### Trifluralin Human Health Ri s k A ss e ss ment DP No. D401005



### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D .C

. 20460

:MEMORANDUM

DATE : Apr i 12

, 201 3 OFFICE OF
CHEMICAL SAFETY AND
POLLUTION PREVENTION



### SUBJECT: Trifluralin: Human Health Ri s k Assessment for the Establis hm ent of To l erances

on Oi l seed Crop Group 20.

PC Code: 036101

Decision No.: 463234

Petition No.: NA

Risk Assessment Type: Single

Chemical/ Aggregate DP Barcode: 0401005 Registration No.: NA Regulatory Action: Section 3 Regi s tration Reregistration Case No.: NA

TXR No.: NA CAS No.: 1582-09

- 8

MRID No. : NA 40 CFR: 180.2 0 7

REVIEWER: Sheila Piper

, Chemist/Risk A ss essor

# .0~**(}l ~**  Na n cy McCarroll, Tox i co l ogist

Shalu Shelat

, Industrial Hygi e ni s t/ORE As s e ss or Risk A sses s m e nt Branc h VI

Health E ffec t s Divi s ion (7509P ) 

# A

THROUGH: Felecia Fort

, Branch Chief 

# .-C 

# kc.tO.:jcJL -tRisk Asse ss ment Branc h VI 

# dJ

Health Effe c t s Division (7509P)

TO: Andrew Ertm a n
, Re v i ew M a nag e r Review e r Barbara M a dd e n, Risk Mana ge r Registration Divi s i on (7505C)

Page 1 

### of 56

### Trifluralin Huma n Healt h R i sk Assessment DP No

. D401005



### 1

. 0 Executive Summary

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

2.0 HED Recommendations

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

2.1 Data Deficiencies

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



### 2

. 2 Tolerance Considerations

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



### 2.2.1 Enforcement Analytical Method

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



### 2.2

. 2 Recommended Tolerances

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



### 2

. 2

. 3 Revisions to Pet i tioned-For Tolerances

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



### 2.2.4 International Harmonization

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



### 2

. 3 Label Recommendations

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



### 2.3.1 Recommendations from Residue Reviews

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

2

. 3.2 Recommendations from Occupational Assessment..

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


### 2.3

. 3 Recommendations from Residential Assessment..

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



### 3.0 Introduction

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



### 3.1 Chemical Identity

........ . .................................................................................. . .... . .... . .. ... .. .. ?



### 3

. 2 PhysicaVChemical Characteristics

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



### 3

. 3 Pesticide Use Pattern

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



### 3.4 Anticipa t ed Exposure Pathways

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



### 3.5 Consideration of Environmental Justice

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



### 4

. 0 Hazard Characterization and Dose

- Response Assessment..

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



### 4.2.1 Completeness of the Toxicology Database

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



### 5

. 1 Residues of Concern Summary and Rationale

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


### 5

. 2 Food Residue Profile

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



### 5

. 3 Water Residue Profile

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


### 5.4 Dietary R i sk Assessment

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



### 5

. 4.1 Description of Residue Data Used in D i etary Assessment

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



### 5

. 4

. 2 Percent Crop Treated Used in Dietary Assessment

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


### 5.4.3 Acute Dietary Risk Assessment

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



### 5.4

. 4 Chron i c Dietary R i sk Assessment

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



### 5.4

. 5 Cancer Dietary Risk Assessment..

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


### 5

. 4

. 6 Summary Table

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



### 6

. 0 Residentia l (Non-Occupational) Exposure/Risk Characterization

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



### 6. 1 Residential Handler Exposure

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



### 6

. 2 Post-Application E xposure

............ . ............ . .... . .. . ... . ... . ... . ...................... . ...... . ........ . ... .. .. . 25



### 6

. 4 Resident i al Risk Estimates for Use in Aggregate Assessment..

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



### 6.5 Residential Bystander Post

- application Inhalat i on Exposure

..... .... ..... .. ...... ... .. .. ........ 31



### 6.6 Spray Drift

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



### 7.0 Aggregate Exposure/Risk Characterization

. ....................... . ... . ... . .. ... .. .. .. .. .. . . ... . .... . ........ 31



### 7.1 Acute A ggregate Risk

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



### 7.2 Short- Term Aggregate Risk.

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



### 7

. 3 Cancer Aggregate Risk

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



### 8.0 Cumulative Exposu r e/Risk Characterization

............................ .. ...... .. .......................... 33



### 9.0 Occupational Exposure/Risk Characterization

............................................................. 33



### 10

. 0 References

.................................... . .. . ... .. . ... ..... . .................... . ............... . .......... .. . ... . .. .. ... . ..... 33 

### Appendix A. Toxicology Profile and Executive Summaries

............................ .. ....... ...... . .. .. .. .41


### A. I Toxicology 

### Data Requirements

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

### 4 1

A

. 2 T oxicity Profiles

... .. . ... . ... .. . . ......................................... .. ... . ... . ... .. .. .. .. . .... . .. .. ... . . ................. 43



### Page 2 of 

### 56

### Trifluralin Human Health Risk Assessment DP No. D401005

Page 3 of 56 Executive Summary

The Interregional Research Project No. 4 (IR

- 4), on behalf of the states of DE and MT has proposed, in PP#2E8011, the establishment of permanent tolerances for residues of the herbicide, trifluralin, in/on Oilseed crop g roup 20. This request is a conversi on of existing R apeseed subgroup 20A , S unflower subgroup 20B , and C ottonseed subgroup 20C tolerances to the O ilseed

crop group 20 tolerance.

Trifluralin (2, 6

- dinitro

- N,N

- dipropyl

- 4

- (trifluoromethyl)benzenamine) is a selective, pre

emergence, dinitroanili ne herbicide registered for the control of annual grasses and certain

broadleaf weeds. Trifluralin is registered for use on a variety of food and feed crops, and in residential setting s , including turf, ornamentals, and vegetable gardens. The petitioner, IR

- 4, is proposing the following tolerances on the food commodities as shown below:

Commodity Proposed Tolerance (ppm) Comment (correct commodity definition)
Cotton, undelinted seed 0.05 Remove cotton, flax, mustard, rapeseed, safflower and

sunflower seed to Oilseed Crop group 20 Flax, seed 0.05
Mustard, seed 0.05 Rapeseed, seed 0.05
Safflower, seed 0.05
Sunflower, seed 0.05

The toxicity database for trifluralin is substantially complete. An immunotoxicity study is required for registration review under the new data requirements for pesticides (40 CFR § 158). Following data evaluation, HED will determine if this study will impact the toxicity endpoints

for trifluralin. As part of the registration review r isk assessment process, the need for the required neurotoxicity battery (acute and subchronic neurotoxicity studies) was discussed by the Hazard and Science Policy Council (HASPOC) on March 15, 2012. The available data on trifluralin and other structurally related dinitroanilines did not indicate a concern for neurotoxicity. The HASPOC concluded that based on a weight

- of

- evidence approach, considering all the available hazard and e xposure information for trifluralin, the acute and subchronic neurotoxicity studies are not needed at this time. The requirement for the immunotoxicity study remains outstanding.

T rifluralin exhibits low acute toxicity in rats via the oral, dermal, and inhalation routes of exposure. In the rabbit studies, trifluralin has an LD 50 

### value of 5000 mg/kg when applied dermally (Toxicity Category IV). It is a slight eye irritant, but not a skin irritant; however, it was found to be a dermal sensitizer in guine a pigs. The kidney is the principal target organ. However, subchronic oral studies in the rat and dog show that the liver is also a target organ with increased liver weights and changes in clinical chemistry parameters. The Agency classified

trifluralin as a Group C

- “possible” human carcinogen. The Q 1 * 

### of 5.79 x 10 - 3 

### (mg/kg/day) - 1 

### was updated to 2.96 x 10 - 3 

### (mg/kg/day) - 1 

### in 2004 based on the Fischer 344 Rat Dietary 3⁄4’s scaling factor (May 11, 2004, TXR No. 0052534)

. Tri f l uralin is not mutagenic in a com prehensive battery of Genetic Toxicology studies and do e s not inhibit the polymerization of microtubules in

### Trifluralin Human Health Risk Assessment DP No. D401005

Page 4 of 56 mammalian cells. There is no concern for quantitative pre

- and/or post

- natal toxicity; the FQPA

SF was reduced to 1x.

Trifluralin is among the gro up of 58 pesticide active ingredients on the initial list to be screened under the Endocrine Disruptor Screening Program (EDSP). Once all required Tier 1 and Tier 2 data have been received and reviewed, the endpoints and safety factors used for risk assess ment purposes will be examined and a new risk assessment performed if necessary. For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/

.

The existing residue chemistry database for trifluralin is adequate for risk assessment purposes. The qualitative nature of the residue in plants and animals ha s been adequately identified,

characterized and is understood. The residue of concern in plants and rotational crops is the parent compound only. No additional data are required at this time; however, there are some data that have been submitted by the registrant as a result of data call

- in (DCIs) requests for trifluralin which were outlined in the most recent residue chemistry chapter (R. Griffin, D296627, 03/04/04) that will be reviewed during the registration review process.

A h ighly conservative acute dietary assessment using tolerance level residues, assuming 100% crop treated demonstrated that estimated risks were less than 1% of the acute p opulation adjusted dose (aPAD) at the 95 th 

### percentile of exposure for females 13

- 49 years old

. There were no appropriate toxicological effects attributable to a single exposure (dose) for the general population or any other population subgroups except fem ales 13

- 49 years old; therefore, these population subgroups were not included in this assessment. The chronic and cancer dietary

assessments w ere somewhat refined assuming tolerance level residues, percent crop treated data,

and Pesticide Data Program (PDP ) monitoring data on commodities which had significant impact on the cancer exposure . The chronic dietary exposure estimates were less than 1% of the chronic population adjusted dose (cPAD) for all population subgroups . The cancer dietary exposure

estima te for the U.S. population is 2.1 x 10 - 7



### .

There are no proposed residential uses at this time; however, there are existing residential uses that have been reassessed in this document to reflect updates to HED’s 2012 Residential SOPs along with policy ch anges for body weight assumptions. The revision of residential exposures will impact the human health aggregate risk assessment for trifluralin. For this assessment, HED considered all the uses that were presented in the 2004 TRED document (D296625. S. R ecore, Residential Exposure Assessment and Recommendations for the Tolerance Reassessment Evaluation Decision (TRED) Document for Trifluralin. May 6, 2004). Trifluralin can be purchased and used by homeowners in residential settings. HED assumes that onl y short

- term exposures are applicable to residential handler risk assessments , and are considered to be protective of intermediate

- term exposure and risk. The short

- term non

- cancer exposure was assessed for adults and children. Residential handler inhalation risk estimates (MOEs) did not exceed HED’s the level of concern ( i.e., MOEs > 100). An adult cancer exposure and risk assessment was also conducted. The handler and post

- application cancer risk estimates for adults ranged f

rom 4 x 10 - 11 

### to 2 x 10 - 6



### .

### Trifluralin Human Health Risk Assessment DP No. D401005

Page 5 of 56 To estimate short

- term aggregate risk, HED combined the chronic dietary (food + water) exposures (as a measure of average dietary exposure) with the short

- term residential post

application exposure. All short

- term exposure s res ulted in MOEs greater than 100 for all populations and are not of concern to HED

. Aggregate cancer risk estimate s ( 1 x 10 - 6 

### ) from trifluralin residues in food and drinking water are below HED’s level of concern for the general U.S. population.

An occupati onal exposure and risk assessment was not conducted at this time, since this request is for a conversion of existing tolerance to a crop group tolerance.

2.0 HED Recommendations

Provided the registrant submits a revised Section F (see Table 2.2.2), there are no human health risks of concern that would preclude the establishment or revision of tolerances for the residue of

trifluralin under 40 CFR 180.207 as follows:

Oilseed Group 20.....................0.05 ppm

2.1 Data Deficiencies

TOXICOLOGY

An immunotoxicity study is required under the new data requirements for pesticides (40 CFR §158).

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate enforcement method is available for trifluralin, Methods GRM96.12 and GRM96.13, w hich utilizes gas chromatography (GC) with electron capture detection (ECD)

. The reported limit of quantitation (LOQ) is 0.01 ppm. Also, trifluralin was evaluated using the FDA multiresidue method and the method is suitable for determining residues of tri fluralin in plant commodities.

