Risk Assessment DP No. D414218

Page 11 of 57 Table 3.2.1 Summary of Directions for Use of Tebuthiuron

Company Formulation

Name EPA Reg.

No. %

a.i Applic ation Equipment and Rate (lb ai/A) Max. No. Applic ation per Season Max. Seasonal

Applic ation Rate (lb ai/A) Use sites Use Directions and Limitations

Rainbow

Weed Killer

4049

13283

- 21 1 (0.00015 lb

ai/ft 2) interval of 90

days

6 lb ai/Ain a 6 year period pads, fire plugs, rights

- of

- way and

industrial areas. resistant gloves

. Do not uses in any

recreational areas or in homes. Do not apply by air. Do not enter until dust settles. Spoon or pump

- feed spreader is prohibited

. Applied anytime except when

gr ound is frozen.

SSI Maxim Co.

Inc. Sprakil Sk

- 13

34913

- 15 1

Sprakil SK

- 26

34913

- 16 2

Sprakil SK

- 13

34913

- 15 1

Sprakil S

- 5

34913

- 10 5 PPE includes long sleeved shirt, long pants

shoes plus socks, and chemical resistant gloves

. Do not use on areas such as walks, driveways, streets. Not apply on or near field crops.

Technical

Dow AgroSciences

LLC Spike

Technical

Herbicide

62719

- 109 99 %

Makhteshim Agan of North America, Inc. Tebuthiuron

Technical

83558

- 33

### Tebuthiuron Human Health Risk Assessment DP No. D414218

Page 12 of 57 3.3 Anticipated Exposure Pathways

E xpos ure to tebuthiuron can be expected through food and drinking water . There are no direct appli cations to agricultural crops. The only source of food exposure is the potential for consumption of secondary residues in meat and milk from livestock fed tebuthiuron

- treated grass forage and hay

. Di etary exposure can also occur from consumption of drinking water. There are

no residential uses of tebuthiuron , so exposure in residential or non

- occupational settings is not likely , however as mention ed previously

, a spray drift assessment was conducted to assess for possible exposure from contact to deposits on off target sites. In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application. Occupational post

- application dermal exposure from workers re

- entering tebuthiuron treated areas is not anticipated be cause the chemical is a non

- selective herbicide used

in non

- agricultural areas.

3.4 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, i n 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/guidanc e/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 exposur es 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 U.S. Department of Agri culture under the National Health and Nutrition Examination Survey, What We E at in America, (NHANES/WWEIA). These food consumption patterns are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and ca tegorized 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 circumstance s warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for children , youths, and adults entering or playing on treated areas

post

- application are evaluated. Further co nsiderations 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 s pecific subgroups.

3.5 Incident Reports

HED completed a review of tebuthiuron incidents in the OPP Incident Data System (IDS) and the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event Notification System for Occupational Risk

- Pesticides (SENSOR) databases. Ba sed on the low frequency and severity of incident cases reported for

tebuthiuron in both IDS and NIOSH SENSOR Pesticides, there does not appear to be a concern

### Tebuthiuron Human Health Risk Assessment DP No. D414218

Page 13 of 57 at this time that would warrant further investigation (M. Hawkins, Updated Review of

Tebuthiuron Incident Reports

, May 7, 2009) . The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be conducted. The Agricultural Health Study (AHS) is also a potential source of information associated w ith human health effects associated with certain pesticides. Tebuthiuron is not included in the AHS

.

4.0 Hazard Characterization and Dose

- Response Assessment

4.1 Toxicology Studies Available for Analysis

The toxicology database for tebuthiuron is not complete but provides sufficient information to adequately identify hazards for risk assessment purposes. The database i ncludes the following

studies:

 90

- Day oral toxicity studies in the rat and dog

,

 28

- D a y dermal toxicity in the rabbit,

 Developmental to xicity in the rat and rabbit,

 2

- Generation re productive toxicity in the rat,

 Chronic t oxicity in the dog,

 Genetic toxicity battery

,

 Metabolism study in the rat, and

 Immunotoxicity study in the rat.

The Hazard and Science Policy Council ( HASPOC

, TXR 0056925 05/27 /2014 ) determined that the acute neurotoxicity study and sub

- chronic neurotoxicity, chronic/carcinogenicity study in the rat, and the carcinogenicity study in the mouse may be waived. A sub

- chronic inhalation study was required and a route

- sp ecific 10x database uncertainty factor has been retained

.

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

T ebuthiuron is highly absorbed (84

- 95%) and rapidly excreted (within 24 hours) following oral administration in rats. Following administration of 14 

### C

- tebuthiuron, metabolites in the urine accounted for up to 97.1% of the dose, and metabolites in the feces accounted for an average of

3.5% of the administered dose. Biliary excretion studies in rats indicated most of the radioactivity eliminated in the feces was absorbed from the gastrointestinal tract and eliminated through the bile. T he major metabolite in 0

- 24 hour urine of male (58.3%) and female (62.1%) rats was identified as hyd roxylated tebuthiuron metabolites (109

- OH and /or 104

- OH). The

second most abundant metabolite was identified as metabolite 106 of tebuthiuron. This comprised between 9

- 15% of the administered dose in 0

- 24 hour urine of low dose rats, and

between 1

- 10% of the administered dose in high dose rats. Two other metabolites identified,

104/109 and 103

- OH, comprised between 2

- 10% of the administered dose in male and female 0

- 24 hour urine. No evidence of bioaccumulation was identified.

### Tebuthiuron Human Health Risk Assessment DP No. D414218

Page 14 of 57 4.3 Toxicological Effects

The most consistent toxicological effect across the mammalian database is decreased body weight, occurring in rats, rabbits and dogs. No effects were observed in mice following long

term exposure up to the highest dose tested (240 mg/kg/day). At higher doses in rats, slight vacuolization of the pancreatic cells were observed, and in dogs, signs of liver toxicity were observed (including increased liver weights and enzyme activity). Toxicity in the 90

- day and long

- term rat and dog studies occurred at si milar doses indicating no progression of toxicity over time. In a dermal toxicity study, no effects were observed up to the limit dose. Based on the available data, no evidence of reproductive, neurological, genotoxic, or immunotoxic effects

were identif

ied in the database.

No evidence of qualitative/quantitative susceptibility was observed in the database. In rabbits significantly decreased fetal body weights were observed at 25 mg/kg/day. An increase in the number of litters with early resorptions was al so observed at this dose level. However, as limited data are available, and the etiology of the increased resorptions is unknown, this effect is considered to reflect toxicity in both the dams and pups. No developmental toxicity was

observed in rat s. In a 2

- generation reproductive toxicity study decreases in pup body weights

were observed on PND 21 in the F1 and F2 generation pups at 26 mg/kg/day. These effects occurred in the presence of maternal toxicity (decreases in F1 female adult bodyweights). In rats, decreases in pup body weights were observed PND 21 in the first and second (F1 and F2) generation pups at 26 mg/kg/day. These effects occurred in the presence of maternal toxicity (decreases in F1 female adult bodyweights).

The ac ute toxicity studies indicate th at tebuthiuron is more toxic following oral ( Toxicity Category II) exposure than either dermal ( Toxicity Category IV) or inhalation ( Toxicity Category III) exposure. This is supported by ADME data, indicating complete and ra pid absorption of tebuthiuron following oral administration. Tebuthiuron is not an eye or skin irritant

and not a skin sensitizer.

In the 2002 Preliminary Human Health Risk Assessment, t ebuthiuron was classified as a Group D compound “not classifiable as to human carcinogenicity .” For more detail on cancer

classification see Section 4.5.3.

4.4 Safety F actor for Infants and Children (FQPA Safety Factor)

HED recommends that the 10X FQPA Safety Factor (for the protection of infants and children)

be reduce d to 1X. No evidence of increased quantitative /qualitative susceptibility was observed.

The effects observed in the rabbit d evelopmental and rat 2

- generation reproduction studies occur in the presence of maternal toxicity . Nevertheless, th ese studies have clearly defined

NOAEL/LOAEL s and the selected points of departure (PODs) are protective of all observed

adverse effects. No clinical signs indicative of neurotoxicity were identifi ed throughout the

database for t ebuthiuron. The dietary and residentia l bystander assessments are based on reliable data and will not underestimate exposure.

4.4 .1 Completeness o f the Toxicology Database

### Tebuthiuron Human Health Risk Assessment DP No. D414218

Page 15 of 57 The toxicology database for tebuthiuron is not complete, but provides sufficient information to adequately identify haza rds for risk assessment purposes. HASPOC ( TXR 0056925 ) decided based on a weight of evidence determination, that the acute neurotoxicity study and subchronic neurotoxicity, chronic/carcinogenicity study in the rat, and the carcinogenicity study in the

mou se may be waived. The required sub

- chronic inhalation study was not waiv ed as the oral endpoint results in unacceptable MOEs for workers . Therefore, an additional 10X uncertainty

factor was retained for the occupational inhalation assessment.

4.4.2 Evidence of N eurotoxicity

No evidence of neurotoxicity was observed in any of the submitted studies for t ebuthiuron. The HASPOC determined that the acute and subchronic neurotoxicity studies are not required at this time based on the following rationale : 1) the lack of neurotoxicity signs in the available toxicology database for tebuthiuron ; 2) the primary toxic effect throughout the database is decreased bodyweights; and 3 ) using an oral POD, the acute and chronic dietary exposures (food

and water ) for te buthiuron result in risk estimates of less than 100% and therefore not of concern.

4.4.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Animal

The available data do not provide evidence of any increased susceptibility in the offspring in

either of the rat or rabbit developmental toxicity studies for tebuthiuron , nor in the rat two

generation reproduction study.

Decreased fetal body weights and early resorptions were observed in the rabbit developmental toxicity study, and decreased post

- natal body weights were observed in the rat 2

- generation toxicity study. Both of these effects occurred in the presence of maternal toxicity. No developmental e ffects were observed occurred in the rat developmental study

.

4.4.4 Residual Uncertainty in the Exposure Datab ase

There are no residual uncertainties in the exposure database. Since the dietary estimates were based on conservative assumptions, HED is confident that th e assessment s do not underestimate dietary (food and water) exposure.

4.5 Toxicity Endpoint and Point of D eparture Selections

4.5.1 Dose

- Response Assessment

A detailed description of the toxicity studies used for selecting toxicity e ndpoints and PODs for various exposure scenarios is presented in Appendix A and summarized in Table 4.5.4

.

For acute dietary assessment of females 13

– 49 years old , the developmental toxicity study in rabbits was selected with a NOAEL of 10 mg/kg/day fo r dams and pups . The LOAEL is 25 mg/kg/day for dams and pups based on early resorptions and decreased fetal body weight s

. E arly resorptions could be from a single exposure during pregnancy and are therefore considered

a potential acute effect

, and therefor e
, appropriate for the acute dietary endpoint scenario for

### Tebuthiuron Human Health Risk Assessment DP No. D414218

Page 16 of 57 females of child

- bearing age

. No appropriate toxicological endpoints attributable to a single exposure were identified f or the general population.

For chronic dietary exposure and risk assessment

, the 2

- generation reproductive toxicity study in rats was selected with a NOAEL of 14 mg/k g/day. The LOAEL is 26 mg/kg/day based on decreased body weights in F1 parental females (13%) and decreased pup body weights (17%) on PND 21 in the F1 and F2 genera tion (5

- 8%). The 2

- generation reproductive toxicity study was selected for the chronic dietary exposure because the endpoint is applicable to the population of concern ( general population ) and the duration of exposure

. As the NOAEL/LOAEL values are

simil ar between the developmental and 2

- generation toxicity studies (10/14 mg/kg and 25/26 mg/kg

, respectively) , t he 14 mg/kg/day NOAEL represents a smaller dose spread between the

NOAEL/LOAEL of both studies and the agency is confident that the NOAEL of 14 mg/kg/day is protective of both the developmental effects observed in the rabbit and the parental and offspring

effects in rats.

For short

- term incidental oral exposure (1

- 30 days), the 2

- generation reproductive toxicity study

in rats was selected with a NOAEL of 14 mg/kg/day . The LOAEL is 2 6 mg/kg/day based on decreased body weights in F1 adult females (13%) and decreased pup body weights on PND 21 in the F1 and F2 generation (5

- 8%). The endpoint of concern in this study (bodyweight) is appropriate for the age of the population (infant and children) and the duration of concern.

I ntermediate and long

- term incidental oral exposure assessment are not required because these

exposure lengths are not expected based on current use patterns

.