2.2. 2 Recommended Tolerances

Tolerances should be established for residues of the dinitroaniline herbicide trifluralin, including its metabolite and degradate, in or on the commodities listed below. For plant and livestock commodities, the tolerances should be established as follows:

Tolerances are established for residues of trifluralin , including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be d etermined by only trifluralin α 

### ,α,α

- trifluoro

- 2,6

- dinitro

N,N

- dipropyl

- p

- toluidine , in or on the commodity

.

### Trifluralin Human Health Risk Assessment DP No. D401005

Page 6 of 56 Table 2.2.2. Proposed Tolerance Commodity Proposed Tolerance (ppm) Comment (correct commodity definition)
Cotton, undelinted seed 0.05 Remove cotton, flax, mustard, rapeseed, safflower and

sunflower seed to Oilseed Crop group 20 Flax, seed 0.05
Mustard, seed 0.05 Rapeseed, seed 0.05
Safflower, seed 0.05
Sunflower, seed 0.05

2.2. 3 Revisions to Petitioned

- For Tolerances

As noted in Table 2.2.2 above, the request for the conversion of the canola/rapeseed, sunflower seed and cottonseed tolerances to the oilseed crop 20 tolerances will remain the same.

2.2.4 International Harmonization

There are Maximum Residue Limits (MRLs) established by Canada, but not with Codex.

Mexico adopts US tolerances for its export purposes

. 

### Canada’s MRLs are harmonized with the

establi shed U.S. tolerances.

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

There are no label recommendations needed as part of residue chemistry action.

2.3.2 Recommendations from Occupational Assessment

There are no proposed occupational uses as part of this action.

2.3.3 Recommendations f rom Resident ial Assessment

At this time there are no label recommendations from the updated residential exposure and risk

assessment.

3.0 In troduction

### Trifluralin Human Health Risk Assessment DP No. D401005

Page 7 of 56 3.1 Chemical Identity

Table 3.1 Test Compound Nomenclature

Chemical Structure

Common Name Trifluralin

Company experimental name

IUPAC name α,α,α

- trifluoro

- 2,6

- dinitro

- N,N

- dipropyl

- p

- toluidine

CAS Name 2,6

- dinitro

- N,N

- dipropyl

- 4

- (trifluoromethyl)benzenamine

CAS Registry Number 1582

- 09

- 8

End

- use product/EP Treflan® 5G, Treflan® E.C., Trifluralin® 4EC



### 3.2 Physical/Chemical Characteristics

Trifluralin has low water solubility and is strongly bound to soil components. Trifluralin is almost insoluble in water, with a solubility of 0.2 to 0.4 mg/L at 25°C. It is somewhat volatile,

and has a moderately high log octanol

- water partition coefficient. The full complement of physiochemical properties for this active ingredient is shown in Table 3.2.

Table 3. 2 Physicochemical Properties

Parameter Value Reference

Melting point/range 42

- 49 C

D207577, 4/9/97, K. Dockter pH 5.9 ± 0.1 saturated aqueous solution

Density or specific gravity (22 C) 1.36 g/mL

Water solubility (25 C) <1 ppm

Solvent solubility (25 C) readily soluble in organic solvents such as acetone, acetonitrile, chloroform, dichloromethane, ethyl acetate, and toluene at >100 g/100 mL, and in

hexane at 5

- 6.7 g/100 mL or

methanol at 3.3

- 4 g/100 mL

Vapor pressure (25 C) 6.1 x 10 - 3 Pa

Dissociation constant (pK

a ) not required; does not dissociate

Octanol/water partition coefficient (log K

ow ; 20 C) 4.83

UV/vis absorption spectrum not available

### Trifluralin Human Health Risk Assessment DP No. D401005

Page 8 of 56 3.3 Pesticide Use Pattern

Trifluralin is a selective, pre

- emergence fluorinated dinitroaniline herbicide used to control annual grasses and broadleaf weeds on a variety of food crops and non

- food uses, including

residential uses. Trifluralin end

- uses products for food and feed cro ps include emulsifiable concentrates (EC, 36.4; 50.8% ai) and a granular formulation (G, 10% ai). These formulations may be applied using ground or aerial equipment and the application timing may be dormant,

pre

- plant, or pre

- emergence.

Table 3.3 . Summar y of Trifluralin Food Use Pattern Table

Site Application Type Formulation [EPA Reg. No] Maximum

Application Rate (lb ai/A) Max #

Appls Min

Retreat

ment

Interval (days) Use Directions and

Limitations

Cotton Soil incorporated treatment Preplant, postplant , or preemergence in spring Ground or aerial equipment 10% G [62719

- 131]

4lb/gal EC [62719

- 250] [33660

- 32] [33660

- 33] [66222

- 46]

5lb/gal EC [33660

- 31] 1.0 1 NA Appl. of the EC formulation may be made alone or as a

tank mix with other

herbicide. Post plant appl. may be made from 4 tree leaf stage up to layby.

A 90

- day PHI has been

established Soil incorporated treatment Fall prior to spring planting Ground or aerial equipment 1.25 1 NA

Soil or water incorporated

treatment Preplant, postplant , or

preemergence Ground or aerial equipment 2.0 2 NS Use rate for conservation tillage cotton only. Water incorporation should
be made with a min of 0.75”

of water.

The maximum seasonal use

rate is 2.0 lb ai/A. Postplant application may be

made from 4 tree leaf stage up to layby.

A 90

- day PHI has been

established. Soil incorporated treatment

Spring (preplant) or fall

Ground or aerial equipment 4lb/gal EC [62719

- 250] [33660

- 32] [33660

- 33] [66222

- 46]

5lb/gal EC [33660

- 31] 2.0 2 NS Use limited to all cotton producing states except AZ

and CA for control of rhizome Johnsongrass. Two year treatment program

which consists of a double rate application for 2 consecutive years.

Flax Soil incorporated treatment Fall (preplant)

Ground or aerial equipment 10% G [62719

- 131]

4lb/gal EC [62719

- 250] [33660

- 32] [33660

- 33] 1.0 1 NA Animal grazing on flax straw is prohibited after application of EPA Reg

. No

. 33660

- 31,

33660

- 32, 33660

- 33, and

66222

- 46

### Trifluralin Human Health Risk Assessment DP No. D401005

Page 9 of 56 [66222

- 46]

5lb/gal EC [33660

- 31] Rapeseed (including canola and crambe ) Soil incorporated treatment Spring (preplant) or fall Ground or aerial equipment 10% G [62719

- 131]

4lb/gal EC [62719

- 250] [33660

- 32] [33660

- 33] [66222

- 46]

5lb/gal EC [33660

- 31] 1.0 1 NA Use prohibited in AK. The grazing or harvesting of treated crop for livestock forage is prohibited.

The max. rate is 0.8 lb ai/A for EPA Reg. No. 33660

- 32

and 336600

- 33 in MT.

Soil incorporated treatment Spring (preplant) or fall Ground or aerial equipment 4lb/gal EC [33660

- 32] [33660

- 33] 0.8 1 NA Appl. rate is for use in MT only. The grazing or harvesting of treated crop for livestock forage is prohibited.

Safflower Soil incorporated treatment Spring (preplant) or fall Ground or aerial equipment 10% G [62719

- 131]

4lb/gal EC [62719

- 250] [33660

- 32] [33660

- 33] [66222

- 46]

5lb/gal EC [33660

- 31] 1.25 1 NA In MT, the max. rate is 1.0 lb ai/A for EPA Reg. No

. 33660

- 31, 33660

- 32, and

33660

- 33

Soil incorporated treatment Spring (preplant) or fall Ground or aerial equipment 4lb/gal EC [33660

- 32] [33660

- 33]

5lb/gal EC [33660

- 31] 1.0 1 NA Appl. rate is for use in MT only.

Sunflower Soil incorporated treatment Spring (preplant) or fall Ground or aerial equipment 10% G [62719

- 131]

4lb/gal EC [33660

- 32] [33660

- 33] [62719

- 250]

5lb/gal EC [33660

- 31] 1.0 1 NA Appl. of the EC formulations may be made alone or as a

tank mix with other

herbicides. Use of EPA Reg. No

. 33660

- 32, and 33660

- 33 limited to MN, ND, and SD.

### Trifluralin Human Health Risk Assessment DP No. D401005

Page 10 of 56 3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the existing uses of trifluralin on canola/rapeseed, flax, mustard, sunflower, safflower, and

cottonseed

. Humans might be exposed to trifluralin in food and drinking water be cause triflural in may be applied directly to growing crops. In addition, these applications can result in trifluralin reaching surface and ground water, both of which can serve as a source of drinking water. The currently registered use may result in the potential for both residential and occupational

exposures. In an occupational setting, applicators may be exposed while handling the pesticide prior to an application, during an application , as well as entering in a previously treated area

. There also may be exposure during an application and entry into previously treated residential (non

- occupational) areas.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf . As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to populatio n subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compi led by USDA’s National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on ag e, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in devel opment as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

The most recent human health risk assessment was completed in 2004 (R. Griffin, D296628) to support the Tolerance Reassessment Decision (TRED) document; a scoping document was released in 2012 (Piper et al., 2 012, D397497). Since that time, no new data have been received.

T he available toxicity database for trifluralin has been determined to be substantially complete and is sufficient for assessing the toxicity and characterizing the hazard of trifluralin. A s part of the 2007 revised toxicology data requirements, acute and chronic neurotoxicity and immunotoxicity studies were required for trifluralin. Subsequently, the Hazard and Science Policy Council (HASPOC) met on March 15, 2012 to discuss data requireme nts for the

### Trifluralin Human Health Risk Assessment DP No. D401005

Page 11 of 56 neurotoxicity battery (acute and subchronic neurotoxicity studies) for the registration review risk assessment. The available data on trifluralin and other structurally related dinitroanilines do not indicate a concern for neurotoxicity so the HASPOC concluded that these studies are no longer required (Rury, 2012; TXR 0055275). The requirement for the immunotoxicity study remains outstanding

.

4. 1 Absorption, Distribution, Metabolism, & Elimination (ADME)

In the rat metabolism study on trifluralin, the focus was on urinary metabolites. The data indicated that the metabolic profiles were generally similar for both sexes. Many non

- conjugated (20

- 30) and conjugated (10

- 20) urinary metabolites were recovered with the majority present at

1

- 2% of the total urinary radioactivity. No single metabolite accounted for > 8

- 10% of the total urinary radioactivity and no parent compound was detected. Four metabolic pathways were identified: 1) oxidative N

- dealkylation of one or both propyl groups and metabolites that were hydroxylated on the propyl side chain; 2) reduction of one or both nitro groups to the corresponding amine; 3) cyclization reactions to give a variety of substituted and unsubstituted

benzimidazole met abolites; and 4) conjugation reactions, including acetylation of the reduced nitro groups, sulfate, and glucuronic acid conjugates.

A dermal absorption study is not available for trifluralin; however, HIARC used a 3% dermal absorption rate from a percutan eous absorption study in monkeys with ethalfluralin a s the surrogate for trifluralin (TXR 0051869).

4. 2 Summary of Toxicological Effects

In general, the toxicity profile for trifluralin demonstrates that the kidney and the liver are the principal target organs in rats and dogs. In s ubchronic oral studies liver effects include increased liver weights and changes in clinical chemistry parameters. Kidney effects include decreased kidney weights, kidney and bladder tumors, increased BUN, increases in total protein, aspartate

aminotransferase (AST) and lactate dehydrogenase (LDH) in the urine. Also, protein electrophoresis of urine samples showed α 1

- globulin and α 2

- globulin. In the kidneys, tubular hyaline casts, minimal cortical tubular epithelial regeneration, observed microscopically, and an increased incidence of progressive glomerulo

- nephritis were seen. In dogs exposed to trifluralin for 1 year, multifocal cortical tubular cytoplasmic pigment deposition was noted in the kidneys

of both sexes. In the subchronic studies, blood effects such as lower hemoglobin levels and changes in clinical chemistry were reported in rats.