For short and int ermediate

- term dermal exposure, a 28

- day rabbit dermal toxicity is available. However, the dermal study does not evaluate the endpoint of concern, resorptions. Therefore

, the 2

- generation reproductive toxicity study in rats was selected with a NOAEL of 1 4 mg/kg/day . The LOAEL is 2 6 mg/kg/day based on decreased body weights in F1 females (13%) and decreased pup body weights on PND 21 in the F1 and F2 generation (5

- 8%). A dermal risk assessment is being conducted for the following reasons : the dermal toxic ity study conducted is not protective of the adverse outcome (resorptions) of concern for pregnant females ; no dermal absorption data are available

, and the physical properties of the chemical support the potential for dermal absorption (log K
ow 

### of 1.8 and a molecular weight of < 500)

. As discussed above, the

2

- generation reproductive toxicity study with a NOAEL of 14 mg/kg was selected as it is protective of both developmental effects in rabbits and offspring effects observed in the rats.

Ther e is no proposed long

- term use; therefore, risk assessment for long

- term dermal exposure is not required.

For short and intermediate

- term inhalation exposure, n o route

- specific inhalation study is

available for tebuthiuron. Consequently, the 2

- generation reproductive toxicity study with a NOAEL of 14 mg/kg was selected for risk assessment , because it is protective of both developmental effects in rabbits and offspring effects observed in the rats. There is no proposed long

- term use; therefore, risk asses sment for long

- term inhalation exposure is not required.

For acute and chronic dietary, in cidental oral and dermal exposure s a 100X uncertainty factor is applied (interspecies factor of 10X and intraspecies factor of 10X). An additional 10x database

### Tebuthiuron Human Health Risk Assessment DP No. D414218

Page 17 of 57 unce rtainty factor has been applied for inhalation exposure due to the lack o f a subchronic inhalation study

.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

When there are potential occupational and residential exposures to a pesticide, the risk assessment must address exposures from three major sources: incidental oral, dermal, and

inhalation

. Oral , dermal, and inhalation routes can be combined as the points of departure are based on the same study and toxicological effect s o f decreased body weight.

4.5.3 Cancer Classification and Risk Assessment Recommendation

In the 2002 Preliminary Human Health Risk Assessment, Tebuthiuron was classified as a Group D compound “not classifiable as to human carcinogenicity

. ” There is no co ncern for mutagenicity. In the rat carcinogenicity study, there was no evidence of carcinogenicity. The mouse carcinogenicity study was inadequate to determine carcinogenic activity due to the lack of adverse effects at the highest dose tested. In 2004, H ED’s Dosage Adequacy Review Team (DART) determined that the mouse carcinogenicity needs to be repeated due to the lack of effects at the highest dose tested. On March 13, 2014, however, HASPOC , based on a weight of evidence approach considering all of the available hazar d and exposure information for

tebuthiuron concluded that a repeat mouse study is not required. Despite the inadequacy of the mouse carcinogenicity study, EPA has determined that an additional mouse carcinogenicity study is not needed and that the rat chronic/carcinogenicity study will be adequate for assessing chronic risk, including cancer. This finding is based upon t he following conclusions: (1) the rat

is more sensitive than the m ouse for the chronic assessment; (2) the effect seen in the most sensitive species (rats) and m ost sensitive sub population (i. e

. , F1 offspring) in the two

generation rat reproduction study has been used as the point of departure for the chronic assessment; (3) a new mouse study would only use doses well abo ve the current POD for the chronic assessment; and (4) even if a new mouse study identified positive carcinogenicity effects, that finding would not result in the adoption of a quantitative linear assessment of cancer risk due to the negative carcinogenici ty finding in the rat study and the lack of a positive finding for genotoxicity.

### Tebuthiuron Human Health Risk Assessment DP No. D414218

Page 18 of 57 4. 5

. 4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk

Assessment

Table 4.5.4. Summary of Toxicological Doses and Endpoints for Tebuthiuron for Use in 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 (General Population) No appropriate endpoint attributable to a single dose was identified. An acute RfD was not established.

Acute Die tary (Females 13 to 49 years of age ) NOAEL = 10 mg/kg/day UF A 10x

UF H 10x

FQPA SF = 1X aRfD = 0.1

mg/kg/day

a PAD = 0.1 mg/kg/day Developmental Toxicity (rabbit)

MRIDs: 00020644, 40776301

LOAEL = 25 mg/kg/day, based on significantly decreased fetal weights and increased resorptions.

Chronic Dietary (All populations ) Parental

NOAEL=14 mg/kg/day UF A 10x

UF H 10x

FQPA SF = 1X cRfD =cPAD 0.14

mg/kg/day 2

- Generation Reproductive Toxicity

MRIDs: 00090108

Parental LOAEL = 26 mg/kg/day, based on decreased body weights in F1 females (13%)

Incidental Oral

Short

- Term (1

- 30 days) Offspring

NOAEL = 14 mg/kg/day UF A 10x

UF H 10x

FQPA SF = 1X LOC = 100x 2

- Generation Reproductive Toxicity

MRIDs: 00090108

Offspring LOAEL = 26 mg/kg/day, based on decreased pup body weights on PND 21 in the F1 and F2 generation (5

- 8%).

Dermal

Short

- Term (1

– 30 days) and

Intermediate

- Term (1

– 6 months) NOAEL = 14 mg/kg/day UF A 10x

UF H 10x LOC = 10 0x 2

- Generation Reproductive Toxicity

MRIDs: 00090108

Parental LOAEL = 26 mg/kg/day, based on decreased body weights in F1 females (13%)

Offspring LOAEL = 26 mg/kg/day, based on decreased pup body weights on PND 21 in the

F1 and F2 generation (5

- 8%).

Inhalation

Short

- Term (1

- 30 days) and

Intermediate

- Term (1

– 6 months) NOAEL = 14 mg/kg/day UF A 10x

UF H 10x

FQPA UF DB = 10X LOC = 1000x 2

- Generation Reproductive Toxicity

MRIDs: 00090108

Parental LOAEL = 26 mg/kg/day, based on decreased body weights in F1 females (13%)

Offspring LOAEL = 26 mg/kg/day, based on decreased pup body weights on PND 21 in the F1 and F2 generation (5

- 8%).
Cancer (oral) Classification: "Not classifiable as to human carcinogenicity".

Point of Departure (POD) = A data point or an estimated point derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse eff ect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animals to humans (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF D B = Data base Uncertainty Factor. FQPA SF = FQPA Safety Factor. aPAD =

acute population adjusted dose. cPAD = chronic population adjusted dose. RfD = reference dose.

### Tebuthiuron Human Health Risk Assessment DP No. D414218

Page 1 9 of 57 4.6 Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies t o 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 toxic ity. 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 ra tios 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 tebuthiuron

, 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), tebuthiuron is subject to the endocrine screening part of the Endocr ine 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 occurrin g 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 stag e of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and

establish a dose

- response relatio nship 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 contain s 58 pesticide active ingredients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 1 

### and includes some pesticides scheduled for registration review and chemicals found in water

. Neither of these lists should be construed as a list of known or likely endocrine disruptors.

For further information on the status of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our

website. 2



### 5.0 Dietary Exposure and Risk Assessment

5.1 Summary of Plant and Animal Metabolism Studies

Plant

1 See http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0477

- 0 074 for the final second list of chemicals.

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

### Tebuthiuron Human Health Risk Assessment DP No. D414218

Page 20 of 57 Tebuthiuron metabolism in grass is adequately understood

. All data requirements for the magnitude of the residue in plants have been evaluated and deemed acceptable. A metabolism study (MRID 00020756) was submitted in which a [ 14 

### C] tebuthiuron solution (labeled in the

5

- position of the thiadiazole ring; specific activity of 16.9 μCi/mg) was applied to the surface of

the soil in which 10

- week old tall fescue (0.374 lb ai/A), little bluestem and Indian grass (0.75 lb ai/A.) were grown. The residues of concern are the parent compound and its metabolites 103 (OH), 104, and 109 ( Dodd, N., 12/10/87). See Appendix B for structures. Two major metabolic pathways are involved: N

- demethylation of te buthiuron to form 104 and alkyl hydroxylation of the dimethylethyl side chain to form 103(OH).

Livestock

The regulatory requirements for data depicting the magnitude of the residue in m ilk, and

livestock tissues are fulfilled. The livestock feeding study (MRID 43703201) depicting the magnitude of the residue in milk, and livestock tissues (fat, meat, liver, and kidney), demonstrate

a transfer of tebuthiuron residues. The residues of con cern in milk are tebuthiuron and metabolites 104, 104(OH), 106, 109; the residues of concern in livestock commodities are tebuthiuron and its metabolites 104, 106, 108, and 109. No poultry or swine feed items are associated with the registered uses on grass; there is no reasonable expectation of detectable residues of tebuthiuron and its metabolites in poultry and swine commodities resulting from the

uses and no tolerances are needed

.

Current tolerances are adequate to cover secondary transfer of resi dues.

Rotational Crops

Tebuthiuron is only used for the restoration of grasses in natural rangelands, permanent pasturelands and in non

- cropland areas such as energy and transportation rights

- of

- ways; rotational crops are not concomitant to these uses.

5.1.1 Summary of Environmental Degradation

Tebuthiuron is persistent, mobile and can potentially leach to ground water. Tebuthiuron is not lipophilic. It is resistant to biological and c hemical degradation, and its principle route of dissipation in t he environment appears to be off

- site transport. Transport to ground water through leaching and to surface water through run

- off and off

- target spray drift are likely as a result of the chemical’s environmental persistence and low adsorption to soil. Ba sed on the available data, the parent and degradate 104 (residues of concern) are persistent and mobile.

5.1.2 Residues of Concern Summary and Rationale

For dietary risk assessment, HED previously concluded that the residue of concern in plants are

the parent compound and its metabolites 103, 103(OH), 104, and 109. As stated previously, t he residues of concern in livestock commodities (fat, meat, kidney, and liver) are tebuthiuron and its metabolites 104, 106, 108, and 109; the terminal residues of con cern in milk are tebuthiuron and metabolites 104, 104(OH), 106, 109, and 109(OH).

### Tebuthiuron Human Health Risk Assessment DP No. D414218

Page 21 of 57 For the drinking water assessment, HED previously concluded that the parent compound and degradate 104 should be included in the drinking water risk assessment. Additiona lly, the metabolism assessment review committee ( MARC ) committee did not recommend including the other degradates in a drinking water risk assessment because they were not likely to be present. Metabolites 103(OH), 104(OH) and 109 (OH) were not detected i n the environmental fate studies although identified as residues of concern. The drinking water risk assessment included metabolites 106, 108 and 109 based on aerobic soil metabolism and soil photolysis assumptions

and on similarity in structure and that they have comparable chemical properties as the parent compound. The structures a re shown in Appendix B, Figure B.1

.

5 .2 Food Residue Profile

Tebuthiuron is not registered for agricultural uses. Its use is limited to application to grasses.

No residues in raw agricultural commodities are expected. However, residues are seen in livestock feedstuff, and those residue s do appear to transfer to livestock fed tebuthiuron

- treated

feedstuffs. The highest residues are found in meat by products (kidney/liver), with residues also found in fat, meat, and milk.

5.3 Water Residue Profile

T he estimated drinking water residues used in the dietary risk assessment were provided by the Environmental Fate and Effects Division (EFED) in the following memorandum: “ Tier II Estimated Surface Drinking Water Concentrations and Estimated Ground Water Concentration (EDWCs) for Tebuthiuron for Use in Human Health Risk Assessment, ” (D 414241

, I. Abdel

Saheb,01/16/2014 ). Water residues were incorporated in the dietary exposure e valuation modeling ( DEEM

- FCID ) into the food categories “water, direct, all sources” and “water, indirect, all sources.”

Only the parent compound and degradates 104, 106, 108, and 109 were included in the drinking water exposure estimates (i.e., A ppend ix B, Table B3 and Figure A) for the details. The values entered into the dietary exposure assessment model to assess the contribution from drinking water were specified by the results of the Pesticide Root Zone Model for Groundwater, ( PRZM

GW) modeling pr ogram. No percent crop area ( PCA ) adjustment is applied to estimated ground drinking water concentrations (EDWCs).

EFED has developed six standard drinking water modelling scenarios that represent vulnerable

watersheds i n specific areas in the country. “Crop

- specific” modelling scenarios are not

available for all crops, however each groundwater scenario represents a different region known

to be vulnerable to groundwater contamination. For chemicals which have a very lim ited number of labeled crops, as long as those limited crops are grown all over the country, the maximum registered application rate is used in each of the six modelling scenarios. For tebuthiuron, which is registered on grasses only, the water number der ived from using the grass

rate in the Wisconsin corn scenario. T he scenario that results in the highest estimated environmental concentration, is used in the dietary assessment as an estimate of the drinking

water concentrations that would arise in that v ulnerable watershed from the specific registered

### Tebuthiuron Human Health Risk Assessment DP No. D414218

Page 22 of 57 uses. This scenario does not imply that the pesticide is actually registered for use on corn. Since the WI corn scenario produced the highest EDWCs and it was used in the dietary assessment. See Appendix B, Table B4 for summary of EDWCs residues.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Th e unrefined chronic dietary exposure and risk analysis is based on tolerance

- level residues

, direct incorporation of drinking water residues (chronic) and the DEEM default processing factor

for dried beef

. Th e partially refined acute dietary exposure and risk analysis is based on

tolerance

- level residues, time series distribution of drinking water residues and the DEEM default processing factor for dried beef

.

5.4.2 Percent Crop Treated Used in Dietary Assessment

Percent crop treated refinements were not applicable to these assessments, tolerance

- level

residues are established on animal and non

- food grass (forage and hay) commodities.

5.4.3 Acute Dietary Risk Assessment

The acute dietary food (tolerance level residues) and water (time series water distribution) risk

estimates reported in the tables are for females 13

- 49 years old. An acute assessment was performed o nly for females 13

- 49 years old since an acute endpoint for the gene ral population

was not selected

. The resulting dietary (food and water) risk estimates are not o f concern (less

than 100% ) ; acute dietary risk for females 13

– 49 years old is 93 % of the aPAD at the 95 th


### percentile

.

5.4.4 Chronic Dietary Risk Assessment

The chronic dietary risk estimates reported in the tables below are for the general U.S. Population, all infants (< 1 year old), children 1

- 2, children 3

- 5, children 6

- 12, youth 13

- 19,

females 13

- 49, adults 20

- 49, and adults 50

- 99 years. The resulting dietary risk estimates are not

o f concern ; (less than 100% ); t he most highly exposed population subgroup is all infants at 72 %

of the cPAD, while the general U.S. population utilized 30 % of the cPAD.

5.4.5 Summary Table

Table 5. 4.5 Summary of Dietary (Food and Drinking Water) Exposure and Risk for Tebuthiuron

* The subpopulation(s) with the highest risk estimates bolded

Population Subgroup Acute Dietary (95 th Percentile) Chronic Dietary

Dietary Exposure (mg/kg/day) %

aPAD Dietary Exposure

(mg/kg/day) %

cPAD

General U.S. Population 0.042379 30

All Infants (<1 year old) 0.100488 72

Children 1

- 2 years old 0.088184 63

### Tebuthiuron Human Health Risk Assessment DP No. D414218

Page 23 of 57 Table 5. 4.5 Summary of Dietary (Food and Drinking Water) Exposure and Risk for Tebuthiuron

* The subpopulation(s) with the highest risk estimates bolded

Population Subgroup Acute Dietary (95 th Percentile) Chronic Dietary

Dietary Exposure (mg/kg/day) %

aPAD Dietary Exposure

(mg/kg/day) %

cPAD

Children 3

- 5 years old 0.064471 46

Children 6

- 12 years old 0.043157 31

Youth 13

- 19 years old 0. 0 31694 23

Adults 20

- 49 years old 0.039849 29

Adults 50

- 99 years old 0.039135 28

Females 13

- 49 years old 0.093157 93 0.039754 28



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no registered residential uses for tebuthiuron. Residential handler and post

- application exposure assessments are not included in this document.

6. 1 Residential Bystander Post

- application Inhalation Exposure

Based on the Agency's current practices, a quantitative post

- application inhalation exposure assessment was not performed for tebuthiuron at this time

. However, volatilization of pesticides may be a source of post

- app lication 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 3 

### . The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorpo rate post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are developed, the Agency may revisit the need for a quantitative post

- application inhalation exposure assessment for tebuthiuron.

6. 2 Spray Drift

Off

- target movement of pesticides can occur via many types of pathways and it is governed by a variety of factors. Sprays that are released and do not deposit in the application area end up off

target and can lead to exposures to those it may directly c ontact. They can also deposit on surfaces where contact with residues can eventually lead to indirect exposures ( e.g. , children playing on lawns where residues have deposited next to treated fields). The potential risk

estimates from these residues can b e calculated using drift modeling onto 50 feet wide lawns coupled with methods employed for residential risk assessments for turf products.

3 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html

### Tebuthiuron Human Health Risk Assessment DP No. D414218

Page 24 of 57 The approach to be used for quantitatively incorporating spray drift into risk assessment is based on a premise of compliant applications which, by definition, should not result in direct exposures to individuals because of existing label language and other regulatory requirements intended to prevent them. 4 

### Direct exposures would include inhalation of the spray plume or being sprayed directly. Rather, the exposures addressed here are thought to occur indirectly through contact with impacted areas, such as residential lawns, when compliant applications are conducted. Given this premise, exposures for children (1 to < 2 years old) and adults who have contact with turf where residues are assumed to have deposited via spray drift thus resulting in an indirect exposure are the focus of this analysis analogous to how exposures to turf products are

considered in risk assessm ent.

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 tebuthiuron. 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 recently revised (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 available. 5

, 6 

### 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 speci fically 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 be evaluated unless it is not plausible based on the anticipated use pattern (e.g., he rbicides are not typically applied to tree canopies) or specific label prohibitions (e.g., aerial applications are not allowed). Section 6

. 2.1 and Appendix D provide the screening level drift related risk

estimates.

In many cases, risks are of concern w hen 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

e stimates represent plausible options for pesticide labels

4 This approach is consistent with the requirements of the EPA’s Worker Protection Standard.

5 http://www.agdrift.com/

6 Note that for many cases the scenarios outlined in the screening approach represent actual use practice so risk assessors sho uld

be aware and characteriz e these appropriately.

### Tebuthiuron Human Health Risk Assessment DP No. D414218

Page 25 of 57 6. 2 .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. Tebuthiuron can be applied via groundboom, and aerial equipment at a maximum rate of 6 lb ai/ac re to large acreages of pastureland/rangeland as well as for total vegetative control in non

- cropland areas

. The recommended drift scenario screening level options are listed below:

 Groundboom applications ; are based on the AgDRIFT option for high boom h eight and
using very fine to fine spray type using the 90 th 

### 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). 7



### In addition to the screening level spray drift scenarios described above, additional results are provided which represent viable drift reduction technologies (DRTs) that represent poten tial risk management options. In particular, different spra y qualities have been considered as well as the impact of other application conditions (e.g., boom height, use of a helicopter instead of fixed wing aircraft, crop canopy conditions).

Dermal risk estimates based on 100% absorption were calculated for adul ts. Dermal and

incidental oral risk estimates for children 1 to <2 years old were combined because the toxicity endpoint for each route of exposure is the same . The total applicable level of c oncern is 100 so

MOEs < 100 represent risk estimates of concer n. Adult dermal and c hildren’s (1 to <2 year old) dermal and incidental oral risk estimates from indirect exposure to tebuthiuron related to spray

drift result in buffers that rang e from 0 feet to greater than 15 0 feet depending on the nozzle type, drople t size, and application equipment. Aerial application has more risk estimates of concern. Dermal absorption data could lead to refinement in the spray drift analysis

.

Spray drift analysis r esults are presented in Appendix D Table s D. 1 and D .2

. Appropriate drift reduction technologies such as changing the spray type/nozzle configuration to coarser spray applications may in less drift and reduced risk concerns (i.e., higher MOEs) from aerial applications. Similarly, using coarser sprays and lowe ring boom height for groundboom

sprayers reduces risk concerns.

7 AgDRIFT allows for consideration of even finer spray patterns characterized as very fine to fine. However, this spray patter n was not selected as the common screening basis since it is used less commonly for most agriculture. .

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 26 of 57 7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, H ED must consider and aggregate tebuthiuron pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposure s and risks from various sources, HED considers both the route and duration of exposure. There are no residential uses of tebuthiuron; therefore, the aggregate risk includes only exposure from food and drinking water. The acute and chronic dietary risk e stimates are not of concern (less than 100% ) of the aPAD and cPAD, respectively (see Section 5.0 for specific information on the dietary exposure estimates).

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has follo wed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as

to tebuthiuron and any other substances and tebuthiuron does not appear to produce a toxic metabolite produced by other subst ances. For the purposes of this tolerance action, therefore,

EPA has not assumed that tebuthiuron has a common mechanism of toxicity with other

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

common mechanism of tox icity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have

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

9.0 Occupational Exposure/Risk Characterization

9.1 Short

- /Intermediate Handler Risk

HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each t ask. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by a handler can cause exposure levels to differ in a manner specific to each application event.

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the registered and proposed uses of tebuthiuron . The quantitative exposure/risk as sessment developed for occupational handlers is based on the following scenarios:

 Mixing/loading DF/WDG for aerial application;

 Mixing/loading DF/WDG for groundboom application;

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 27 of 57  Loading P/G for aerial application;

 Loading P/G for tractor drawn spreader application;

 Applying DF/WDG by aerial application;

 Applying DF/WDG by groundboom application;

 Applying P/G for aerial application;

 Applying P/G for tractor drawn spreader application;

 Loading/applying P/G for application with belly grinder;

 Loading/apply ing P/G for application with a rotary push

- type spreader;

 Mixing/loading/applying DF/WDG for mechanically pressurized handgun application;

 Mixing/loading/applying DF/WDG for manually pressurized handwand application;

 Mixing/loading/applying DF/WDG for bac kpack application;

 Applying P/G by cup;

 Applying P/G by spoon;

 Applying P/G by shaker can;

 Applying P/G by hand; and

 Flaggers from aerial application of spray and granules.

Chemigation applications are prohibited on the product labels.

Exposure is most likely to be short (1 to 30 days) and intermediate

- term (1 to 6 months) given the use pattern and limitations. There are no agricultural crop use sites and the recommended timing of application is prior to the resumption of active seasonal growth in the spring when the ground is not frozen or before expected seasonal rainfall. A pplications are limited to once every two to three years and to twice every six years. However it is possible that a commercial applicator could apply the product over a period o f weeks within a region. Therefore, based on

the use pattern short

- term and intermediate

- term exposures are expected for tebuthiuron.

Estimates of dermal and inhalation exposure were calculated for various levels of personal protective equipment. Resu lts are presented for “baseline,” defined as a single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator, as well as baseline with the addition of various levels of PPE as necessary ( e.g., gloves, respirator, engineering control, etc). W orker protection standard (WPS) language should appear on all registered labels. Currently two out of the three pelleted tebuthiuron formulations do not have any WPS listed on the labels. The DF and WDG formulations list PPE as baseline dermal attire plus gloves. The granular formulations direct tractor drawn spreaders and loaders to use a respirator with NIOSH approved filter with the addition of baseline dermal plus chemical resistant gloves

Based on the assessment of registered uses
, there are risk estimates of concern ( i.e., dermal

MOEs <100 and inhalation MOEs < 1000) for the short/intermediate dermal and inhalation exposure. In evaluating handler exposure scenarios, the dermal MOE values range from 0.18 to 7,1 00 at baseline dermal (i.e., no gloves ) , 1 .8 to 71,000 with gloves, and 2.4 to 71 ,000 with double layer protection consisting of baseline dermal with the addition of a coverall

. In evaluating handler exposure scenarios, the inh alation MOE values range from 2 6 to 64 ,000 at

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 28 of 57 baseline i nhalation ( i.e., no respirator), 130 to 320,000 with PF5 respirator, 260 to 64 0,00 0 with a PF10 respirator, and 970 to 480 ,000 with engineer ing controls. See Appendix E, tables E .1.1 through E .1.3 for occupational risk estimate summary.

A total aggregated risk index (ARI) was used since the LOC values for dermal exposure (100)

and inhalation exposure (1000) are different. The target ARI is 1; therefore, ARIs of less than 1

are risk estimates of concer n. Several of the occupational handler scenarios remain a risk of

concern even with the addition of doubler layer dermal PPE consisting of double layer dermal

wear, respirators

, and engineering controls . These scenarios are as follows :

 Mixing/loading of DF/WDG and P/G f or aerial applications on pastureland/rangeland ( 4

and 6 lb ai/acre ) has a baseline PPE combined 0.1 ARI value

. ARI values ranges from

0.02

- 0.25 with various PPE additions including engineering control such as a closed mixing/loading syst em ;

 Mixing/loading P/G f or aerial applications on non

- crop land (6 lb ai/acre) has a baseline

PPE combined 0.06 ARI value

. A RI values ranges from 0.07

- 0.16 with various PPE additions including engineering control such as a closed mixing/loading system;

 Aerial application of P/G on pasturelan d, which resulted in a combined 0.16 ARI value

with the use of engineering controls and on non

- crop l and a combined ARI value of 0.11.

 Flagger exposure to aerial spray of tebuthiuron on pastur eland resulted in an ARI of 0.74 with double layer dermal PPE and PF10 respirator;

 Mixing/Loading/Applying DF/WDG with backpack, manually pressurized handgun, mechanically pressurized handwand resulted in an ARIs <1 even with double layer dermal PPE and PF10 respirator ;

 Mixing/Loading/Applying P/G with a belly grinder, and hand dispersal, resulted in ARIs <1 even with double layer dermal PPE and PF10 respirator.