In male rats, trifluralin was associated with increased incidence of thyroid follicular cell combined adenoma, papillary a denoma, cystadenoma, and carcinoma tumors. It has been classified as a Group C (“Possible” Human Carcinogen). Extensive testing showed, however, that trifluralin is neither mutagenic nor genotoxic, and does not inhibit the polymerization of

microtubules in mammalian cells. It is also not a neurotoxicant and does not appear to be an

immunotoxicant.

### Trifluralin Human Health Risk Assessment DP No. D401005

Page 12 of 56 4. 3 Safety Factor for Infants and Children (FQPA Safety Factor)

As required by the Food Quality Protection Act (FQPA) of 1996, the potential of increased susceptibility of infants and children from exposure to trifluralin was evaluated at the 2003

HIARC. It was concluded that the FQPA Safety Factor (SF) could be remov ed (1x). There was qualitative evidence of increased susceptibility in the rat developmental toxicity study, where fetal developmental effects (increased resorptions and wavy ribs) occurred in the presence of less severe maternal effects (decreases in bod y weight gain, clinical signs, and changes in organ weights). Qualitatively, there is also an indication of increased sensitivity in the 2

- generation reproduction study in the rat in that offspring effects (decreased fetal, neonatal and litter viability) were observed at a dose level where there was less severe maternal toxicity (decreased body weight, body weight gain and food consumption).

However, the Committee recommended that the FQPA SF be reduced to 1 x in assessing the risks posed by this chemic al. The rationale for this recommendation was the low concern for qualitative susceptibility in the developmental rat study because the dose response was well characterized, the developmental effects were seen in the presence of maternal toxicity, and cle ar NOAELs/LOAELs were established for maternal and developmental toxicities. There was also a low concern for the qualitative susceptibility observed in the rat reproduction study since the

dose

- response was also well characterized; there was a clear NOAE L/LOAEL for maternal and developmental toxicities; and the effects were seen at a high

- dose level (295/337 mg/kg/day). Offspring viability was not adversely affected in the two other 2

- generation studies with trifluralin at dose levels up to 100 and 148 m g/kg/day. Similarly, there are no residual uncertainties for pre

- and postnatal toxicit y since the doses selected for overall risk assessment

will address the concerns seen in these studies.

Finally, there were no data gaps in the consideration of the FQ PA SF. The committee further recommended that a developmental neurotoxicity study was not required because in the available database, trifluralin does not appear to be a neurotoxic chemical.

4. 3 .1 Completeness of the Toxicology Database

The toxicology database for trifluralin is sufficient for assessing risk to h uman h ealth. Additionally, HASPOC recommended that the acute and sub

- chronic neurotoxicity test should be

waived. Consequently, the only data gap that remains is for immunotoxicity testing

.

4. 3 .2 Evidence of Neurotoxicity

HASPOC concluded, based on a weight of evidence (WOE) approach that the neurotoxicity battery is not required for trifluralin at this time. This decision was based on the following considerations: 1) lack of neurotoxici ty in the available toxicology studies for trifluralin; 2) lack of neurotoxicity seen in chemicals of the same class; 3) the known target effects of trifluralin are

in the kidneys; 4) the use of acute and chronic oral PODs from the rat developmental study and the chronic dog study, respectively, resulted in dietary risk estimates of 0.1% of the aPAD for

females 13

- 49 years and 0.3% of the cPAD for children 1

- 2 years old, the highest subpopulation; 5) the most sensitive endpoint (nephrotoxicity) is used for assessing risks via the non

- dietary

### Trifluralin Human Health Risk Assessment DP No. D401005

Page 13 of 56 exposure scenarios, and 6) considering the potential impact of these studies providing a point of departure (POD) lower than those used in the overall risk assessment.

4. 3 .3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animals

There was qualitative evidence of increased susceptibility in the rat developmental toxicity study, where fetal developmental effects (increased resorptions and wavy ribs) occurred in the presence of less severe maternal ef fects (decreases in body weight gain, clinical signs, and changes in organ weights). Also q ualitatively, there is an indication of increased sensitivity in

the 2

- generation reproduction study in the rat in that offspring effects (decreased fetal, neonatal and litter viability) were observed at a dose level where there was less severe maternal toxicity (decreased body weight, body weight gain and food consumption). These issues were addressed by the FQPA SF committee, which recommended that the FQPA SF be reduced to 1 x.

4. 3 .4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties for pre

- and postnatal toxicit y since the doses selected for overall risk assessment will address the qualitative concerns seen in the rat development al toxicity study and in the rat reproduction study.

4. 4 Toxicity Endpoint and Point of Departure Selections

A detailed description of the toxicity studies used for selecting toxicity endpoints and points of departure (PODs) for various exposure scenar ios, as well as a detailed rationale for selection of the toxicity endpoints are presented in Tables 4. 4 .4.1.

4

. 4 .1 Dose

- Response Assessment

Endpoints selected for the non

- occupational human health assessment are presented below:

Acute Reference Dose (a RfD) Established for Females 13

- 50 Years of Age: The endpoint used for establishing the acute population adjusted dose (aPAD) was selected from the developmental toxicity study in rats. This endpoint is considered appropriate for females of childbearing age (13

- 50 years old) since the effects could occur due to a single in utero exposure. An aPAD of 1.0 mg/kg/day was derived from a NOAEL of 100 mg/kg/day and a 100

- fold uncertainty factor (UF) that included a 10x

- UF for interspecies extrapolations, 10x

- UF for intraspecies variations, and a 1x FQPA SF. The LOAEL of 500 mg/kg/day was based on reduced ossification of the vertebrae and ribs; thickened, wavy or bent ribs; and increased total litter resorptions.

Acute Di etary Endpoint for All Populations (Including Infants and Children): A dose and endpoint were not selected for this risk assessment because there were no appropriate toxicological effects attributable to a single exposure observed in the oral toxicity stu dies including maternal effects in the developmental rat or rabbit toxicity studies.

### Trifluralin Human Health Risk Assessment DP No. D401005

Page 14 of 56 Chronic Reference Dose (aRfD) for All Population : The endpoint used for establishing the chronic population adjusted dose (cPAD) was selected from the chronic dog feeding study. The cPAD of 0.024 mg/kg was derived from a NOAEL of 2.4 mg/kg/day and a 100

- fold factor that

included a 10x

- UF for interspeci es extrapolations, 10x

- UF for intraspecies variations, and a 1x FQPA SF. The LOAEL of 40 mg/kg/day is based on an increased frequency of abnormal stools, decreased body weights and body weight gains, decreased erythrocytes and hemoglobin, and

increased th rombocytes (males).

A margin of exposure (MOE) of 100 is applied to all of the following residential and occupational oral, dermal or inhalation exposure scenarios:

Short (1

- 30 days) Term Incidental Oral: The endpoint used for establishing the short

- and

intermediate

- term incidental oral exposure w ere selected from the two generation reproductive rat study in which the NOAEL is 200 ppm (10 mg/kg/day). T he LOAEL for offspring toxicity is 650 ppm (32.5 mg/kg/day), based on decreased pup weights in bot h generations and increased relative to body liver weights in the F2b females.

Short (1

- 30 days) Term Dermal Endpoints : A study was not selected for short (1

- 30 days)

- term dermal exposure because in the three dermal toxicity studies [21/28 days in rabbi ts (MRID 41993810); 21/28 days in rats (MRID 00152888); and 31

- days in rats (MRID 00153171), trifluralin was tested up to the limit dose (1000 mg/kg/day) and caused no systemic toxicity. HIARC also recommended that products containing trifluralin should b e labeled as a

SENSITIZER.

Short (1

- 30 days)

- Term Inhalation Endpoints : The endpoint used for establishing the short

- term inhalation exposure was the 30

- day inhalation toxicity study in rats. The NOAEL for this study was 81 mg/kg/day. The LOAEL for this study is 270 mg/kg/day based on increased methemoglobin and bilirubin in females and dyspnea and ruffled fur in males and females.

4. 4 .2 Recommendations for Combining Routes of Exposure for Risk Assessment

As part of performing a human health ris k assessment, HED considers the potential for concurrent trifluralin exposure via oral, dermal, and inhalation routes. When there are potential occupational and/or residential exposures to a pesticide, the risk assessment must address exposures from oral, dermal, and inhalation routes and determine whether the individual exposures may be combined across several exposure pathways. Short

- term oral, dermal and inhalation should not be aggregated together because there is no dermal hazard or endpoint, and

the incidental oral and inhalation endpoints are based on different toxicological effects. However, residential inhalation exposures can be aggregated with chronic dietary exposures, and incidental oral child exposures can be aggregated with chronic dietary exposures.

### Trifluralin Human Health Risk Assessment DP No. D401005

Page 15 of 56 4. 4 .3 Cancer Classification and Risk Assessment Recommendations

Trifluralin has been classified as a Category C (“possible”) human carcinogen by the Cancer Peer Review Committee (TXR 007362) in 1987. The carcinogenic risk was quant ified by the Q 1 

### * approach.

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

Assessments

Table 4. 4 .4.1 summarizes the toxicological doses and endpoints selected for the acute and chronic dietary risk assessments; the incidental short and intermediate

- term oral assessments as well as the short, intermediate, and long

- term dermal and inhalation non

- occu pational risk assessments for trifluralin. The FQPA Safety Factor Committee determined that the 10x factor for sensitivity to infants and children should not be retained (1x). Therefore, an MOE of 100 is adequate for all non

- occupational exposure assessme nts

4. 4 .5 Conclusions

The toxicity database for trifluralin is complete except for an immunotoxicity study required under the 2007 revised 40CFR Part 158 Toxicology Data Requirements.

Table 4. 4 .4.1: Summary of Toxicological Points of Departure and Endpoints for Trifluralin for Used in Dietary and Non

- dietary

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 (Females 13

- 50 years of age) NOAEL = 100

mg/kg/day UF A =10x

UF H =10x FQPA SF =1 100 mg/kg/day NOAEL 100 (UF)

aRfD = 1.0 mg/kg/day

aPAD = 1.0 mg/kg/day Developmental Toxicity Study Rat (MRID 00151899, 00159620, 40392310) LOAEL = 500 mg/kg/day, based on

reduced ossification of the vertebrae and ribs; thickened, wavy or bent ribs; and increased total litter resorptions

Acute Dietary

(General population, including infants and children) No endpoints identified from the available developments toxicity studies (rat and rabbit) appropriate for an acute dietary assessment for trifluralin.

Chronic Dietary (All populations) NOAEL = 2.4 mg/kg/day UF A =10x

UF H =10x FQPA SF =1 2 .4mg/kg/day NOAEL 100 (UF)

cRfD = 0.024 mg/kg/day

cPAD = 0.024 mg/kg/day Chronic (capsule) Toxicity

– Dog (MRID 42447001) LOAEL = 40 mg/kg/day, based on

increased frequency of abnormal stool, decreased body weights and body weight gains, and decreased erythrocytes and hemoglobin and increased thrombocytes (males)

### Trifluralin Human Health Risk Assessment DP No. D401005

Page 16 of 56 Table 4. 4 .4.1: Summary of Toxicological Points of Departure and Endpoints for Trifluralin for Used in Dietary and Non

- dietary

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

Incidental Oral

Short

- Term (1

- 30 days) NOAEL = 10 mg/kg/day UF A =10x

UF H =10x FQPA SF =1 Residential LOC for

MOE = 100 Two

- generation Reproduction Study in Rats (MRID 00151901, 00151902, 00151903, 00159619 LOAEL = 32.5 mg/kg/day, based on decreased pup weights in both generations and increased relative to body liver weights in the F2b female s

Dermal

Short

- Term (1

- 30 days) No quantification required since there was no systemic toxicity at the limit dose in the dermal toxicity studies. There are no developmental toxicity concerns. The HIARC also recommended that the products containing trifluralin should be labeled SENSITIZER

Inhalation Short

- term (1

- 30 days) NOAEL = 300 mg/m 3 ( 81 mg/kg/day) UF A =10x

UF H =10x FQPA SF =1 Residential LOC for

MOE = 100 30

- Day Inhalation Study

- Rat (MRID 40392312)

LOAEL = 1000 mg/m 3 (270 mg/kg/day), based on increased methemoglobin and bilirubin in females and the incidence of dyspnea

and ruffled fur in males and females

Cancer (oral, dermal, inhalation) Classification: Group C (“Possible” Human Carcinogen) Q 1 * = 2.96 X 10 - 3 (mg/kg/day) - 1 (TXR No. 00052534)

1 Explanation of Abbreviations: Point of Departure (PoD) = A data point or an estimated point that is 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 effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF A = extrapolation from ani mal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA safety factor. PAD = population adjusted dose (a= acute; c = chronic). RfD = reference dose. MOE = margin of

expos ure. LOC = level of concern.



### 5.0 Dietary Exposure and Risk Assessment

The existing residue chemistry database for trifluralin is adequate for risk assessment purposes. No additional data are required at this time; however, there are some submitted d ata received as a

result of a Data Call

- In (DCIs) request for trifluralin which was outlined in the most recent residue chemistry chapter (R. Griffin, D296627, 03/04/04) that will be reviewed during the registration review process. The qualitative nature of the residues of trifluralin in plants and animals has been adequately identified, characterized and is understood.

5.1 Residues of Concern Summary and Rationale

The HED Metabolism Assessment Review Committee (MARC) has reviewed the trifluralin toxicology and metabolism data (03/09/04) and the recommendation is shown in Table 5.1 . The

### Trifluralin Human Health Risk Assessment DP No. D401005

Page 17 of 56 Agency has determined that tolerances for trifluralin residues in eggs and poultry tissue are not required based on the results of the respective poultry metabolism and feeding studies (CFR §180.6(a)(3)).

Table 5.1. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression

Matrix Residues included in Risk

Assessment Residues included in Tolerance Expression

Plants Primary Crop Trifluralin Trifluralin

Rotational Crop Trifluralin Trifluralin

Livestock Ruminant Trifluralin and metabolites

TR

- 2, TR

- 4, TR

- 5, TR

- 6,

TR

- 7, TR

- 14, TR

- 15, TR

42, and TR

- 44 Trifluralin

Poultry Not Applicable Not Applicable

Drinking Water Trifluralin and its major degradates TR

- 4, TR

- 6,

and TR

- 15 Not Applicable



### 5 .2 Food Residue Profile

No residue data were submitted with this petition. The Interregional Research Project No. 4 (IR

4) has request ed the conversion of the canola/rapeseed, sunflower seed and cottonseed tolerances to the oilseed crop group 20. The proposed use pattern for members of the rapeseed (subgroup 20A), sunflower (subgroup 20B), and cottonseed (subgroup 20C) is similar to the e xisting registered use for canola/rapeseed, flax, mustard, sunflower, safflower, and cottonseed. Trifluralin has tolerances for canola/rapeseed for seed, flax, mustard, safflower, sunflower, and cottonseed at 0.05 ppm (40 CFR 180.207).

5.3 Water Residue Profile EFED Drinking Water Assessment, D401006, Faruque Khan, 07/02/2012.



### For the dietary risk assessment, the Environmental Fate and Effects Division (EFED) provided high

- end, conservative estimates of drinking water concentrations ( EDWCs ) based on a dr inking water assessment previously performed for the Tolerance Reassessment Eligibility Decision (TRED) (D296624, December 3, 2003). The EDWCs for oilseed crops are based on the maximum proposed application rates for aerial and ground applications specifie d in the proposed product labels (Treflan ® 

### HFP, and Treflan ® 

### TR

- 10). The most conservative estimates were obtained from aerial application of trifluralin to LA sugarcane as a surrogate scenario for Hawaii at the maximum labeled annual application rate of 4 l bs a.i./acre, applied twice annually at 2 lbs a.i./acre. The updated EDWCs for sugarcane are lower than the previously reported EDWCs in the TRED (U.S. EPA 2003) due to two applications at 2.0 lbs a.i./A as prescribed in current labels instead of 1 applic ation at 4.0 lbs/A per year used in the previous assessment.

### Trifluralin Human Health Risk Assessment DP No. D401005

Page 18 of 56 The EDWCs for trifluralin and its major degradates TR

- 4 ( α
, α
, α

- trifluoro

- 5

- nitro

- N4,N4

- dipropyl

- toluene

- 3,4

- diamine) , TR

- 6 ( 5

- trifluoromethyl

- 3

- nitro

- 1,2

- benzenediamine) and TR

- 15 ( 2

- ethyl

- 7

- nitro

- 5

- (trifluoromethyl) benzimidazole) are the residues of concern in drinking water. The EDWCs of total toxic trifluralin residue for various crops were generated with the coupled

models PRZM and EXAMS for surface water and SCI

- GROW for groun d water. The upper

bound EDWCs for trifluralin and its major degradates are provided in Table 5.3 for the human

health risk assessment.

Table 5.3. Estimated Drinking Water Concentrations (EDWCs) of Trifluralin and its Degradates for Surface Water using PRZM/EXAMS and Groundwater using SCIGROW

Drinking Water Source (model) Use

Scenario (modeled rate) 1

- in

- 10 year acute
( 

### μg/L ) 1

- in

- 10 year chronic

( 

### μg/L ) 30

- year average

( 

### μg/L )

Surface Water (PRZM/EXAMS) Sugarcane:

FL Sugarcane STD (2 app. X 1.0 lbs ai/acre) 3.89 (A) 1 0.74(A) 0.59(A)

Sugarcane: LA Sugarcane STD (2 app. X 1.0 lbs ai/acre)

LA Sugercane STD 2 app. X 2.0 lbs ai/acre) 2 11.92(A)

23.83 (A) 3

19.37 (G) 4 0.99(A)

1.97(A) 3

1.76 (G) 4 0.80(A)

1.59(A) 3

1.35 (G) 4

Oilseed:

CA Cotton STD 1app. X 2.0 lbs ai/acre) 3 12.82 (A) 0.35 (A) 0.33 (A)

Oilseed:

MS Cotton STD 1 app. X 2.0 lbs ai/acre) 3 21.35 (A) 1.08 (A) 0.84 (A)

Oilseed:

NC Cotton STD 1 app. X 2.0 lbs ai/acre) 3 19.63 (A) 0.99 (A) 0.88 (A)

Oilseed:

ND Canola STD 1app. X 1.25 lbs ai/acre) 3 8.16 (A) 0.30 (A) 0.25 (A)

Groundwater (SCI

- GROW) For sugarcane

(2 app. X 2.0lbs a.i./acre)

Cottonseed 1 app. X 2.0 lbs/Acre

Oil Seed 1 app. X 1.25 lbs a.i./acre 2.75E

- 02 5

1.37E

- 02

8.58 E

- 03 2.75

- 02 5

1.37E

- 02

8.58 E

- 03 2.75E

- 02 5

1.37E

- 02

8.58 E

- 03

1 = Aerial application

2 = LA Sugarcane STD scenario was used as a surrogate scenario to calculate EDWCs for trifluralin uses in Hawaii

3 = Bolded EDWCs are recommended exposure values for surface water sources for human health risk assessment

4

= Ground application. Exposure from ground application of trifluralin is compared with aerial application for the highest exposure scenario (LA S ugarcane STD) for sugarcane at 4.0.lbs/a.i./A.

5 = Groundwater EDWC can be used for acute, chronic and cancer chronic concerns

### Trifluralin Human Health Risk Assessment DP No. D401005

Page 19 of 56 5.4 Dietary Risk Assessment Dietary Exposure and Risk Memorandum, D4 10618, S. Piper

, 04/02/2013



### 5.4.1 Description of Residue Data Used in Dietary Assessment

Tolerance level residues were used for the acute dietary assessment. For chronic and cancer dietary assessments, Pesticide Data Program (PDP) monitoring data were used for carrot, orange, orange juice, pepper, potato, and tomato which had a significant impact on the cancer exposure. High end modeled drinking water estimates were directly incorporated into the assessment. In

order to assess short

- term aggregate risk to trifluralin, average dietary exposure estimates (i.e., food and drinking water) were calculated.

5.4.2 Percent Crop Treated Used in Dietary Assessment

For the acute dietary exposure assessment, 100%CT was assumed for all commodities. A verage percent crop treated estimates (D406856, J. Alsadek , 12/12/2012) were used in the chronic and cancer dietary risk assessments for the following crops that are currently registered for trifluralin: almonds: 1%; asparagus: 20%; barley: 1%; green bean: 25%; broccoli: 10%; cabbage: 40%; canola: 2.5%; cantalou pe: 25%; carrot: 40%; cauliflower: 10%; celery: 12.5%; corn: 1%; cotton: 30%; cucumber: 2.5%; dry bean/pea: 10%; garlic: 5%; grapefruit: 1%; grape: 2.5%; honeydew: 20%; lemon: 1%; onion: 2.5%; orange: 1%; peach: 1%; peanut: 5%; pecan: 1%; pepper: 25%; pist achio: 2.5%; potato: 2.5%; pumpkin: 5%; sorghum: 1%; soybean: 5%; squash: 5%; sugarbeet: 2.5%; sugarcane: 5%; sunflower: 10%; tomato: 60%; walnut: 1%; watermelon: 10%;

and wheat: 1%.

5.4.3 Acute Dietary Risk Assessment

An unrefined, acute dietary expos ure assessment using tolerance levels, default DEEM processing factors, and assuming 100% crop treated (CT) for the proposed commodities was conducted for various population subgroups. There were no appropriate toxicological effects attributable to a sing le exposure (dose) for the general population or any other population subgroups except females 13

- 49 years old; therefore, these population subgroups were not included in this assessment. For food and drinking water, the acute dietary risk estimate is bel ow HED’s level of concern (<100% of the acute population adjusted dose (aPAD)) at the 95 th


### percentile of exposure. The acute dietary exposure estimate for females 13

- 49 years old is less

than 1% of the aPAD.

5.4.4 Chronic Dietary Risk Assessment

The chronic dietary exposure and risk estimates are somewhat refined since they assume tolerance levels, %CT data, and DEEM default processing factors. Pesticide Data Program (PDP) monitoring data were used for carrot, orange, orange juice, pepper, potato, and tomato which had a significant impact on the cancer exposure. Combined chronic dietary exposure estimates for food and drinking water are well below HED’s level of concern. Using the DEEM

FCID software, dietary exposure is less than 1% for the U.S. p opulation and all infants the most highly exposed population subgroup.

### Trifluralin Human Health Risk Assessment DP No. D401005

Page 20 of 56 5.4.5 Cancer Dietary Risk Assessment

The Agency classified trifluralin as a Group C

- “possible” human carcinogen. The Q 1 * 

### is 2.96 x 10 - 3 

### (mg/kg/day) - 1



### . For food and drinking water, t he cancer dietary exposure estim ate for the U.S. population is 2.1 x 10 - 7



### .

5.4.6 Summary Table

Table 5. 4. 6. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Trifluralin

Population Subgroup Acute Dietary (95 th Percentile) Chronic Dietary Cancer

Dietary Exposure (mg/kg/day) %

aPAD Dietary

Exposure (mg/kg/day) %

cPAD Dietary

Exposure (mg/kg/day) Risk

General U.S. Population

N/A 0.000078 <1 0.000070 2.1 x 10
- 7

All Infants (<1 year old) 0.000213 <1

N/A N/A Children 1

- 2 years old 0.000158 <1

Children 3

- 5 years old 0.000128 <1

Children 6

- 12 years old 0.000082 <1

Youth 13

- 19 years old 0.000055 <1

Adults 20

- 49 years old 0.000070 <1

Adults 50

- 99 years old 0.000074 <1

Females 13

- 49 years old 0.002305 <1 0.000070 <1



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no proposed residential uses at this time; however, there are existing residential uses that have been reassessed in this document to reflect updates to HED’s 2012 Residential SOPs 1


### along with policy changes for body weight assumptions. The revision of residential exposures will impact the human health aggregate risk assessment for trifluralin. For this assessment, HED considered all the uses that were presented in the 2004 TRED document (D296625. S. Recore, Residential Exposure Assessment and Recommendations for the Tolerance Reassessment Evaluation Decision (TRED) Document for Trifluralin. May 6, 2004). Trifluralin can be purchased and used by homeowners in resid ential settings. The following is a list of use sites in

the residential environment.

vegetable gardens

turf

ornamentals

1 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html

### Trifluralin Human Health Risk Assessment DP No. D401005

Page 21 of 56 6.1 Residential Handler Exposure /Risk Characterization

It has been determined that exposure to pesticide handlers is likely during the residential use of trifluralin in a variety of environments including on turf, vegetable gardens, and ornamentals. The anticipated use patterns and current labeling indicate several major residential exposure scenarios based on the types of equipment and techniques that can potentially be used to make trifluralin applications. The quantitative exposure and risk assessment developed for residential

handlers is based on the scenarios as present in the 2004 Residential Exposure Assessment (D296625).

loading/applying granulars with a belly grinder; loading/applying granulars with a push

- type spreader; loading/applying granulars using a spoon, measuring scoop, shaker can, or via hand; mixing/loading/applying liquids with a hose

- end sprayer; mixing/loa ding/applying liquids with low pressure handwand sprayer; mixing/loading/applying liquids with backpack sprayer; and appl y ing trifluralin impregnated fabric squares to soi l.