9.2 Short

- /Intermediate

- term Post

- Application Risk

9.2.1 Dermal Post

- application Risk

Occupational post

- application dermal exposure from workers re

- entering tebuthiuron treated areas is not anticipated because the chemical is a non

- selective herbicide used in non

- agricultural

areas such as pastureland/rangeland, industrial, and rights

- of

- way sites. O cc upational post

application exposures are not thought to occur because reentry is unlikely. Labels currently

instruct workers to not enter fields until dusts have settled and delay grazing until one year after application. However, some of the labels use the term haying. If pastureland is intended for haying harvest the REI specified on labels should be based on the acute toxicity of tebuthiuron. Therefore, the [156 subpart K] Worker Protection Statement interim REI of 12 hours is adequate

to protect agr icultural workers from post

- application exposures to tebuthiuron from harvesting hay.

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 29 of 57 9.2.2 Inhalation Post

- application Risk

Based on the Agency's current practices, a quantitative post

- application inhalation exposure assessment was not performed for tebuthiuron at this time primarily because of the low acute inhalation toxicity (Toxicity Category III ) and low vapor pressure (2 x 10

- 6 

### mm hg at 25 degrees Celsius). However 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 8 

### . The Agency is in the process of evaluat ing the SAP report as well as available post

- application inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post

applicati on inhalation exposure into the Agency's risk assessments. 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 tebuthiuron.

Although a quant itative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to r esult 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.

8 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 30 of 57 10.0 References

Barnes

, P. Y., July 23, 2009, D363983, Tebuthiuron. Revised : Registration Review Scoping

Document for Human Health Assessments

.

Barnes, Y., January 28, 2010

, 28

, D372760, 

### Tebuthiuron: Response to comments from Dow Agro Sciences on the Registration Review Summary Document (Docket EPA

- HQ

- OPP

- 2009

- 0327).

Barnes

, P. Y., May 23, 2014 , D 418910

, Tebuthiuron

. Dietary Memo for Preliminary Human Risk Assessment for Registration Review.

BEAD Memo August 29, 2013 Tebuthiuron Screening Level Usage Analysis (SLUA) Reporting years: 2004

- 2011.

B obowiec, B., April 15 , 2014, D 418911, Tebuthiuron. Occupational and Residential Assessment to Support Registration Review for Use on Pastureland, Rangeland, Non

- Crop Industrial Areas, and Rights

- of

- Ways.

Burnam

, W., January 31, 2005 , D 312380, TXR 0054232: Tebuthiuron Waiver Requests.

Corbin, M. February 2, 2002, D279066 Addendum to TRED Drinking Water Assessment for

Tebuthiuron.

Deschamp, P. April 22, 2002, D274580, Tebuthiuron: Preliminary Human Health Risk Assessment. HED Chapter for the Tolerance Reassessment Eligibility Decision (TRED).

Funk, S., D217379, December 05, 1995, Tebuthiuron: Ruminant Feeding Study (171

- 4(j)).

CBR S No. 15883. MRID 43703201.

Funk, S Tebuthiuron, Novem ber 22, 1995, D223089, Stor age Stability in Support of the

Ruminan t Feeding Study (171

- 4(e; j)). CBRS No. 16937. MRID 43439301.

Hawkins, M., May 7, 2009 , Update Review of Tebuthiuron Incident Reports.

Ibrahim

, A ., October 31, 2013, D414241, Tier II E stimated Surface Drinking Water

Concentrations and Estimated Ground Water Concentrations (EDWCs) for Tebuthiuron for Use

in Human Health Risk Assessment.

Ibrahim

, A

., January 16

, 20 14

, D414241, Tier II Estimated Surface Drinking Water Concentrations and Estimated Ground Water Concentrations (EDWCs) for Tebuthiuron for Use

in Human Health Risk Assessment.

Leshin, J ., Executive Secretary, May 27 , 2014 , TXR 0056925

, Tebuthiuron: Report of

HASPOC.

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 31 of 57 Kidwell

, J., Executive Secretary, December 9, 2004, TXR 0052580, Tebuthiuron: Report of

the D ose A dequacy R eview T eam (DART ).

Piper, S., April 03, 2002. D281821

, Acute and Chronic Dietary Exposure Assessments for the

TRED

.

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 32 of 57 A ppendix A

. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements
The requirements (40 CFR 158.340) for [ Type of Use (e.g., food vs. non

- food)] for Tebuthiuron are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A1: Summary of Tebuthiuron toxicology data requirements.

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

- Day Dermal

................................ .............................. 870.3250 90

- Day Dermal

................................ .............................. 870.3465 90

- Day Inhalation

................................ .......................... yes

yes

yes

no

yes yes

yes

yes

no

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)

................................ ................... yes

no

yes

yes waived 1

yes

waived 1

waived 1

870.5100 Mutagenicity

— Gene Mutation

- bacterial

..................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

............... 870.5395 Mutagenicity

— Other Genotoxic Effects

....................... yes

yes

yes yes

yes

yes

870.6100a Acute Delayed Neurotox. (hen)

................................ ...... 870.6100b 90

- Day Neurotoxicity (hen)

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

........................ 870.6200b 90

- Day Neuro. Screening Battery (rat)

.......................... 870.6300 Developmental Neurotoxicity

................................ ....... no

no

yes

yes

CR no

no

waived 1

waived 1

no

870.7485 General Metabolism

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

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

................................ ............................. yes

no

yes yes

no

yes Special Studies for Ocular Effects no no

1 ) Acute and subchronic neurotoxicity studies , chronic/carcinogenicity study in the rat, and a carcinogenicity study in the mouse are not required

for Tebuthiuron ( HASPOC TXR0056927

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 33 of 57 A.2 Toxicity Profile s

Table A2: Tebuthiuron Toxicity Profile

Guideline No. Study Type MRID No. (year)/ Classification

/Doses Results

870.3100 90

- Day oral toxicity

(Ha e rlan Rat) 00020662 (1972) Acceptable/Guideline

0, 20, 50, and 125 mg/kg/day NOAEL = 50 mg/kg/day

LOAEL = 125 mg/kg/day based on decreased body weight (25

- 28%) and an increase in slight vacuolization of the pancreatic acinar cells.

870.3100 90

- Day oral toxicity

(Beagle Dog) 00020663 (1972) Acceptable/Guideline

0, 12.5, 25, and 50 mg/kg/day NOAEL = 25 mg/kg/day

LOAEL = 50 mg/kg/day based on significant decreases in body weight and increased ALP activity.

870.3200 21/28

- Day dermal

toxicity 00149733 (1985) 00160796 (1986) Acceptable/Guideline

0, 1000 mg/kg/day NOAEL = 1000 mg/kg/day

No treatment related effects were observed.

870.3700a Prenatal

developmental (Harlan Rats) 00020803 (1972) 40485801 (1972) Acceptable/Guideline

0, 37, 72, and 110 mg/kg/day

GD 6

- 14 Maternal NOAEL = 110 mg/kg/day

D evelopmental NOAEL = 110 mg/kg/day

No treatment related effects were observed.

870.3700b Prenatal

developmental (Dutch rabbits) 00020644 (1975) 40776301 (1988) Acceptable/Guideline

0, 10, and 25 mg/kg/day Maternal NOAEL = 10 mg/kg/day

LOAEL = 25 mg/kg/day based on increased resorptions at the high

- dose.

Developmental NOAEL = 10 mg/kg/day

LOAEL = 25 mg/kg/day based on significantly decreased fetal weights.

870.3800 2

- Generation

Reproduction and fertility effects (Wistar rat) 00090108 (1981) Acceptable/Guideline

0, 14, and 30 mg/kg in males and 0, 14, and 26 mg/kg in females. Parental NOAEL = 14 mg/kg/day

LOAEL = 26 mg/kg/day based on decreased body weights in F1 females (13%).

Repro ductive NOAEL = 26 mg/kg/day.

No effects were observed on reproductive parameters as measured by sperm morphology, fertility index for females, and the number of litters produced.

Offspring NOAEL = 14 mg/kg/day

LOAEL = 26 mg/kg/day bas ed on decreased pup body weights on PND 21 in the F1 and F2 generation (5

- 8%).

870.4100b Chronic toxicity

(Beagle dog, capsule) 00146801 (1985) Acceptable/Guideline

0, 12.5, 25, and 50 mg/kg/day NOAEL = 25 mg/kg/day

LOAEL = 50 mg/kg/day based on decreased body weight (

- 12.5%), increased ALT (4

- 5 fold), AP (3

- fold), and significantly increased absolute and relative liver weights.

870.4200 Carcinogenicity

(Harlan ICR mice) 00020717 (1986) Unacceptable/Guideline

0, 60, 120, and 240 mg/kg/day NOAEL = 240 mg/kg/day

No significant treatment

- related effects were identified.

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 34 of 57 Table A2: Tebuthiuron Toxicity Profile

Guideline No. Study Type MRID No. (year)/ Classification

/Doses Results

870.4300 Combined chronic

toxicity/carcinogenici ty (Sprague

- Dawley rat) 00020714 (1976) 00098190 (1981) 40870101 (1988) Unacceptable/Guideline

0, 20, 40, and 80 mg/kg/day No NOAEL may be established for this study as several major deficiencies were identified. 25% or fewer animals were living at study termination in all groups. Additionally, respiratory infections were prevalent among the controls and treated gr oups confounding the study results.

870.5100 Bacterial reverse gene

mutation assay MRID 00141691 (1984) Acceptable/Guideline There was no increase in mutant colonies in tested bacterial strains exposed up to the limit dose (5000 μg/plate) with or without S9 activation.

870.5100 Bacterial reverse gene

mutation assay MRID 00141690 (1984) Acceptable/Non

- Guideline There was no increase in mutant colonies in any S. typhimurium or E. coli tested strain exposed to tebuthiuron (98.0 %) with or without metabolic

activation. There was no evidence of induced mutant colonies over background in tested S. typhimurium

strains and E. coli strains with or without S9

ac tivation.

870.5300 In vitro mammalian

cell gene mutation MRID 00145041 (1984) Acceptable/Guideline In a mammalian cell gene mutation assay in vitro, cultures of mouse lymphoma were exposed to Tebuthiuron (98.0%) technical at concentrations

limited by cytotoxicity. Mutations were not induced at any concentration with S9

- activation. Tebuthiuron was considered weakly mutagenic but only in the absence

of metabolic activation. No evidence of an increased mutant frequency was observed in the presenc e of

metabolic activation.

870.5550 Unscheduled DNA

synthesis in

mammalian cell

culture MRID 40750901 (1988) Acceptable/Guideline In an unscheduled DNA synthesis (UDS) assay, pri

mary rat hepatocyte cultures were exposed to Tebuthiuron (99.1 %) to the limit of cytotoxicity

(  900 μg/mL). UDS activity was evaluated at concentrations up to 800 μg/mL and there was no

evidence of induction of UDS. There was no evidence

that UDS, as determined by radioactive tracer procedures [nuclear silver grain counts] was induced.

870.5375 In vitro mammalian

cell chromosome

aberration MRID 41134101 (1989) Acceptable/Guideline In a mammalian chromosome aberration assay,

Chinese Hamster Ovary (CHO) cell cultures were exposed to Tebuthiuron (99.08%) at concen trations limited by cytotoxicity. A significant increase in the percent of cells with aberrations was noted in nonactivated and activated cultures at cytotoxic doses. The predominant types of aberrations were chromosome and chromatid breaks. No significant increases were observed at lower concentrations; however, rare complex aberrations, such as triradials, quadriradials and complex rearrangements were noted, providing further suppor t for clastogenicity. Positive control values were acceptable. There was evidence of

an increase in structural chromosomal aberrations over background in the presence and absence of metabolic activation at cytotoxic doses.

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 35 of 57 Table A2: Tebuthiuron Toxicity Profile

Guideline No. Study Type MRID No. (year)/ Classification

/Doses Results

870.5915 In vivo sister

chromatid exchange MRID 40750902 (1988) Acceptable/Guideline In an in vivo cytogenetic assay measuring sister chromatid exchange (SCE) frequency in Chinese

hamster bone marrow cells female Chinese hamsters (3/group) were administered single oral doses o f tebuthiuron (99.1%, Lot No. 729AS7) in 10% aqueous acacia at 3000, 4000, or 5000 mg/kg.

Tebuthiuron was tested up to cytotoxic concentrations. Hypo

- activity was noted in all treatment groups and bone marrow cytotoxicity (as evidenced by an increase

i n the percent division metaphases) was observed at 5000 mg/kg. There was no increase in the number of cells containing SCEs compared to controls at any

concentration of tebuthiuron tested. Cyclophosphamide (50 mg/kg) and vehicle control values were accep table. There was no evidence of an increase in SCEs over background.