HED assumes that only short

- term exposures are applicable to residential handle r risk assessments, and are considered to be protective of intermediate

- term exposure and risk. The

short

- term non

- cancer exposure was assessed for adults and children (see Table 6.1a)

.

The Agency considers all exposure to trifluralin, including the de rmal and inhalation exposure expected for homeowners, to have an associated carcinogenic risk. Carcinogenic risk for homeowner applicators is assessed based on the rates and application methods outlined above. An (upper

- end) assumption is made that the u sers assessed will apply trifluralin each season, as labeled, for 50 years of their life. Specific methods (or scenarios) of application (spreader, sprayer, etc.) are assessed to demonstrate the full range of exposure due to method and area treated, altho ugh users are not expected to use one method for 50 years. Carcinogenic risk for homeowner applicators is assessed by combining dermal exposure (adjusted for an estimated 3% absorption based on ethalfluralin data) and inhalation exposure (100% absorption) , calculating this exposure on a per day basis (“Lifetime Average Daily Dose”, in mg/kg/day), and then quantifying risk by multiplying the updated upper

- bound carcinogenic potency factor (Q 1 

### *) of

2.96 x 10 - 3 

### (mg/kg/day) - 1 

### (updated in 2004, based on the Fis cher 344 Rat Dietary 3⁄4’s scaling factor (TXR No. 0052534) by the combined exposure estimate.

For the carcinogenic risk assessments, the Agency considers the typical application rate for a given use site, if known. The typical application rate is not kn own for most trifluralin applications in residential settings, therefore, with one exception, the maximum

- labeled application rate was used for carcinogenic risk assessment. However, since the labeled rate for established ornamentals is 2 to 4 lbs ai/A, th e Agency has used 3 lbs ai/A for the assessment of

this scenario.

Residential handler inhalation risk estimates (MOEs) did not exceed HED’s the level of concern (i.e., MOEs > 100). An adult cancer exposure and risk assessment was also conducted. A

### Trifluralin Human Health Risk Assessment DP No. D401005

Page 22 of 56 summ ary of the handler and post

- application cancer risk estimates for adults ranged from 4 x 10 -

11 

### to 2 x 10 - 6 

### are provided in Table 6.1b.

### Trifluralin Human Health Risk Assessment DP No. D401005

Page 23 of 56 Table 6.1 a : Short

- Term Residential Handler Exposure and Risk Estimates for Trifluralin

Exposure Scenario Level of

Concern Use Site Inhalation Unit Exposure Maximum Application

Rate 1 Amount

Treated or Handled Daily 2 Inhalation

Dose 3 MOE 4

Mixer/Loader/Applicator

Loading/Applying Granules with a belly grinder 100 ornamental (pre

- plant)

0.039 0.000459 lbs ai/ft 2

1200 ft 2 0.00027 300,000

ornamental (post

- plant) 0.0000918 lbs ai/ft 2 0.000054 1,500,000

turf 0.0000689 lbs ai/ ft 2 0.00004 2,000,000

vegetable gardens 0.0000941 lbs ai/ft 2 0.000055 1,500,000

Loading/Applying Granules with a push

- type spreader 100 ornamental (pre

- plant)

0.0026 0.000459 lbs ai/ft 2 1200 ft 2 0.000018 4,500,000

ornamental (post

- plant) 0.0000918 lbs ai/ft 2 1200 ft 2 0.0000036 23,000,000

turf 3 lbs ai/acre 0.5 acres 0.000049 1,700,000

vegetable gardens 0.0000941 lbs ai/ft 2 1200 ft 2 0.0000037 22,000,000

Loading/applying granulars using a spoon 100 ornamental (pre

- plant)

0.087 0.000459 lbs ai/ft 2 1200 ft 2 0.0006 140,000

ornamental (post

- plant) 0.0000918 lbs ai/ft 2 1200 ft 2 0.00012 680,000

turf 0.0000689 lbs ai/acre 100 ft 2 0.0000075 11,000,000

vegetable gardens 0.0000941 lbs ai/ft 2 1200 ft 2 0.00012 660,000

rose bushes 0.00043 lbs ai/bush 50 bushes 0.000023 3,500,000

Loading/applying granulars using a cup or shaker can 100 ornamental (pre

- plant)

0.013 0.000459 lbs ai/ft 2 1200 ft 2 0.00009 900,000

ornamental (post

- plant) 0.0000918 lbs ai/ft 2 1200 ft 2 0.000018 4,500,000

turf 0.0000689 lbs ai/acre 100 ft 2 0.0000011 72,000,000

vegetable gardens 0.0000941 lbs ai/ft 2 1200 ft 2 0.000018 4,400,000

rose bushes 0.00043 lbs ai/bush 50 bushes 0.0000035 23,000,000

Loading/applying granulars by hand 100 ornamental (pre

- plant)

0.38 0.000459 lbs ai/ft 2 1200 ft 2 0.0026 31,000

ornamental (post

- plant) 0.0000918 lbs ai/ft 2 1200 ft 2 0.00052 160,000

turf 0.0000689 lbs ai/acre 100 ft 2 0.000033 2,500,000

vegetable gardens 0.0000941 lbs ai/ft 2 1200 ft 2 0.00054 150,000

rose bushes 0.00043 lbs ai/bush 50 bushes 0.0001 790,000

Mixing/loading/applying liquids with a hose

- end

sprayer; 100 flowers, trees and shrubs

vegetable gardens 0.0014 0.047 lbs ai/gallon 5 gallons 0.000009 9,000,000

### Trifluralin Human Health Risk Assessment DP No. D401005

Page 24 of 56 Table 6.1 a : Short

- Term Residential Handler Exposure and Risk Estimates for Trifluralin

Exposure Scenario Level of

Concern Use Site Inhalation Unit Exposure Maximum Application

Rate 1 Amount

Treated or Handled Daily 2 Inhalation

Dose 3 MOE 4

Mixing/loading/applying liquids with manually pressurized hand wand 100 flowers, trees, and shrubs

vegetable gardens 0.018 0.047 lbs ai/gallon 5 gallons 0.000053 1,500,000

Mixing/loading/applying liquids with back pack

sprayer 100 flowers, trees, and shrubs

vegetable gardens 0.14 0.047 lbs ai/gallon 5 gallons 0.00041 200,000

1 Based on registered non

- occupational (residential) uses as assessed in the 2004 Residential Assessment (D296625)

2 Exposure Science Advisory Council Policy #9.1 and 2012 Residential Standard Operating Procedures

3 Inhalation Dose = Inhalation Unit Exposure (mg/kg) x Application Rate (lb ai/acre or ft 2 or gal) x Amount Treated or Handled (A or gallons/day) /BW ( 80 kg)

4 Inhalation MOE = Inhalation NOAEL ( 81 mg/ kg/day)/ Inhalation Dose (mg/kg/day)

### Trifluralin Human Health Risk Assessment DP No. D401005

Page 25 of 56 Table 6.1 b : Cancer Residential Handler Exposure and Risk Estimates for Trifluralin

Exposure Scenario Total ADD (mg/kg/day) 1 Total LADD

(mg/kg/day) 2 Cancer Risk Estimate 3

Loading/Applying

Granules with a belly grinder ornamental (pre

- plant) 7.43E

- 02 6.52E

- 04 2E

- 06

ornamental (post

- plant) 1.51E

- 02 1.32E

- 04 4E

- 07

turf 1.10E

- 02 9.69E

- 05 3E

- 07

vegetable gardens 1.51E

- 02 1.32E

- 04 4E

- 07

Loading/Applying

Granules with a push

- type spreader ornamental (pre

- plant) 1.88E

- 04 1.65E

- 06 5E

- 09

ornamental (post

- plant) 3.66E

- 05 3.21E

- 07 1E

- 09

turf 5.09E

- 04 4.47E

- 06 1E

- 08

vegetable gardens 3.77E

- 05 3.31E

- 07 1E

- 09

Loading/applying granulars using a

spoon ornamental (pre

- plant) 1.90E

- 03 1.67E

- 05 5E

- 08

ornamental (post

- plant) 3.80E

- 04 3.34E

- 06 1E

- 08

turf 2.35E

- 05 2.06E

- 07 6E

- 10

vegetable gardens 3.80E

- 04 3.34E

- 06 1E

- 08

rose bushes 7.30E

- 05 6.41E

- 07 2E

- 09

Loading/applying granulars using a cup or shaker can ornamental (pre

- plant) 1.13E

- 04 9.92E

- 07 3E

- 09

ornamental (post

- plant) 2.25E

- 05 1.98E

- 07 6E

- 10

turf 1.38E

- 06 1.21E

- 08 4E

- 11

vegetable gardens 2.27E

- 05 1.99E

- 07 6E

- 10

rose bushes 4.39E

- 06 3.85E

- 08 1E

- 10

Loading/applying granulars by hand ornamental (pre

- plant) 3.56E

- 02 3.13E

- 04 9E

- 07

ornamental (post

- plant) 7.12E

- 03 6.25E

- 05 2E

- 07

turf 4.43E

- 04 3.89E

- 06 1E

- 08

vegetable gardens 7.34E

- 03 6.45E

- 05 2E

- 07

rose bushes 1.40E

- 03 1.23E

- 05 4E

- 08

Mixing/loading/app lying liquids with a

hose

- end sprayer; flowers, trees and shrubs

vegetable gardens 1.10E

- 02 9.67E

- 05 3E

- 07

Mixing/loading/app lying liquids with manually pressurized hand

wand flowers, trees, and shrubs

vegetable gardens 5.65E

- 03 4.96E

- 05 1E

- 07

Mixing/loading/app lying liquids with back pack sprayer flowers, trees, and shrubs

vegetable gardens 1.14E

- 02 1.00E

- 04 3E

- 07

1 Total ADD (mg/kg/day) = Dermal ADD (mg/kg/day) + Inhalation ADD (mg/kg/day).

2 Total LADD (mg/kg/day) = Total ADD (mg/kg/day) × [Days per year of exposure (5 days/yr) ÷ 365 days/year] × [Years per lifetime of exposure (50yrs) ÷ Lifetime expectancy (78yrs)].

3 Cancer risk estimates = Total LADD (mg/kg/day) * Q 1 * , where Q 1 * = [ 2.96 x10 - 3 ] (mg/kg/day)

- 1

.



### 6.2 Post

- Application Exposure

There is the potential for post

- application exposure for individuals exposed as a result of being in an environment that has been previously treated with trifluralin. The quantitative exposure/risk assessment for residential post

- application exposures is based on the following scenarios:

### Trifluralin Human Health Risk Assessment DP No. D401005

Page 26 of 56 vegetable gardens (4.1 lbs ai/acre) golf course turf (3 lbs ai/acre)

turf (3 lbs ai/acre)

All residential exposures are considered to short

- term duration (1

- 30 days).

The lifestages selected for each post

- application scenario are based on an analysisprovided as an Appendix in the 2012 Residential SOPs 2 

### . These lifestages are not the only lifestages that could be potentially exposed for these post

- application scenarios; however, the assessment of these lifestages is hea lth protective for the exposures and risk estimates for any other potentially exposed lifestages. Chemical

- specific TTR day was available for the trifluralin post

- application

exposure assessment.