### A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRf D) (Females 13

- 49 years old)

Study Selected: Developmental Toxicity in rabbits

MRIDs: 00020644 and 40776301 Dose and Endpoint for Risk Assessment : NOAEL= 10 mg/kg/day increased resorptions at LOAEL of 25 mg/kg/day. Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA Safety Factor ) Comments on Study/ Endpoint/Uncertainty Factors : This study is considered to be the most appropriate for acute dietary dose and endpoint selection. Unlike the increased resorptions, the fetal body weight reductions at 25 mg/kg/day, were no considered to be an acute effect. Thus, the basis for the acute dietary risk assessment for females of reproductive age is the resorptions. Note: No endpoint was selected for the general population. The endpoint from the developmental rabbit study for females 13

- 49 would be protective of any clinical signs seen at much higher doses in the acute oral toxicity study in rats.

Acute RfD = = 0.1 mg/kg/day



### A.3.2 Chronic Reference Dose (cRfD)

Study Selected: 2

- Generation Reproduction Study in Rats

MRIDs: 00090108 Dose and Endpoint for Risk Assessment : Parental NOAEL= 14 mg/kg/day. Parental LOAEL = 26 mg/kg/day, based on decreased body weights in F1 females (13%).

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 36 of 57 Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA Safety Factor ) Comments on Study/Endpoint/Uncertainty Factors : The 2

- generation reproduction study in rats is appropriate for both the population of concern (adults) and the duration of exposure.

Chronic RfD = = 0. 14 mg/kg/day



### A.3.3 Incidental Oral Exposure (Short

- term, 1

- 30 days)

Study Selected: 2

- Generation Reproduction Toxicity Study in Rats

MRIDs: 00090108 Dose and Endpoint for Risk Assessment : Offspring NOAEL= 14 mg/kg/day based on decreased pup body weights on PND 21 in the F1 and F2 generation (5

- 8 %) at the LOAEL of 26 mg/kg/day

. Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA Safety Factor )

Comments on Study/Endpoint/Uncertainty Factors: The endpoint of concern in this study is appropriate for the population (infant and children) and the duration of concern.

A.3. 4

. Dermal Exposure (Short

- , Intermediate

- Term) (Based on e

- review post

- ToxSAC meeting)

Study Selected: 2

- Generation Reproduction Toxicity Study in Rats

MRIDs: 00090108 Dose and Endpoint for Risk Assessment : Offspring NOAEL= 14 mg/kg/day based on decreased pup body weights on PND 21 in the F1 and F2 generation (5

- 8 %) at the LOAEL of 26 mg/kg/day

. Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA Safety Factor )

Comments on Study/Endpoint/Uncertainty Factors: A dermal risk assessment is being conducted for the following reasons 1) physical properties of the chemical suppor t the potential for dermal absorption and 2) resorptions observed in the developmental toxicity study occurred in the absence of other maternal effects, and therefore, use of the dermal toxicity study which does not test pregnant animals may be under

- prote ctive as resorptions are not measured. The 2

- generation reproductive toxicity study with a NOAEL of 14 mg/kg was selected a s the NOAELs and LOAELs are similar (10/14 mg/kg and 25/26 mg/kg), the 14 mg/kg/day NOAEL represents a smaller dose spread between th e NOAEL/LOAEL of both studies, and is protective of both the developmental effects observed in the rabbit and offspring effects in pups. There is no proposed long

- term use; therefore, risk assessment for long

- term dermal exposure is not required.

A.3.5 I nhalation Exposure (Short

- , and Intermediate

- Term) (Based on e

- review post ToxSAC meeting)

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 37 of 57 Study Selected: 2

- Generation Reproduction Toxicity Study in Rats

MRIDs: 00090108 Dose and Endpoint for Risk Assessment : Offspring NOAEL= 14 mg/kg/day based on decreased pup body weights on PND 21 in the F1 and F2 generation (5

- 8 %) at the LOAEL of 26 mg/kg/day

. Uncertainty Factor: 100 0 x (10x interspecies extrapolation, 10x intraspecies variability, 10x database uncertainty (inhalation study required by HASPOC), 1 x FQPA Safety Factor )

.

Comments on Study/Endpoint/Uncertainty Factors: No route

- specific inhalation study is

available for tebuthiuron

. The 2

- generation reproductive toxicity study with a NOAEL of 14 mg/kg was selected as it is protective of both developm ental effects in rabbits and offspring

effects observed in the rats. T here is no proposed long

- term use; therefore, risk assessment for long

- term inhalation exposure is not required.

A.4 Executive Summaries

A.4.1 Subchronic Toxicity

870.3100 90

- Day Oral Toxicity

- Rat

The NOEL is 1000 ppm (50 mg/kg) in the diet based on increased relative liver, kidney, prostate, spleen and gonad weights in high

- dose males and females. There was also slight vacuolization of the pancreatic acinar cells in the high

- dos e group of both sexes.

Classification: CORE

- Minimum data.

870.3150 90

- Day Oral Toxicity

– Dog

Anorexia was noted especially in the high

- dose animals, leading to weight loss. No mortality was observed. Behavior and appearance were unremarkable. No abn ormalities were observed in hematological or urinalysis studies.

Clinical chemistry findings indicated increased BUN in the 2000 ppm females; in addition, this group exhibited increasing levels of ALP, up to 4

- fold over the control group. Females at 1000 ppm demonstrated increased relative thyroid and spleen weights.

The LOAEL is 50 mg/kg/day based on significant decreases in body weight and increased ALP activity. The NOAEL is 25 mg/kg/day.

870.3200 21/28

- Day Dermal Toxicity

– Rat

No effects we re observed up to the limit dose.

A.4.2 Prenatal Developmental Toxicity

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 38 of 57 870.3700a Prenatal Developmental Toxicity Study

– Rat

In a developmental toxicity study (MRID 00020803, 40485801), 25 presumed pregnant Harlan rats per group were administered tebu thiuron (purity not given; Lot No. 1093

- 316A

- 259) at dietary concentrations of 0, 600, 1200, or 1800 ppm on gestation days (GD) 6

- 15, inclusive. Doses to the animals were 0, 37, 72, or 110 mg/kg/day, respectively. Individual data for maternal body weight s and food consumption, cesarean parameters, and fetal examinations were given in MRID 40485801. On GD 20, dams were sacrificed and subjected to gross necropsy; pancreatic tissue was saved from 10 females/group for histopathological examination. Fetal se x, weight, and viability were determined and each fetus was examined for external abnormalities. Approximately one

- third of all fetuses were fixed in Bouin’s solution for subsequent visceral

examination and the remainders were cleared for skeletal examina tion.

All dams survived to terminal sacrifice. No treatment

- related clinical signs of toxicity, changes in body weight, body weight gain, or food consumption were observed in any group. No

treatment

- related lesions were observed in any dam at necropsy. Pancreatic tissue, as evaluated by both gross and microscopic examination, appeared normal.

The maternal NOAEL is 110 mg/kg bw/day.

No differences were observed between the treated and control groups for pregnancy rate, number of corpora lutea/dam, num ber of implantation sites/dam, pre

- or post

- implantation losses, number of fetuses/litter, fetal body weights, or fetal sex ratios. No dead fetuses were observed. No

treatment

- related abnormalities were found in any fetus.

The developmental NOAEL is 11 0 mg/kg bw/day.

This study is classified as Acceptable/Guideline and satisfies the requirements for a developmental toxicity study [870.3700 (§83

- 3a)] in rats. It should be noted that test article concentrations in the diets were not measured; therefore, it may be possible that the doses to the

animals were different from nominal.

870.3700b Prenatal Developmental Toxicity Study

– Rabbit

In a developmental toxicity study (MRID 00020644, 40776301, 41122401), 15 presumed pregnant Dutch belted rabbits per group were administered tebuthiuron (96.5% a.i.; Lot No.:

B30

- 23

- 149) by gavage at doses of 0, 10, or 25 mg/kg/day on gestation days (GD) 6

- 18,

inclusive.

No clinical signs of toxicity were observed in any animal. No effects on body weights, body weight changes, or food consumption were noted for the treated groups as compared with the

controls. No treatment

- related lesions were found at gross necropsy. An increase in total early resorptions and the percentage of litters with early resorptions was observed in the high

- dose

group.

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 39 of 57 The maternal toxicity LOAEL is 25 mg/kg/day based on increased resorptions at the high

dose. The NOAEL is 1 0 mg/kg/day.

No differences between the treated and control groups were noted for pregnancy rate or numbers of corpora lutea, implantations, or fetuses/litter. A decrease in the mean fetal body weight was observed at 25 mg/kg/day (17.3%). An increase in t otal early resorptions and the percentage of litters with early resorptions was observed in the high

- dose group. Additionally, an increase in early resorptions was indicated in the range

- finding study at doses of 25 mg/kg/day and above.

The developmental toxicity LOAEL is 25 mg/kg/day based on decreased fetal body weights and increased early resorptions. The developmental toxicity NOAEL is 10 mg/kg/day.

The developmental toxicity study in the rabbit is classified Acceptable/Guideline and satisfies

the guideline requirement for a developmental toxicity stud y (OPPTS 870.3700; OECD 414) in

the rabbit.

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects

– Rat

In a two

- generation reproduction study (MRID 90108), tebuthiuron (Lot No. 00880

- 1L

- 1, X

35920, 98.0% a.i.) was fed to groups of 25 male and 25 female Wistar rats per dose at dietary concentrations of 0, 100, 200, and 400 ppm. The dietary levels corresponded to doses of 6

- 7, 13

- 14, and 26

- 28 mg/kg/day, respectively, for F 0 

### and F 1 

### males and 7

- 8, 14

- 15, and 30

- 31 mg/kg/day, respectively, for F 0 

### and F 1 

### females averaged over the premating period only. Adult rats of both generation were fed the treated or control diets during the premating period (98 days

for F 0 

### and 124 days for F 1 

### rats) and during mating, gestation, and lactation of two litters per generation. Pups from the F 1a 

### litters were selected to parent the F 2 

### generation.

No treatment

- related deaths, clinical signs of toxicity, gross lesions, or microscopic lesions were

obse rved in adult rats of either generation. No treatment

- related effects were observed on body weight, body weight gain, food consumption, or food efficiency in F 0 

### male rats, F 1 

### male rats, or

F 0 

### female rats fed any dose at any time during the study including the premating, mating, gestation, and lactation periods. F 1 

### females in the 200 and 400 ppm groups had mean weekly body weights 7

- 9% (not biologically significant) and 8

- 13% (p<0.01 or <0.05), respectively, less than the control group throughout the prema ting period starting with day 21 for the 200 ppm group and day 7 for the 400 ppm group. Weight gain over the entire premating period was 7% (N.S.) less than controls for 200 ppm group F 1 

### females and 14% (p<0.05) less for the 400 ppm group. Cumulative foo d consumption was not significantly affected, but food efficiency was reduced by 13% (p<0.01) for 400 ppm group F 1 

### females. It is important to note that the body weight decreases of F1 parents occurred only at the high

- dose where F1 pups had impaired body weight gain. Throughout the database, adult rat body weight impairment does not begin until doses 3 to 4 fold higher than administered in this study.

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 40 of 57 The parental systemic LOAEL was established at 400 ppm (26 mg/kg/day) based on

dec r eases in body weight and weight gain in F1 female rats. The parental systemic NOAEL was established at 200 ppm (14 mg/kg/day).

No effects were observed on reproductive parameters as measured by sperm morphology, fertility index for females, and the numb er of litters produced.

The reproductive LOAEL was not established; the NOAEL was established at 400 ppm (26 mg/kg/day)

.

Biologically significant decreases in pup body weights (5

- 8%) were observed on PND 7

- 21 in

the F1 and F2 litters.

The offspring LOA EL was established at 400 ppm (26 mg/kg/day) based on decrease pup body weights on PND 7

- 21. The offspring NOAEL was established at 200 ppm (14 mg/kg/day).

This study is classified Acceptable/Guideline and satisfies the guideline requirement for a two

ge neration reproductive study (OPPTS 870.3800, §83

- 4) in the rat. This study was conducted years before the test guidelines were established; therefore, some of the elements of a two

generation reproduction study were not included in this study. Neverthele ss, this study had a sufficient number of required elements to be used for the evaluation of reproductive and offspring toxicity. The reviewer notes that the rats could have tolerated a higher dose, which may

have allowed for better characterization of teb uthiuron toxicity to developing rats.

A.4.4 Chronic Toxicity

870.4 100b Chronic Toxicity

– Dog

All animals survived to scheduled termination. Clinical signs of toxicity in high

- dose animals included anorexia, emesis, and diarrhea. Absolute body weight s for females and food consumption for males and females were not affected by treatment. Body weights of the high

dose males were less than those of the controls throughout most of the study with statistical significance attained occasionally. Overall we ight gains by the high

- dose males and females were 67% and 82%, respectively, of the control levels. No treatment

- related ophthalmological lesions, changes in urinalysis parameters, or microscopic lesions were noted and gross necropsy

was unremarkable.

T hrombocyte counts were significantly (p  0.05) increased in high

- dose males at 6 and 12 months as compared with the controls. Alanine aminotransferase (ALT) levels were increased in

males after 1 month and in females after 3 months to 186

- 529% and 228

- 40 7%, respectively, of the control group levels. In addition, alkaline phosphatase (AP) levels in males were increased

to 283

- 408% of the control levels at 6 and 12 months. Statistical significance was not attain ed at

all

- time points for the increases in e nzyme levels due to large variability between individual

animals.

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 41 of 57 Absolute liver weights were significantly (p  0.05) increased in the high

- dose males and females. No other differences in absolute organ weights were found. Also for the high

- dose groups, significant (p  0.05) differences in organ weights relative to final body weight included

increased relative l iver weights in males and females, increased relative kidney weights in females, and increased relative thyroid weights in males.

The LOAEL was established at 50 mg/kg/day based on clinical signs (anorexia, emesis, and diarrhea), decreased body weight ga ins, increased alanine aminotransferase and alkaline phosphatase (males only) levels, increased absolute and relative liver weights, increased relative kidney weights (females only), and increased relative thyroid weights (males only).

The NOAEL was estab lished at 25 mg/kg/day.

This study is classified as Acceptable/Guideline and satisfies the guideline requirements for a chronic toxicity study [OPPTS 870.4100 (83

- 1b)] in dogs.

A.4.5 Carcinogenicity

870.4300a Combined Chronic Toxicity/Carcinogenicity

– Rat

In a chronic toxicity/carcinogenicity study (MRID 0020714), tebuthiuron (>97% a.i., lot number,

6SG43 and B30

- 23

- 149 ) was administered to male and female Wistar rats (40/group/sex) at dietary concentrations of 400, 800, or 1600 ppm (20, 40, and 80 mg/ kg/day, based on the default food factor of 0.05). Two control groups of 60 male and 60 female Wistar rats administered untreated basal diet. No interim sacrifice was conducted for this study. Two replicate studies

were carried out.

No treatment

- relate d effects were reported for clinical signs, mortality, or clinical pathology in male or female rats receiving any dose of the test material. The mortality rate for all groups was high. During the first year of treatment, 10

- 19% of males died while at the end on the study, only 26% of all rats remained alive. Pneumonia affected the majority of animals in all groups at various times during the study; antibiotic treatment was required during one episode. Absolute body weights presented graphically indicat ed that high

- dose males and females weighed less than controls throughout most of the study. The magnitude of the reduction in absolute body weight could not be determined for assessment of statistical or toxicological significance. A

15% reduction in bo dy weight in high

- dose females was observed at study termination. Food consumption was measured but not reported.

Relative kidney weights were depressed in high

- dose male rats, but no histopathological correlates were observed. Each animal was necrops ied, but gross findings were not tabulated. Vacuolization of pancreatic acinar cells (generally slight or affecting only a few cells) was observed in 11 males and 13 females receiving the high

- dose and in none of the controls of either sex. Only selecte d histopathological data were presented in the summary tables of the study report; therefore, a complete assessment of histopathological findings could not be conducted.

No treatment

- related neoplasms were reported; common neoplasms included pituitary ade nomas and mammary fibro adenomas in female rats. The microscopic findings in the pancreatic acinar

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 42 of 57 cells were generally slight, affected only a few cells, and caused no physiological effect on glucose levels.

Based on the results of this study (decreased terminal body weight in females), the LOAEL for systemic toxicity was established at 80 mg/kg/day ; a LOAEL was not established in males. The NOAEL was established at 40 mg/kg/day in females at 80 mg/k/day in females.

This chronic toxicity/carcinogenicit y study in the rat is Unacceptable/Guideline and does not satisfy the guideline requirement for a chronic toxicity/carcinogenicity oral study [OPPTS 870.4300 (§83

- 5)] in the rat. There were numerous deficiencies in this study. The major

deficiencies are l isted as follows:

 The mortality rate for all groups was high, leaving only 25% or fewer animals in some groups out of an initial number of at least 80 per group.

 Respiratory infections were very prevalent in all groups and may have affected the

outcome of the study.

 Summary tables were not available for clinical signs, body weights, body weight gains, food consumption, urinalysis data, and gross findings.

 Summary tables for microscopic findings were not complete, contained errors, and did

not include the n umber of animals examined at each anatomical site.

 The data were not analyzed statistically.

 The evidence suggests that this study does not comply with GLP procedures.

870.4200b Ca rcinogenicity (feeding)

– Mouse

In a carcinogenicity study (MRID 00020717) Tebuthiuron (>97% a.i., lot # B30

- 23

- 149) was administered to groups of 80 Harlan ICR mice/sex/dose in pelleted diet at dose levels of 400, 800, or 1600 ppm (equivalent to 60, 120, or 240 mg/kg/day based on the de fault food factor of 0.15) for 2 years. The control group, consisting of 120 males and 120 females was fed untreated pelleted diet. Animals were equally subdivided by dose and sex into two sub

- studies; the second

sub

- study was started 1 week after the fi rst. It should be noted that animals were not assigned by body weight.

Although there was a statistically significant decrease (32.4 g, 12%) in the terminal body weights of high

- dose females in one of the sub

- studies (M9153), this is likely due to the h igher body weight (36.7 g) of the control females in this sub

- study. The terminal body weight of the control

females in the other sub

- study was 34.1 g.

There were no compound related effects on mortality, clinical signs, hematology or clinical chemistry, organ weights, or gross or microscopic pathology.

The LOAEL for systemic toxicity was not established. The NOAEL was established at 1600 ppm (240 mg/kg/day).

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 43 of 57 At the doses tested, there was no treatment related increase in tumor incidence when

compare d to that of controls. Dosing was not considered adequate based on the absence of systemic effects.

This carcinogenicity study in the mouse is Unacceptable/Guideline and does not satisfy guideline requirements for a carcinogenicity study [OPPTS 870.4200; OECD 451] in mice.

A.4.6 Mutagenicity

Table A.4.6: Tebuthiuron Mutagenicity Studies

Study Results

870.5100 Bacterial reverse gene mutation

assay There was no increase in mutant frequency in tested bacterial strains exposed up to the limit dose (5000 μg/plate) with or without S9 activation.

870.5100 Bacterial reverse gene mutation

assay There was no increase in mutant frequency in any S. typhimurium or E. coli tested

strain ex posed to tebuthiuron (98.0% ) with or without metabolic activation. There was no evidence of induced mutant colonies over background in tested S. typhimurium

strains and E. coli strains with or without S9 activation.

870.5300

In vitro mammalian cell gene

mutation In a mammalian cell gene mutation assay in vitro, cultures of mouse lymphoma were exposed to Tebuthiuron (98.0%) technical at concentrations limited by cytotoxicity. Mutations were not induced at any concentration with activation. Tebuthiuron was considered weakly mut agenic but only in the absence of metabolic activation. No evidence of an increased mutant frequency was observed in the presence of metabolic

activation.

870.5550 Unscheduled DNA synthesis in

mammalian cell culture In an unscheduled DNA synthesis ass ay, pri mary rat hepatocyte cultures wer e exposed
to Tebuthiuron (99.1% ) to the limit of cytotoxicity (  900 μg/mL). UDS activity was evaluated at concentrations up to 800 μg/mL and there was no evidence of induction

of UDS. There was no evidence that uns cheduled DNA synthesis, as determined by radioactive tracer procedures [nuclear silver grain counts] was induced.

870.5375

In vitro mammalian cell

chromosome aberration In a mammalian chromosome aberration assay, Chinese Hamster Ovary (CHO) cell cultures were exposed to Tebuthiuron (99.08%) at concentrations limited by cytotoxicity. A significant increase in the percent of cells with aberrations was noted

in nonactivated and activated cultures at cytotoxic doses. The predominant types of aberrations were chromosome and chromatid breaks. No significant increases were observed at lower concentrations; however, rare complex aberrations, such as triradials, quadriradials and complex rearrangements were noted, providing further support for clastogenicity. Positive control values were acceptable. There was evidence of an increase in structural chromosomal aberrations over background in the presence and absence of metabolic act ivation at cytotoxic doses.

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 44 of 57 870.5915

In vivo sister chromatid exchange In an in vivo cytogenetic assay measuring sister chromatid exchange (SCE) frequency in Chinese hamster bone marrow cells female Chinese hamsters (3/group) were administered single oral doses of tebuthiuron (99.1%, Lot No. 729AS7) in 10% aqueous acacia at 3000, 4000, or 5000 mg/kg.

Tebuthiuron was tested up to cytotoxic concentrations. Hypo

- activity was noted in all treatment groups and bone marrow cytotoxicity (as evidenced by an increase in the percent division metaphases) was observed at 5000 mg/kg. There was no increase in the number of cells containing SCEs compared to controls at any concentration of tebuthiuron tested. Cyclophosphamide (50 mg/kg) and vehicle control values were acceptable. There was no evidence of an increase in SCEs over backg round.



### A.4.7 Neurotoxicity

870.6200 Acute Neurotoxicity Screening Battery

- Rat

Waived by HASPOC.

870.6200 Subchronic Neurotoxicity Screening Battery

- Rat

Waived by HASPOC.

A.4.8 Metabolism

870.7485 Metabolism

– Rat

Terminal distribution data showed no significant amounts of residual radioactivity in any tissue examined, but the skin showed the highest amounts relative to other tissues. Excretion was rapid at both the low and high dose levels in both sexes, but was delayed during the first 12 hours post

dose, indicating saturation of biotransformation or excretion. Six metabolites of tebuthiuron were identified. The major metabolite in 0

- 24 hour urine of male (58.3%) and female (62.1%) rats was identified as hydroxylated tebuthiuron metabolit es (109

- OH and /or 104

- OH). The

second most abundant metabolite was identified as metabolite 106 of tebuthiuron. This comprised between 9

- 15% of the administered dose in 0

- 24 hour urine of low dose rats, and

between 1

- 10% of the administered dose in high dose rats. Two other metabolites identified,

104/109 and 103

- OH, comprised between 2

- 10% of the administered dose in male and female 0

- 24 hour urine. Feces contained minor amounts of 104

- OH and 109

- OH, accounting for an average of 3.5% of the administered dose.

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 45 of 57 A .4.9 Immunotoxicity

870.7800 Immunotoxicity

- Rat

In an immunotoxicity study (MRID #48722705 ), Tebuthiuron (99.8 % a.i

., Lot no. EQ 4821, TSN 100583) was administered to female Crl: WI ( Han) (10 /dose) in the diet at dose levels of 0,

40 0, 100 0, or 200 0 ppm (equivalent to 0, 33.8

, 8 4 .9

, and 1 48 mg/kg/day, respectively) for 29 days. T he positive control group (10 females) was administered 20 mg/kg bw/day of cyclophosphamide (10 mL/kg at a concentration of 5 mg/mL) by intraperitoneal injection from study Days 24

- 28. During the study, clinical condition, bodyweight, food and water consumption, organ weight, and macroscopic pathology were evaluated. On the study Day 24

, all animals in all grou ps received a single intravenous dose of sheep red blood cells (SRBC) ( 4 x

10 8 

### SRBC/mL, 0.5 mL/animal). At sacrifice , selected organs were removed and weighed ( kidney, liver, spleen and thymus). The anti

- SRBC IgM response was measured with Enzyme

Linked Immunosorbent A ssay (ELISA)

.

There were no premature deaths and no treatment

- related effects on clinical signs. Animals in 2000 or 1000 ppm groups had treatment

- related decreases in body weight, body weight gain and food consumption throughout the study. Animals in 2000 ppm group also had treatment related consistently higher reticulocyte counts than the control. There were statistically significant decreased in absolute and relative thymus weights; statistically significant increased relative liver weights; and statistically significant decreased in absolu te kidney and spleen weights in this group. P ositive control group treated with cyclophosphamide had statisticall y significant

decreased in absolute and relative spleen an d thymus weights. There was lower body weight gain from study Day 22

- 29, when compa red to the vehicle control group; however, it was not statistically significant.

The systemic LOAEL was 1000 ppm (equivalent to 84.9 mg/kg/day ) based on decreased body weight and body weight gain

. The systemic NOAEL was 400 ppm (equivalent to 33.8 mg/ kg/day ).