As noted, no acute dietary or short

- term dermal points o f departure have been selected for

trifluralin ; therefore ; only incidental oral post

- application non

- cancer risk estimates for children 1<2 years old have been provided. Non

- cancer post

- application scenarios assessed are as

follows: Incidental oral (hand to mouth

, object to mouth , and soil ingestion ) exposure from granular applications to turf using chemical

- specific TTR values

Table 6.2 a : Short

- Term Residential Post

- application Exposure and Risk Estimates for

Trifluralin
Lifestage Post

- application Exposure Scenario Dose MOEs

1 <2 year old Granular application to

Turf Hand to Mouth 0.00022 45,000

Object to Mouth 0.00001 730,000

Incidental Soil Ingestion 0.0001 98,000



### Although post

- application exposures to children are expected, when assessing cancer risk, the only adult post

- application residential scenarios that are applicable, using the current methods, are the following:

Dermal exposure to residues on lawns Dermal exposure to golf course turf Dermal exposure in home vegetable gardens

Table 6.2 b : Cancer Residential Post

- application Exposure and Risk Estimates for Trifluralin

Lifestage Post

- application Exposure Scenario LADD 1

(mg/kg/day) Cancer Risk 2

Adult Turf Dermal 1.3E

- 06 4 E

- 09

Adult Golf course Dermal 9.2E

- 08 3 E

- 10

Adult Vegetable Garden

- Granular Dermal 2.8E

- 04 8 E

- 0 7

Adult Vegetable Garden

- Liquid Dermal 2.8E

- 04 8 E

- 0 7

2 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html

### Trifluralin Human Health Risk Assessment DP No. D401005

Page 27 of 56 1 Dermal LADD = Dermal dose * average days of exposure ( 2 )/year x (50) years of expected exposure/ (365 days/year x 7 8 year lifetime)

2 Cancer risk estimates = LADD * Q 1 * , where Q 1 * = 2. 9 6 x10 - 3 (mg/kg/day) - 1



### 6.3 Combined Residential Risk Estimates (Multiple Exposure Scenarios)

There may be post

- application residential exposure scenarios for trifluralin which could be combined for purposes of an aggregate exposure assessment. Combinations for residential exposure scenarios should have a reasonable probability of occurring on a s ingle day and the pest that an individual is attempting to control must be considered. It is reasonable that an adult may treat their turf and garden on the same day.

### Trifluralin Human Health Risk Assessment DP No. D401005

Page 28 of 56 Table 6.3a: Non

- Cancer Residential Handler Combined (Multiple Exposure S cenarios) E xposure and Risk Estimates for Trifluralin

.
Exposure Scenario s Route of Exposure Inhalation

Dose Combined

Inhalation Dose Combined

Inhalation MOEs

Outdoor Scenario (Turf/Garden) Loading/Applying Granules with a belly grinder Turf

Garden

Inhalation 0.00004 0.000095 850,000 0.000055

Loading/Applying Granules with a push

- type spreader Turf

Garden 0.000049 0.0000527 1,500,000 0.0000037

Loading/applying granulars using a

spoon Turf

Garden 0.0000075 0.0001275 640,000 0.00012

Loading/applying granulars using a cup or shaker can Turf

Garden 0.0000011 0.0000191 4,200,000 0.000018

Loading/applying granulars by

hand Turf

Garden 0.000033 0.000573 140,000 0.00054

Table 6.3b: Cancer Residential Handler Combined (Multiple Exposure Scenarios) Exposure and Risk Estimates for Trifluralin

Exposure Scenarios Route of Exposure LADD Combined Total

LADD 1 Combined Total

Cancer Risk 2

Outdoor Scenario (Turf/Garden) Loading/Applying Granules with a belly grinder Turf

Garden

Inhalation

and

Dermal 9.69E

- 05 2.29E

- 04 7E

- 07

1.32E

- 04

Loading/Applying Granules with a push

- type spreader Turf

Garden 4.47E

- 06 4.80E

- 06 1E

- 08 3.31E

- 07

Loading/applying granulars using a spoon Turf

Garden 2.06E

- 07 3.55E

- 06 1E

- 08 3.34E

- 06

Loading/applying granulars using a cup or shaker can Turf

Garden 1.21E

- 08 2.11E

- 07 6E

- 10 1.99E

- 07

Loading/applying granulars by hand Turf

Garden 3.89E

- 06 6.84E

- 05 2E

- 07 6.45E

- 05

1 Residential combined total lifetime average daily dose combines r easonably conservative, high end dermal AND inhalation handler exposures ( Table 6.1 ) for the Turf and Garden scenarios that may

co

- occur

. 2 Cancer risk estimates = LADD * Q 1 * , where Q 1 *

= 2.96 (mg/kg/day)

- 1

### Trifluralin Human Health Risk Assessment DP No. D401005

Page 29 of 56 6.4 Residential Risk Estimates for Use in Aggregate Assessment

Table 6.4 reflects the residential risk estimates that are recommended for use in the aggregate

assessment for trifluralin.

The recommended residential exposure for use in the adult non

- cancer aggregate assessment reflects inhalation exposure from applying granules by hand to pre

plant ornamentals (Table 6.1 a ). The recommended residential exposure for use in the children 1<2 ye ars old non

cancer aggregate assessment reflects hand

- to

- mouth exposures from granular application to residential turf (Table 6.2a). The recommended residential exposure for use in the adult cancer aggregate assessment reflects dermal and inhalation exposu re from loading/applying granules with a belly grinder to pre

- plant ornamentals (Table 6.1 b )

.

### Trifluralin Human Health Risk Assessment DP No. D401005

Page 30 of 56 Table 6.4 a

. Recommendations for the Short

- Term Residential Exposures for the Trifluralin Aggregate Assessment 1

Lifestage Handler Exposure

(mg/kg/day) 2 Residential

Handler Total Exposure (mg/kg/day) 3 Residential

Handler

Total MOE 4 Post

- application Exposure (mg/kg/day) 5 Residential Post

application Total Exposure (mg/kg/day) Residential Post

application MOE 6 Dermal Inhalation Dermal Inhalation Oral

Short

- Term

Adult N/A 0.0026 0.0026 31,000 N/A N/A N/A N/A N/A

Child N/A N/A N/A N/A N/A N/A 0.00022 0.00022 4 5,000

1 Bolded risk estimates should contribute to the residential exposure portion of the aggregate assessment.

2 Handler exp osure represents high

- end inhalation exposure, applying granules by hand to pre

- plant ornamentals (Table 6.1 a ).

3 For adults, residential total exposure combines the highest d ermal and inhalation exposures, where applicable. For young children, total residenti al exposure combines high

- end post application incidental oral AND dermal exposure, where applicable

. 4 Total MOE = 1 / (1/Dermal MOE) + (1/Inhalation MOE). Dermal NOAEL = N/A mg/kg/day; Inhalation NOAEL = 81 mg/kg/day

5 Post

- application exposure represen ts high

- end dermal, inhalation and/or incidental oral exposure for the relevant exposure duration

6 Total MOE = 1/ (1/Dermal MOE) + (1/Inhalation MOE) + (1/Incidental oral MOE). Dermal NOAEL = N/A mg/kg/day, Inhalation NOAEL = 81 mg/kg/day; Incidental oral

NOAEL = 10 mg/kg/day.

Table 6.4b. Recommendations for the Residential Exposures for the Trifluralin Cancer Aggregate Assessment 1

Lifestage Handler ADD

(mg/kg/day) 2 Residential

Handler LADD (mg/kg/day) 3 Residential

Handler

Cancer Risk

Estimate 4 Post

- application ADD (mg/kg/day) 2 Residential Post

application LADD (mg/kg/day) 3 Residential Post

application MOE 6 Dermal Inhalation Dermal Inhalation Oral

Short

- Term

Adult 0.074 0.00027 6.52E

- 04 2 E

- 06 7.9E

- 02 N/A N/A 2.8E

- 04 8 E

- 0 7

1 Bolded risk estimates should contribute to the residential exposure portion of the cancer aggregate assessment.

2 Handler exposure represents high

- end dermal and inhalation dose , applying granules by with a belly grinder to pre

- plant ornamentals (Table 6.1 b ) and Post

- application exposure represents high

- end dermal dose,

3 LADD (mg/kg/day) = (dermal ADD (mg/kg/day)+ inhalation ADD (mg/kg/day)) × [Days per year of exposure (5 days/yr) or (2 days/yr) ÷ 365 days/year] × [Years per lifetime of exposure (50yrs) ÷ Lifetime expectancy (78yrs)].

4 Cancer risk estimates = Total LADD (mg/kg/day) * Q 1 * , where Q 1 * = [ 2.96 x10 - 3 ] (mg/kg/day)

- 1

.

### Page 31 of 56

6.5 Residential Bystander Post

- application Inhalation Exposure

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

- application inhalation exposure assessment was not performed for trifluralin at this time primari ly because of the low acute inhalation toxicity (Toxicity Category IV) and low vapor pressure ( 6.1 x 10 - 3 

### Pa ) . However, volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/sap/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedure s to identify the need for and, subsequently, the way to incorporate 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 trifluralin.

6.6 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also b e a potential source of exposure from the ground application method employed for trifluralin. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop t he best spray drift management practices (see the Agency’s Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aer ial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropri ately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift
management pra ctices to reduce off

- target drift with specific products with significant risks

associated with drift.

It is noted that the 3 lb ai/acre application rate for turf was modeled to estimate post

- application residential exposure of children. As this rate is equal to or higher than many of agricultural application rates, this scenario is protective of any exposure of farm children via spray drift from agricultural trifluralin applications considered in this assessment.

7.0 Aggregate Exposure/Risk Characteriza tion

In accordance with the FQPA, HED must consider and aggregate trifluralin pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. Separate residential exposure scenarios (dermal, inhalation, and oral) are combined when it is likely they can occur simultaneously based on the use

- pattern and the behavior associated with the exposed population.

### Page 32 of 56

7.1 Acute Aggregate Risk

Acute aggregate risks result from exposure to residues in food and drinking water alone. As a result, the acute aggregate risk assessment is equivalent to the acute dietary risk assessment discussed in Section 5.4.3 above. The risk estimate for the popul ation subgroup Females 13

- 49 years old, the only subgroup for which an acute dietary endpoint was established, is not of

concern. The acute dietary exposure estimate for female 13

- 49 years old is less than 1% of the

aPAD.

7.2 Short

- Term Aggregate Risk

To est imate short

- term aggregate risk, HED combined the chronic dietary (food + water) exposures (as a measure of average dietary exposure) with the short

- term residential postapplication exposure for children and residential handler exposure for adults . All short

- term

exposure s resulted in MOEs greater than 100 for all populations and are not of concern to HED.

Short

- term aggregate risks are summarized in Table 7.2 below.

Table 7.2 Short

- Term Aggregate Risk Calculations

Population Short

- Term Scenario

LOC for Aggregate

Risk 1 Dietary

MOE 2 MOE Oral

Residential Exposure 3 MOE

Dermal

Residential Exposure 4 MOE

Inhalation

Residential Exposure 5 Aggregate

MOE (food, water, and residential) 6



### Adult 100 135, 000 NA NA 31, 000 25, 000

Child 100 63, 000 45, 000 NA NA 26, 000

1 An UF of 100x was applied to account for interspecies extrapolation (10x) and intraspecies variation (10x) and no additional UF/SF are required. See Table 4.5.4.1

2: MOE food + water = short

- term oral NOAEL (10 mg/kg/day)/chronic dietary exposure from DEEM.

3: MOE oral = short

- term incidental oral NOAEL (10 mg/kg/day)/hand

- to

- mouth residential exposure

4: MOE dermal = NA see table 6.4a

5: MOE inhalation = short

- term inhalation NOAEL (81 mg/kg/day)/residential inhalation exposure 6: Aggregate MOE (food + water + residential) =
__________________1__________________

1/MOE Dietary + 1/MOE Oral + 1/MOE Dermal + 1/MOE Inhalation



### 7. 3 Cancer Aggregate Risk

The aggregate cancer risk assessment for the general U.S. population takes into account exposure estimates from dietary consumption of trifluralin from food, residential and drinking water sources. Exposures from residential uses are based on the lifetime average daily dose and assume an exposure period of 5 days per year and 50 years of exp osure in a lifetime

. Average

food+ water source dietary exposure was used. Estimated cancer risk for the general U.S. population includes infants and children; therefore, in accordance with HED Policy, a children’s cancer risk estimate was not reported s eparately.

### Page 33 of 56

The cancer potency estimate for trifluralin is 2.96 x 10 - 3 

### (mg/kg/day) - 1



### . A ggregate cancer risk

estimate from trifluralin residues in food and drinking water are below HED’s level of concern for the general U.S. population.