There were no statistically significant dif ferences observed in anti

- SRBC IgM levels in treated groups when compare to the vehicle control group. High inter

- individual variability was noted in all the treatment groups as well as in the control g roup. Evaluation of the individual animal data of this study did not show any trend or distribution that would demonstrate significant suppression of anti

- SRBC antibody response. Positive control group had statistically significant

d ecrease in the anti SR BC IgM levels. This confirmed the ability of the test system to detect

immuno

- suppressive effects and confirmed the validity of the study design.

The Natural Killer (NK) cells activity was not evaluated in this study. The toxicology database

for tebuthiu ron does not reveal any evidence of immunotoxicity. The overall weight of evidence suggests that the chemical does not directly target the immune system. Under HED guidance a NK cell activity assay is not required at this time.

The NOAEL for immunoto xic ity was 2000 ppm (equivalent to 148 mg/kg/day ), the highest

dose tested

. The immunotoxicity LOAEL was not established.

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 46 of 57 This immunotoxicity study is classified acceptable /guideline and satisfy the guideline requirement for an immunotox icity study (OPPTS 870.7800) in rats

.

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 47 of 57 Appendix B

. Physical/Chemical Properties

Table B 1: Chemical Identity of Tebuthiuron

Common Name Tebuthiuron

Chemical Name N

- [5

- (1,1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- y1] N,N ’dimethyl urea

IUPAC 1

- (5

- tert

- butyl

- 1,3,4

- thiadiazol

- 2

- yl)

- 1,3

- dimethylurea

PC Code 105501

Chemical Abstracts Number 34014

- 18

- 1

Registration Review Case Number 0054

Chemical Structure

Table B 2: Physico

- Chemical Properties for Tebuthiuron

Parameter Value Reference

Molecular Weight 228.3 PubChem

Melting point/range 161 oC at 760 mm Hg

D256269, A. Smith, 06/29/1999

WSSA Herbicide Handbook

Committee. Herbicide Handbook of the Weed Science Society of America, 6th Ed. WSSA, Champaign,

IL. 1989. pH NA: Solid at 25 oC

Water solubility 2.5 mg/mL

Solvent solubility (g/100mL) 25.0 in chloroform 0.37 in benzene

17.0 in methanol 7.0 in acetone

0.61 in hexane 6.0 in acetonitrile

Vapor pressure 2 x 10

- 6 mm Hg at 25 degrees Celsius

Chemical class/use Herbicide Urea carbamate

Soil Half

- life 12 to 15 months w/40 in rainfall 1996 EXTOXNET

Partition

- coefficient in n

octanol / water K ow = log P 1.8 ; pH=7 at 25 C MSDS

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 48 of 57 Table B3: Summary of Metabolites and Degradates to be Included in the Risk Assessment and Tolerance Expression Followed by Chemical Structures in Figure A.

Matrix

Plants Primary

Crop Combi ned residues of the herbicide tebuthiuron ( 103): (N

- (5

- (1,1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- yl)

-

N,N'

- dimethylurea) and its metabolites

, 103(OH ): N

- (5

- (2

- hydroxy

- 1,1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- yl)

- N,N'

- dimethylurea, 104: N

- (5

- (1,1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- yl)

- N

- methylurea, and 109: N

- (5

- (1,1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- yl)

- N'

- hydroxymethyl

- N

- methylurea.

Livestock Ruminant Combined residues of the herbicide tebuthiuron (103): (N

- (5

- (1,1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- yl)

- N,N'

- dimethylurea) and its metabolites 104: N

- (5

- (1,1

- dimethyl ethyl)

- 1,3,4

- thiadiazol

- 2

- yl)

- N

- methyl

- urea, 106: N

- (5

- (1,1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- yl)urea, 108: 2

- dimethylethyl

- 5

- amino

- 1,3,4

- thiadiazole,

and 109: N

- (5

- (1,1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- yl)

- N'

- hydroxymethyl

- N

- methylurea.

Milk Combined residues of the herbicide tebuthiuron (103): (N

- (5

- (1,1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- yl)

- N,N'

- dimethylurea) and its metabolites 104: N

- (5

- (1,1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- yl)

- N

- methyl

- urea, 104 (OH): N

- (5

- (2

- hydroxy

- 1,1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- yl)

- N

- methylurea, 106: N

- (5

- (1,1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- yl)urea, 109: N

- (5

- (1,1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- yl)

- N'

- hydroxymethyl

- N

- methylurea, and 109 (OH): N

- (5

- (2

- hydroxy

- 1,1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- yl)

- N'

- hy droxymethyl

- N

- methylurea

Drinking Water Combined residues of the herbicide tebuthiuron (103): (N

- (5

- (1 , 1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- yl)

- N,N'

- dimethylurea) and its metabolites 104 : N

- [5

- (1,1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- yl]

- N

- methy

- lurea.



### Table B.4:

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 49 of 57 The drinking water model s and their descriptions are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/. Table B5 : T ebuthiuron EDWCs for the Wisconsin Corn Scenario in Groundwater

Drinking Water

Source

(Model) Highest Daily Value

Acute Post Breakthrough average

Chro n ic Average simulation Breakthrough

Time

(μg/L) (μg/L ) (days)

Groundwater (PRZM

- GW) 2020 * 1740 2230

* A time series water residue distribution was used in the acute dietary assessment.

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 50 of 57 Appendix C . Residue Summary Table

Table C.1: International Residue Limits for Tebuthiuron (105501; 05

- NOV

- 2013)
Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 1 Codex

40 CFR 180.390

(a) General (1) combined residues of the herbicide tebuthiuron (N

- (5

- (1,1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- yl)

- N,N'

- dimethylurea) and its metabolites N

- (5

- (2

- hydroxy

- 1,1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- yl)

- N,N'

- dimethylurea, N

- (5

- (1,1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- yl)

- N

- methylurea, and N

- (5

- (1,1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- yl)

- N'

- hydroxymethyl

- N

- methylurea None None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 1 Codex Grass, forage 10.0 Grass, hay 10.0 (2) combined residues of the herbicide tebuthiuron (N

- (5

- (1,1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- yl)

- N,N'

- dimethylurea) and its metabolites N

- (5

- (1,1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- yl)

- N

- methylurea, N

- (5

- (1,1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- yl)urea, 2

- dimethylethyl

- 5

- amino

- 1,3,4

- thiadiazole, and N

- (5

- (1,1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- yl)

- N'

- hydroxymethyl

- N

- methylurea None None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 1 Codex
Cattle, fat 1.0
Cattle, meat 1.0 Cattle, meat byproducts 5.0
Goat, fat 1.0
Goat, meat 1.0 Goat, meat byproducts 5.0
Horse, fat 1.0
Horse, meat 1.0 Horse, meat byproducts 5.0 Sheep, fat 1.0 Sheep, meat 1.0 Sheep, meat byproducts 5.0

US Canada Mexico 1 Codex (3) combined residues of the herbicide tebuthiuron (N

- (5

- (1,1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- yl)

- N,N'

- dimethylurea) and its metabolites N

- (5

- (1,1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- yl)

- N

- methylurea, N

- (5

- (2

- hydroxy

- 1,1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- y l)

- N

- methylurea, N

- (5

- (1,1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- yl)urea,

N

- (5

- (1,1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- yl)

- N'

- hydroxymethyl

- N

- methylurea,

and N

- (5

- (2

- hydroxy

- 1,1

- dimethylethyl)

- 1,3,4

- thiadiazol

- 2

- yl)

- N'

- hydroxymethyl

- N

methylurea None None

Co mmodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 1 Codex

Milk 0.8 Completed: M. Negussie; 11/05/2013

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 51 of 57 Appendix D

. Spray Drift

Table D. 1 : Adult Risk Estimates (MOEs) Related to Indirect Exposure to Spray Drift for Tebuthiuron for the Dermal Route of Exposure

Crop/Rate Group Spray Type/

Nozzle Configuration Applicatio

n Rate (lb ai/A) Estimate

d or Adjusted

TTR (ug/cm2) At

Edge 10

Feet 25

Feet 50

Feet 75

Feet 100

Feet 125

Feet 150

Feet 200

Feet 250

Feet 300 Feet

Dermal

MOE Dermal

MOE Dermal

MOE Dermal

MOE Dermal

MOE Dermal

MOE Dermal

MOE Dermal

MOE Dermal

MOE Dermal

MOE Dermal

MOE

Pastureland

Aerial Fine to

Medium

4 0.4446 36 45 55 72 95 120 150 170 230 270 330

Medium to

Coarse 44 60 81 110 160 210 270 320 440 580 720

Coarse to Very

Coarse 51 75 110 180 250 330 420 520 720 930 1,200

AT401, M, 10 mph, 37% SD 40 51 66 89 120 60 190 220 290 360 440

WASP, M, 10 mph, 37% SD 43 55 72 110 150 190 230 270 360 440 520

AT401, C, 10 mph, 25% SD 47 66 94 140 200 260 320 390 550 720 850

WASP, C, 10 mph, 25% SD 55 77 110 180 250 330 410 520 720 930 1,000

AT401, VC, 10 mph, 20% SD 53 81 130 210 300 410 520 670 930 1,200 1,600

WASP, VC, 10 mph, 20% SD 68 110 160 260 370 490 670 780 1,200 1,300 1,600

Groundboom High Boom

Fine to

Medium/Coarse 190 490 720 1,000 1,300 1,600 1,900 1,900 2,300 3,100 3,100

Low Boom

Fine to

Medium/Coarse 280 780 1,200 1,600 1,900 2,300 3,100 3,100 4,700 4,700 4,700

High Boom

Fine to

Medium/Coarse 6 0.6669 130 330 480 690 890 1,000 1,200 1,200 1,600 2,100 2,100

Low Boom

Fine to

Medium/Coarse 190 520 780 1,000 1,200 1,600 2,100 2,100 3,100 3,100 3,100

1. The AT401 is the representative fixed wing aircraft and the WASP is the representative helicopter

.

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 52 of 57 Table D.2: Children (1<2 years old) Risk Estimates (MOEs) Related to Indirect Exposure to Spray Drift for Tebuthiuron for the Combined D ermal and Oral Routes of Exposure

Crop/Rate Group Spray Type/

N ozzle Configuration Appli

cation

Rate (lb ai/A) Estimated

or Adjusted

TTR t (ug/cm2) At

Edge 10 Feet 25 Feet 50 Feet 75 Feet 100 Feet 125 Feet 150 Feet 200 Feet 250 Feet 300 Feet

Combin

ed

MOE Combine

d MOE Combine

d MOE Combine

d MOE Combine

d MOE Combine

d MOE Combine

d MOE Combine

d MOE Combine

d MOE Combine

d MOE Combine

d MOE

Pastureland

Aerial Fine to

Medium

4 0.4446 18 22 27 36 47 61 73 86 110 140 160

Medium to

Coarse 22 30 40 56 80 100 130 160 220 290 360 Coarse to Very

Coarse 25 37 56 87 120 160 210 260 360 460 580
AT401, M, 10 mph, 37% SD 20 25 33 44 59 77 94 110 140 180 220
WASP, M, 10 mph, 37% SD 21 27 36 54 73 94 120 140 180 220 260
AT401, C, 10 mph, 25% SD 23 33 47 69 98 130 160 190 270 360 420
WASP, C, 10 mph, 25% SD 27 38 55 87 120 160 200 260 360 460 510
AT401, VC, 10 mph, 20% SD 26 40 64 100 150 200 260 330 460 580 770
WASP, VC, 10 mph, 20% SD 33 52 81 130 180 240 330 380 580 660 770