Table 7.5 Aggregate Cancer Risk Estimates

Population Cancer Slope

Factor (Q 1 *) (mg/kg/day)

- 1 Food and Water

Exposure (mg/kg/day) 1 Residential

Exposure (LADD mg/kg/day 2 Aggregate

Cancer Risk (food, water, residential) US Population 2.96 E

- 0 3 0.00007 0.00028 1 E

- 06

1 Food and water exposure may different than the chronic exposure value, since EFED calculates the water exposure differently.

2 Cite source of residential exposure values used in aggregate assessment (Table 6.4b ).

3 Aggregate Cancer Risk = (Q 1 *) (Food & Water Exposure + LADD)



### 8.0 Cumulative Exposure/Risk Characterization

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

to triflu ralin and any other substances, and trifluralin does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed trifluralin has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerni ng 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

Since this request is for a conversion of existing tolerance to a crop group tolerance, a n occupational exposure and risk assessment was not conducted at this time,

10.0 References

DP#: 4 10618 Subject: Trifluralin: Acute, Chronic, and Cancer Aggregate Dietary ( Food and Drinking

Water ) Exposure and Risk Assessmen ts for the Section 3 Registration Action on Oilseed Crop Group 20.

From: S.Piper

To: A. Ertman and B. Madden

Date: 04/02 /12

MRIDs: NA

### Page 34 of 56

DP#: 401006 Subject: Drinking Water Exposure Assessment to Establish Tolerances of Parent

Trifluralin and its Degradates for Oilseed Crop Group 20.

From: F. Khan

To: A. Ertman and B. Madden

Date: 07/02/2012

MRIDs: NA

00044337 Emmerson , J.L.; Pierce, E.C.; McGrath, J.P.; et al. (1980) The Chronic Toxicity of

Compound 36352 (Trifluralin) Given as a Component of the Diet to Fischer 344 Rats

for Two Years: Studies R

- 87 and R

- 97. (Unpublished study received Sep 18, 1980

under 1471

- 35; subm itted by Elanco Products Co., Div. of Eli Lilly and Co., Indianapolis, Ind.; CDL:243289

- A, 243290)

00044338 Emmerson, J.L.; Owen, N.V.; McGrath, J.D.; et al. (1980) The Chronic Toxicity of

Compound 36352 (Trifluralin) Given as a Component of the Diet to the B6C3F1

Mouse for 24 Months: Studies M

- 9067 and M

- 9077. (Unpublished study received Sep 18, 1980 under 471

- 35; submitted by Elanco Products Co., Div. of Eli Lilly and Co., Indianapolis, Ind.; CDL:243291

- A; 243292; 243293)

00126661 Oberly, T.; Emerson , J.; Bewsey, B.; et al. (1983) The Effect of Trifluralin

(Compound 36352) on the Induction of Forward Mutation at the Thymidine Kinase Locus of L5178Y Mouse Lymphoma Cells: Study 830201MLA2055. (Unpublished study received Apr 5, 1983 under 1471

- 70; submi tted by Elanco Products Co., Div. of Eli Lilly and Co., Indianapolis, IN; CDL:249846

- C)

00124928 Weisburger, J.; Weisburger, E.; Powers, M.; et al. (1977) Bioassay of Trifluralin for

Possible Carcinogenicity: DHEW Publication No. (NIH) 78

- 834; Pre

- RPAR R eview Submissions #4 and #5. (Unpublished study received Nov 9, 1977 under 1471

- 35; prepared by U.S. National Institutes of Health, National Cancer Institute, Div. of Cancer Cause and Prevention, Carcinogenesis Testing Program and others, submitted by Ela nco Products Co., Div. of Eli Lilly and Co., Indianapolis, IN; CDL:233235

- A; 233234)

00132820 Bridge, T.; van Lier, R.; Adams, E.; et al. (1982) Percutaneous Absorption of 14C

Ethalfluralin (EL

- 161, Compound 94961) in Monkeys: St udies M

- 6162 and P03282. (Unpublished study received Dec 2, 1983 under 4F3006; submitted by Elanco Products Co., Div. of Eli Lilly and Co., Indianapolis, IN; CDL:072180

- B)

00133426 Neal, S.; Emmerson , J.; Probst, G.; et al. (1983) The Effect of Trifluralin (Compound

36352) on the in vivo Induction of Sister Chromatid Exchange in Bone Marrow of Chinese Hamsters: Study 830207SCE2055. (Unpublished study received Dec 9, 1983 under unknown admin. no.; sub mitted by Elanco Products Co., Div. of Eli Lilly and Co., Indianapolis, IN; CDL:251921

- K)

### Page 35 of 56

00148318 Young, R. (1984) Evaluation of Triflurex Technical (Trifluralin) in the

CHO/HGPRT Forward Mutation Assay: Final Report: LBI Project No. 22207. Unpublishe d study prepared by Litton Bionetics, Inc. 27 p.

. 00148319 Moore, M. (1984) Evaluation of Triflurex Technical in the Rat Dominant Lethal

Assay: Final Report: Project No. 22203. Unpublished study prepared by Litton Bionetics. 69 p.

00148320 Ivett, J. (1984) Mutagenicity Evaluation Triflurex Technical, Batch No. 5320 in the

Bone Marrow: Cytogenic Assay: Final Report: LBI Project No. 22202. Unpublished study prepared by Litton Bionetics. 32 p.

00148345 Jagannath, D. (1984) Mutagenicity Evaluation of Triflurex Tech (Trifluralin) Batch

5230 in the Ames Salmonella/Microsome Plate Test: Final Report: LBI Project No. 20988. Unpublished study prepared by Litton Bionetics, Inc. 19 p.

00151894 Mellano, D. (1982) Study of the Capacity of the Test Article H OE 38474 OH at 208

to Induce "Unscheduled DNA Synthesis" in Cultured Hela Cells: Study No. M 372. Unpublished study prepared by Istituto Di Ricerche Biomediche "Antoine Marxer" S.p.A. 19 p.

00151895 Leist; Weigand; Kramer (1981) Testing of Hoe 38474

- A ctive Ingredient for

Mutagenicity in the Micronucleus Test following Oral Administration to NMRI Mice: (Code: HOE 38474 OH AT 208): Report No. 285/81. Unpublished report prepared by Hoechst Aktiengesellschaft. 16 p.

00151896 Horstmann (1984) Dominant

- l ethal Test for Determination of Mutagenic Effect in

Male NMRI

- mice after Oral Administration: Trifluralin: Code: Hoe 38474 OHZD99 0002: Report No. 84.0763. Un

- published report prepared by Hoechst Aktiengesellschaft. 89 p.

00151898 Fumero, S. (1982) Stu dy of the Mutagenic Activity "In Vitro" of the Compound HOE

38474 OH AT 208 with Schizosaccharomyces Pombe: Study No. M 374. Unpublished study prepared by Instituto Di Ricerche Biomediche "Antoine Marxer" S.p.A. 16 p.

00151899 Baeder, Weigand, Kramer (1 983) Testing for Embryotoxicity in Wister Rats following

Oral Administration: HOE 38474

- Active Ingredient: Report No. 83.0557: Study No.G2R0383. Unpublished study prepared by Hoechst Aktiengesellschaft. 51 p.

00151901 Becker, H. (1984) Multiple Generation Study in the Rat: Trifluralin Substance

TechnicalGrade (Code : HOE 38474 OH AT210): Project No. 008875. Unpublished study prepared by Research & Consulting Co., AG. 604 p.

00151902 Ellgehausen, H. (1984) Determina tion of Trifluralin Substance Technical Grade (Code : HOE 38474 O H T210) in Rodent Feed: Project No. 008875. Unpublished study prepared by Research & Consulting Co. 26

### Page 36 of 56

00151903 Westen, H. (1984) Multiple Generation Study in Rat: Trifluralin Substance

Technical Grade (Code: HOE 38474 O H AT210): Pathology Report Part II: Project

No008875. Unpublished study prepared by Research & Consulting Co., AG. 704 p.

00151904 Ullmann , L. (1982) 30 Day Repeated Dose Inhalation Toxicity Study with HOE 38474 OH AT 210 Active Ingredient (Technical) in Rats: Part 1: Project No. 005488. Unpublished study prepared by Research & Consulting Co., Ltd. 400 p.

00151905 Suter, P. (1983) 13

- Wee k Toxicity Study with Trifluralin (HOE 38474 O H AT210) in Mice following Dietary Administration: Report: Project No. 008842. Unpublished study prepared by Research & Consulting Co., AG. 223 p.

00151906 Schutz; Weigand; Kramer (1980) Repeated

- dose (3 Months) Oral Toxicity Study of

the Active Substance HOE 38474 (Code: HOE 38474 O H AT204) Administered in the Feed to Rats: Report No. 618/80. Unpublished study prepared by Hoechst Aktiengesellschaft. 422 p.

00151907 Brunk; Weigand; Kramer (1981) Tox icology Testing of Trifluralin (Hoe 38474 OH AT 204) by Repeated Oral Administration to Beagle Dogs for Six Months: Report No. 636/81. Unpublished report prepared by Hoechst Aktiengesellschaft. 742 p

00151908 Bathe, R. (1984) 12

- Month Oral Toxicity (Fee ding) Study in Beagle Dogs: Trifluralin

Substance Technical Grade (Code: HOE 38474 O H AT210): Project No. 008864: Report Part 1. Unpublished study prepared by Research & Consulting Co. 439 p

00152419 Byrd, R. (1984) A Teratology Study of Trifluralin ( El

- 152, Compound 36352)

Administered Orally to Charles River CD Rats: Study R08484. Unpublished study prepared by Lilly Research Labs. 308 p.

00152421 Byrd, R. (1984) A Teratology Study (II) of Trifluralin (El

- 152, Compound 36352)

Administered Orally to Dutch Belted Rabbits: Study B01784. Unpublished study prepared by Lilly Research Labs. 223 p.

00153171 Suter, P. (1982) 31 Days Dermal Toxicity Study with Hoe 38474 OH AT 210 Active

Ingredient (Technical) in Rats: Project 005490. Unpublished study prepared by Research & Consulting Co., Ltd. 450 p.
00152888 Negilski, D. (1985) Subchronic (21

- day) Dermal Toxicity Study in New Zealand

White Rabbits with Technical Trifluralin: Study B00184. Unpublished study pr epared by Lilly Research Laboratories. 222 p.

00153173 Engelbart (1979) Test for Mutagenicity in Bacteria Strains in the Absence and

Presence of a Liver Preparation: Hoe 38474 OH AT204 (Active Ingredient) Trifluralin: Report No. 74/79. Unpublished stu dy prepared by Hoechst AG. 7 p.

00155261 Leist, K. (1981) Four Hour LC50 Aerosol Inhalation Toxicity Study in Rats on HOE

38474 OH at 210 Active Ingredient (Technical): Report: Project 005477. Unpublished study prepared by Research & Consulting Co. Ltd. 37 p.

### Page 37 of 56

00157154 Jordan, W. (1983) A Preliminary Dietary Study of the Effects of Trifluralin on the

Urinary Tract of Male Fischer 344 Rats: Study No. R15083: Report No. 1. Unpublished study prepared by Lilly Research Labs. 89 p.

00 157156 Usher, R. (1985) A Special Urinalysis Study in Fischer 344 Rats Maintained on Diets

Containing Trifluralin (Compound 36352) for Three Months: Study No. R04785. Unpublished study prepared by Lilly Research Labs. 711 p.

00157482 Vigna, E. (1985) Trifluralin Technical: Acute Dermal Toxicity Study in Rats: RBM

Exp. No. 2159. Unpublished study prepared by Istituto di Ricerche Biomediche "Antoine Marxer", RBM S.p.A . 13 p.

00157483 Vigna, E. (1985) Trifluralin Technical: Acute Eye Irritation Study in Rabbits: RBM

Exp. No. 2160. Unpublished study prepared by Istituto di Ricerche Biomediche "Antoine Marxer", RBM S.p.A. 15 p.

00157484 Bassi, L. (1985) Trifluralin Technical: Dermal Sensitization Study in Guinea Pigs:

RBM Exp. No. I 892. Unpublishe d study prepared by Istituto di Ricerche Biomediche "Antoine Marxer", RBM S.p.A. 15 p.