Groundboom High Boom

Fine to

Medium/Coarse 94 240 360 510 660 770 920 920 1,200 1,500 1,500

Low Boom Fine

to
Medium/Coarse 140 380 580 770 920 1,200 1,500 1,500 2,300 2,300 2,300

High Boom

Fine to

Medium/Coarse 6 0.6669 63 160 240 340 440 510 620 620 770 1,000 1,000

Low Boom Fine

to
Medium/Coarse 93 260 380 510 620 770 1,000 1,000 1,500 1,500 1,500

1. The AT401 is the representative fixed wing aircraft and the WASP is the representative helicopter.

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 53 of 57 Appendix E

. Occupational Exposure Scenarios and Risk Estimates

Table E.1: Occupational Dermal Handler Non

- Cancer Exposure and Risk Estimates for Tebuthiuron

Exposure Scenario Crop / Target Category Application Rate 2 Amount

Handled / Area

Treated 3 Dermal Unit Exposures (ug/lb

ai) 1 Dermal Dose (mg/kg/day) 4 Dermal MOE 5

Formulation Application

Equipment Value Units Value Units SL/No

G SL/G DL/G EC SL/No

G SL/G DL/G EC SL/No

G SL/G DL/G EC

Mixer/Loader

DF/WDG Aerial Pastureland Rangeland 4

lb ai/A 1200

acres 227 51.6 41.2 9.8 13.6 3.1 2.48 0.59 1 4.5 5.6 24

Groundboom 200 227 51.6 41.2 9.8 2.28 0.52 0.41 0.1 6.1 27 34 140

Groundboom Non

- crop

land 6 200 227 51.6 41.2 9.8 3.4 0.77 0.62 0.15 4.1 18 23 95

P/G Aerial Pastureland Rangeland 4

1200 8.4 6.9 3.4 8.6 0.50 0.41 0.20 0.52 28 34 69 27

Non

- crop land 6 8.4 6.9 3.4 8.6 0.76 0.62 0.31 0.77 19 23 46 18

Tractor

- drawn spreader Pastureland

Rangeland 4

200 8.4 6.9 3.4 8.6 0.08 0.07 0.03 0.09 170 200 410 160

Non

cropland 6 8.4 6.9 3.4 8.6 0.13 0.10 0.05 0.13 110 130 270 110

Applicator

Spray Aerial Pastureland Rangeland 4

lb ai/A 1200

acres 2.08 0.13 110

Groundboom 200 78.6 16.1 12.6 5.1 0.79 0.161 0.126 0.05 18 87 110 270

Groundboom Non

- crop

land 6 200 78.6 16.1 12.6 5.1 1.18 0.24 0.19 0.08 12 58 74 180

P/G Aerial Pastureland Rangeland 4

1200 1.7 0.10 140

Non

- crop land 6 0.15 92

Tractor

- drawn Spreader Pastureland

Rangeland 4

200 9.9 7.2 4.2 2 0.1 0.072 0.04 0.02 140 190 330 700

Non

- crop land 6 9.9 7.2 4.2 2 0.15 0.11 0.06 0.03 94 130 220 470

Hand dispersal Non

- crop

land and Rights

- of

way 0.00014 lb ai/ft2 10,000 ft2 104000 71000 40280 1.83 1.24 0.71 7.7 11 20

Shaker can 112 11.2 11.2 0.002 0.0002 0.0002 7100 71000 71000

Flagger
Spray

Aerial Pastureland Rangeland 4 lb ai/A

350 acres 11 12 10.6 0.19 0.21 0.185 73 67 76

P/G 2.75 2.73 1.59 0.05 0.05 0.03 290 290 500

Non

- crop land 6 lb ai/A 2.75 2.73 1.59 0.072 0.07 0.04 190 200 330

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 54 of 57 Mixer/Loader/Applicator

DF/WDG Backpack

Non

- crop land and Rights

- of

way 1.6 lb ai/gallon 40 gallons 8260 8260 4120 6.61 6.61 3.3 2.1 2.1 4.2

Manually

pressurized

Handwand 100000 430 365 80 0.34 0.293 0.18 41 48

Mechanically

pressurized Handgun 1000 gallons 1300 390 290 26 7.8 5.8 0.54 1.8 2.4

P/G Belly grinder

6 lb ai/ A 1

acres 10000 9300 5700 0.75 0.7 0.43 19 20 33

Rotary spreader 5 440 240 130 0.17 0.09 0.05 85 160 290

Cup 0.00014 lb ai/ft2 10,000 ft2 112 11.2 11.2 0.002 0.0002 0.0002 7100 71000 71000

Spoon 4170 3030 1580 0.07 0.05 0.03 190 260 510

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (May 2013); Level of mitigation: Dermal baseline PPE includes no gloves, long sleeved shirt, long pants, socks plus shoes. The addition of gloves and double layer protec tion is included in the far right column for comparison. Eng. Controls (EC) assumes enclosed cockpits for the aerial and ground application of tebuthiuron for all formulations. Shaded out cells are not applicable to scenario or there is no dermal unit exp osure data

. 2 Based on registered labels (Table 3.2.1).

3 Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treate d or Amount Hand led Daily (A or gal/day) ÷ 80 (kg).

5 Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg/kg/day).

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 55 of 57 Table E.2: Occupational Inhalation Handler Non

- Cancer Exposure and Risk Estimates for Tebuthiuron

Exposure Scenario Crop / Target Category Application Rate 2 Amount

Handled / Area

Treated 3 Inhalation Unit Exposures

(ug/lb ai) 1 Inhalation Dose (mg/kg

- day) 4 Inhalation MOE 5

Formulation Application

Equipment Value Units Value Units No

R PF5

R PF10

R EC No

- R PF5 R PF10 R EC No

- R PF5 R PF10

R EC

Mixer/Loader

DF/WDG Aerial Pastureland Rangeland 4

lb ai/A 1200

acres 8.96 1.79 0.9 0.24 0.54 0.11 0.05 0.014 26 130 260 970

Groundboom 200 8.96 1.79 0.9 0.24 0.09 0.018 0.009 0.002 160 780 1600 5800

Groundboom Non

- crop

land 6 200 8.96 1.79 0.9 0.24 0.14 0.03 0.01 0.004 100 520 1000 3900

P/G Aerial Pastureland Rangeland 4

1200 1.7 0.34 0.17 0.08 0.10 0.02 0.010 0.005 140 690 1400 2800

Non

- crop land 6 1.7 0.34 0.17 0.08 0.15 0.03 0.02 0.01 92 460 920 1900

Tractor

- drawn Spreader Pastureland

Rangeland 4

200 1.7 0.34 0.17 0.08 0.02 0.003 0.002 0.0008 820 4100 8200 17000

Non

- crop land 6 1.7 0.34 0.17 0.08 0.03 0.01 0.002 0.001 550 2700 5500 11000

Applicator

Spray Aerial Pastureland Rangeland 4

lb ai/A 1200

acres 0.005 0.0003 48000

Groundboom 200 0.34 0.07 0.03 0.04 0.003 0.0007 0.0003 0.0004 4100 21000 41000 33000

Groundboom Non

- crop

land 6 200 0.34 0.07 0.03 0.04 0.005 0.001 0.0005 0.0006 2700 14000 27000 22000

P/G Aerial Pastureland Rangeland 4

1200 1.3 0.08 180

Non

- crop land 6 1.3 0.12 120

Tractor

- drawn Spreader Pastureland

Rangeland 4

200 1.2 0.24 0.12 0.22 0.01 0.002 0.001 0.002 1200 5800 12000 6400

Non

- crop land 6 1.2 0.24 0.12 0.22 0.02 0.004 0.002 0.003 780 3900 7800 4200

Hand dispersal Non crop

land and Rights

- of

way 0.00014 lb ai/ft2 10,000 ft2 470 94 47 0.008 0.002 0.0008 1700 8500 17000

Shaker can 12.5 2.5 1.25 0.0002 0.00004 0.00002 64000 320000 640000

Flagger

Spray

Aerial Pastureland Rangeland 4

lb ai/A 350 acres 0.35 0.07 0.04 0.006 0.001 0.0006 2300 11000 23000

P/G Pastureland Rangeland 4 0.15 0.03 0.02 0.004 0.001 0.0004 5300 27000 53000

Non

- crop land 6 0.15 0.03 0.02 0.004 0.001 0.0004 3600 18000 36000

Mixer/Loader/Applicator

DF/WDG Backpack 1.6 40 gallons 2.58 0.52 0.26 0.002 0.0004 0.0002 6800 34000 68000

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 56 of 57 Manually

pressurized

Handwand

Non

- crop

land and Rights

- of

way lb ai/gallon 30 6 3 0.02 0.005 0.002 580 2900 5800

Mechanically

pressurized Handgun 1000 gallons 3.9 0.78 0.39 0.08 0.02 0.01 180 900 1800

P/G Belly grinder

6 lb ai/A 1

acres 62 12.4 6.2 0.005 0.001 0.0005 3000 15000 30000

Rotary spreader 5 10 2 1 0.004 0.0008 0.0004 3700 19000 37000

Cup 0.00014 lb ai/ft2 10000 ft2 12.5 2.5 1.25 0.0002 0.00004 0.00002 64000 320000 640000 Spoon 121 24.2 12.1 0.002 0.0004 0.0002 6600 33000 66000

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (May 2013); Level of mitigation: Inhalation baseline PPE includes no respirator. The addition of PF5, PF10 respirators on handlers is included in the far right column for comparison. Eng. Controls included enclosed cockpits for the aerial application of tebu thiuron for all f ormulations. Shaded out cells are not applicable to scenario or there is no inhalation unit exposure data.

2 Based on registered labels (Table 3.2.1).

3 Exposure Science Advisory Council Policy #9.1.

4 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/da y) ÷ 80 (kg).

5 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

### Tebuthiuron Human Health Risk Assessment DP No. 414218

Page 57 of 57 Table E.3: Occupational Dermal and Inhalation Handler ARI Risk Estimates for Tebuthiuron 1
Exposure Scenario Crop / Target Category Application Rate 2 Amount Handled 3 ARI 4

Formulation application e quipment Value Units SL/No G

+ No

- R SL/G +

No

- R SL/G +

PF5 R DL/G +

PF5 R SL/G +

PF10 R DL/G

+ PF10

R EC

Mixer/Loader

DF/WD

G Aerial Pastureland/Rangeland 4 lb ai/A 1,200

acres 0.01 0.02 0.03 0.04 0.04 0.05 0.19

Groundboom 200 0.04 0.1 0.2 0.24 0.23 0.28 1.1

Groundboom Non

- crop land 6 lb ai/A 200 0.03 0.06 0.13 0.16 0.15 0.19 0.76

P/G Aerial Pastureland/Rangeland 4 lb ai/A 1,200 0.09 0.1 0.2 0.35 0.27 0.46 0.25

Non

- crop land 6 lb ai/A 0.06 0.07 0.15 0.23 0.18 0.31 0.16

Tractor

- drawn Spreader Pastureland/Rangeland 4 lb ai/A
200 0.55 0.58 1.3 2.1 1.6 2.7 1.5

Non

- crop land 6 lb ai/A 0.37 0.39 0.88 1.4 1.1 1.8 1

Applicator

Spray Aerial Pastureland/Rangeland 4 lb ai/A 1,200

acres 1.1

Groundboom 200 0.17 0.72 0.84 1 0.85 1.1 2.5

Groundboom No

- crop land 6 lb ai/A 200 0.11 0.48 0.56 0.7 0.57 0.72 1.7

P/G Aerial Pastureland/Rangeland 4 lb ai/A 1,200 0.16

Non

- crop land 6 lb ai/A 0.11

Tractor

- drawn Spreader Pastureland/Rangeland 4 lb ai/A 200 0.65 0.74 1.4 2.1 1.6 2.6 3.3

Non

- crop land 6 lb ai/A 0.43 0.49 0.98 1.4 1.1 1.7 2.2 Hand dispersal Rights

- of

- Way 0.00014 lb ai/ft2 10,000 ft2 0.07 0.1 0.11 0.2 0.11 0.2

Shaker can 34 59 220 220 340 340

Flagger Spray

Aerial Pastureland/Rangeland 4 lb ai/A 350 acres 0.55 0.52 0.63 0.71 0.65 0.74

P/G Pastureland/Rangeland 1.9 1.9 2.6 4.2 2.7 4.6

Non

- crop land 6 lb ai/A 1.2 1.3 1.8 2.8 1.9 3 Mixer/Loader/Applicator

DF/WD

G Backpack

Non

- crop land, and Rights

- of

- way (e.g., utilities, railroad, roadways) 1.6 lb ai/gallon 40 gallons 0.02 0.02 0.02 0.04 0.02 0.04 Manually

- pressurized

Handwand 0.002 0.24 0.36 0.41 0.38 0.44

Mechanically

pressurized Handgun 1,000 0.005 0.02 0.02 0.02 0.02 0.02

P/G Belly grinder 6 lb ai/A 1

acres 0.18 0.19 0.2 0.32 0.2 0.33

Rotary spreader 5 0.69 1.1 1.5 2.5 1.5 2.7

Cup 0.00014 lb ai/ft2 10,000 ft2 34 59 220 220 340 340

Spoon 1.5 1.9 2.4 4.4 2.5 4.7

1 Refer back to previous table 9.1.1. and 9.1.2 for “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ([May 2013]); Level of mitigation: Dermal baseline ( long sleeve shirt, pants, shoes plus socks), dermal baseline plus gloves, and dermal double layer plus gloves, Inhalation baseline (no respirator), PF5 respirator, and PF10 respirator. Eng. Controls (EC) included enclosed cockpits for the aerial applicati on of tebuthiuron for all formulations. Shaded out cells are not applicable or no unit exposure data

2 Based on registered labels (Table 3.2.1).

3 Exposure Science Advisory Council Policy #9.1.

4 ARI = Aggregate Risk Index = 1÷ [(Dermal LOC ( 100 ) ÷ Dermal MOE) + (Inhalation LOC ( 1000 ) ÷ Inhalation MOE)]