00157485 Vigna, E. (1985) Trifluralin Technical: Acute Dermal Irritation Study in Rabbit:

RBM Exp. No. 2161. Unpublished study prepared by Istituto di Ricerche Biomed iche "Antoine Marxer", RBM S.p.A. 13 p.

00157486 Vigna, E. (1985) Trifluralin Technical: Acute Toxicity Study by Oral Route in Rats:

RBM Exp. No. 2162. Unpublished study prepared by Istituto di Ricerche Biomediche "Antoine Marxer", RBM S.p.A. 13 p.

00 158935 Suter, P. (1986) Oncogenicity Study with Trifluralin Active Ingredient Technical

(HOE 38474 O H AT210) in Mice: Project No. 008853. Unpublished study prepared by Research & Consulting Company AG. 6478 p.

00159616 Ebert, E. (1985) Trifluralin

- Act ive Ingredient Technical Testing for Acute Delayed

Neurotoxicity in White Leghorn Hens: Report No. 85.0742. Unpublished study prepared by Hoechst AG. 38 p.

00159618 Bathe, R. (1985) Trifluralin, Substance Technical Grade: 12

- Month Oral Toxicity

(Feeding) Study in Beagle Dogs: Concentration of Trifluralin, Substance Technical Grade in Dog Feed¿: Project No. 008864: Report No. A32778. Unpublished study prepared by Research & Consulting Co. AG. 4 p.

00159619 Becker, H. (1 985) Trifluralin, Substance Technical Grade: Multiple Generation Study

in the Rat: Diet Preparation, Stability, and Analysis of the Test Article¿: 1st Amendment to Report: Project No. 008875: Report No. A32777. Unpublished study prepared by Research & Co nsulting Co. AG. 4 p

00159620 Baeder; Mayer (1986) Testing for Embryotoxicity in Wistar Rats following Oral

Administration of Hoe 38474: Incidence of Wavy Ribs in Control Studies and at Dose Levels Toxic to Either Dams or Embryos: Supplement to Report N o.83.0557: Report No. 86.0166.Unpublished study prepared by Hoechst AG. 15 p.

00162458 Donaubauer (1986) Carcinogenicity Study in Rats (28

- month Feeding Study):

Trifluralin: Study No. 680: Report No. 85.0087. Unpublished study prepared by
Hoechst Aktie ngesellschaft, Pharma Forschung Toxikologie. 3126 p.

### Page 38 of 56

00162543 Hoyt, J. (1986) A One

- year Two

- generation Reproduction Study in CD Rats

Maintained on Diets Containing Trifluralin (EL

- 152, Com

- pound 36352): Studies R06384 and R13984. Unpublished study pr epared by Lilly Research Laboratories. 778 p.

00162457 Donaubauer (1986) Chronic Feeding Study (24 Months) in Rats: Trifluralin: Study

No. 680: Report No. 85.0302. Unpublished study prepared by Hoechst Aktiengellschaft, Pharma Forschung Toxikologie. 1 837 p.

40138301 Usher, R. (1986) A Supplementary Report of a Special Urinalysis Study in Fischer

344 Rats Maintained on Diets Containing Trifluralin (Compound 36352) for Three Months: Study R04785. Unpublished study prepared by Lilly Research Laboratori es. 263 p.

40334707 Loveday, K. (1987) Evaluation of Trifluralin in the Ames Mutagenesis Assay: ADL

Reference: 88720

- 68. Unpublished study prepared by Arthur D. Little, Inc. 28 p.

40392310 Leist, K.; Penseler , D.; Mayer (1987) Trifluralin Substance Technical Grade (Code:

HOE 38474 OH AT210): Testing for Embryotoxicity in Wistar Rats following Oral Administration: Supplementary Data in Support of Previously Submitted Study Acc. No. 258993: Laboratory Project No . 87.0997, Report No. A 36041. Unpublished study prepared by Hoechst Aktiengesellschaft. 19 p.

40392312 Ullman, L. (1987) 30

- Day Repeated Dose Inhalation Toxicity Study with HOE 38474

OH at 210 in Rats: Amended Version of Previously Submitted Study Acc . No. 258996: Laboratory Project No. 005488, Report No. A 22688 and A 36084. Unpublished study prepared by Research & Consulting Co. Ag. 711 p.

40392313 Suter, P.; Horst, K.; Vogel, W.; et al. (1987) Oncogenicity Study with Trifluralin

Active Ingredient Technical (HOE 38474 OH AT210) in Mice: Supplementary Data in Support of Previously Submitted Study Acc. No. 262516

- 262520: Laboratory Project No. 008853, Report No. A 36197. Unpublished study prepared by Research & Consulting Co. AG. 47 p.

40405007 R ubin, Y.; et al. (1987) Triflurex: Two

- generation Reproduction Study in theRat:

Laboratory Project ID AGN/125/TRI. Unpublished study prepared by Life Science Research Israel Ltd. 1664 p.

40673701 Adams, E.; Glass, S.; Van Lier, R. (1988) Percutaneous (De rmal) Absorption of

Carbon 14

- Trifluralin in Rhesus Monkeys: Laboratory Project ID: P07487 and P03087. Unpublished study prepared by Lilly Research Laboratories. 55 p

.

40765601 Young, R. (1988) Mutagenicity Test on Trifluralin Technical Grade: Batch N umber

39 in the CHO/HGPRT Foreward Mutation Assay: Project ID. 10137

- 0

- 435. Unpublished study prepared by Hazleton Laboratories America, Inc. 46 p.

40765602 Cifone, M. (1988) Mutagenicity Test on Trifluralin, Technical Grade in the Rat

Primary Hepatoc yte Unscheduled DNA Synthesis Assay: Project ID. 10137

- 0

- 447. Unpublished study prepared by Hazleton Laboratories America, Inc. 39 p.

40765603 Ivett, J. (1988) Mutagenicity Test on Trifluralin Technical Grade in the Mouse Bone

Marrow and Spermatogonial Cell Cytogenetics Assay: Project ID. 10137

- 0

- 473. Unpublished study prepared by Hazleton Laboratories America, Inc. 51 p.

### Page 39 of 56

40822202 Adams, E. and Poulsen, R. G. (1988) The Acute Dermal Toxicity and Primary

Dermal Irritation of Technical Trifluralin in the New Zealand White Rabbit. Unpublished study prepared by Lilly Research Laboratories, 18p.

41086101 Adams, E.; Bendele, R.; Emmerson, J. (1989) Reanalysis and Discussion of Urine

Protein Electrophoresis Data from a Special Urinalysis Study in Fischer 344 Rats with Trifluralin (Compound 36352). Unpublished supplemental submission prepared by Lilly Research Laboratories 63p.

41218901 Magnussen, J. (1989) Identification of the Urinary Metabolites of carbon 14Trifluralin in Rats: Project ID: E xperiment ABC

- 0433. Unpublished study prepared by Lilly Research Laboratories. 53 p.

41993810 Vedula, U.; Kociba, R.; Bond, D. (1991) XRM

- 5313: A Formulation Containing

Trifluralin and XRD

- 498

-- 21 Day Dermal Study in New Zealand White Rabbits: Lab Proj ect Number: M

- 005313

- 003A. Unpublished study prepared by The Dow Chemical Co., Tox. Research Lab. 166 p.42447001 Adams, E.; Bernhard, N.; Jordon, W. (1992) A Chronic Toxicity Study of Trifluralin (Compound 036352) Administered Orally to Beagle Dogs for O ne Year (Supp.): Lab Project Number: D07190. Unpublished study prepared by Lilly Research Labs. 470 p.

42972701 Shapiro, R. (1993) EPA Acute Oral Toxicity

- Defined LD50 in Rats: Trilin 5, Lot

#227284: Lab Project Number: T

-- 2527: 2527: P320. Unpublished study prepared by Product Safety Labs. 34 p.

42972702 Shapiro, R. (1993) EPA Acute Dermal Toxicity Limit Test: Rabbits: Trilin 5, Lot

227284: Lab Project Number: T

-- 2530: 2530: P322. Unpublished study prepared by Product Safety Labs. 20 p.

42972703 Shapiro, R. (1993) EPA Acute Inhalation

-- Defined LC50: Rats: Trilin 5, Lot #

227284: Lab Project Number: T

-- 2532. Unpublished study prepared by product Safety Labs. 54 p.

42972704 Shapiro, R. (1993) EPA Primary Eye Irritation: Rabbit: Trilin 5, Lot #227 284: Lab

Project Number: T

-- 2528: P324: E30715

- 1. Unpublished study prepared by Product Safety Labs. 30

42972705 Shapiro, R. (1993) EPA Primary Dermal Irritation Test: Rabbits: trilin 5, Lot 227284:

Lab Project Number: T

-- 2529: 2529: P326. Unpublishe d study prepared by Product Safety Labs 23 p.

42972706 Shapiro, R. (1993) EPA Topical Skin Sensitization Test in Guinea Pigs (Buehler):

Trilin 5, Lot #227284: Lab Project Number: T

-- 2531: 2531. Unpublished study prepared by Product Safety Labs. 33 p.

4 3447301 Kuhn, J. (1994) Trific 10G: Acute Oral Toxicity Study in Rats: Lab Project Number:

0875

- 93. Unpublished study prepared by Stillmeadow, Inc. 11 p.

43447302 Kuhn, J. (1994) Trific 10G: Acute Dermal Toxicity Study in Rabbits: Lab Project

Number: 0876

- 93. Unpublished study prepared by Stillmeadow, Inc. 11 p.

43447303 Holbert, M. (1994) Trific 10G: Acute Inhalation Toxicity Study in Rats: Lab Project

Number: 0877

- 93. Unpublished study prepared by Stillmeadow, Inc. 20 p.

### Page 40 of 56

43447304 Kuhn, J. (1994) Trific 10G: Primary Eye Irritation in Rabbits: Lab Project Number:

0878

- 93. Unpublished study prepared by Stillmeadow, Inc. 18 p.

43447305 Kuhn, J. (1994) Trific 10G: Primary Dermal Irritation in Rabbits: Lab Project

Number: 0879

- 93. Unpublished study prepared by Stillmeadow, Inc. 12 p. 43447306 Kuhn, J. (1994) Trific 10G: Dermal Sensitization Study in Guinea Pigs: Lab Project
Number: 0880

- 93. Unpublished study prepared by Stillme adow, Inc. 17 p.

44135107 Adams, E.; Markham, J. (1996) A One

- Year Two

- Generation Reproduction Study in

CD Rats Maintained on Diets Containing Trifluralin: Supplement #1 to MRID No. 00162543: Lab Project Number: R06384: R13984

- S1: R13984. Unpublished st udy prepared by Lilly Research Labs. 16 p

92062028 Environ Corp. (1990) Dowelanco Phase 3 Summary of MRID 00132820.

Percutaneous Absorption of (Carbon

- 14)

- Ethalfluralin in Monkeys: M

- 6162 and P03282. Prepared by LILLY RESEARCH LABS. 7 p

IARC (1991) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans,

Trifluralin, Vol 53, 1991

USEPA (1979) Trifluralin (Treflan®) Position Document 1/2/3, 44 FR 50911, NTIS #

PB80

- 213937, Aug 30, 1979.

USEPA (1982) Alpha, alpha, alpha

- triflu oro

- 2,6

- dinitro

- N,N

- dipropyl

- p

- toluidine, Trifluralin

(Treflan®) Position Document 4, 47 FR 33777, NTIS# PB82

- 263252, Aug 4,

1982.

MEMORANDUM

Jaeger, R.B. (1986). Peer Review of Trifluralin, dated April 11, 1986. TXR No. 0005578.

Rowland, J. and Doyle, E. (2003). Trifluralin (P.C. Code 036101): Report of the Hazard

Identification Assessment Review Committee, dated May 2, 2003; TXR

No. 0051869. Fricke, R. (2003). Trifluralin: Toxicology Disciplinary Chapter for the Tolerance Reassessment

Eli gibility Decision Document, dated October 2, 2003. Piper, S. (2004). Trifluralin: Metabolism Assessment Review Committee Briefing

Memorandum, dated January 6, 2004. Griffin, R (2004). Trifluralin: Human Health Risk Assessment. DP Barcode 296628, d ated May

7, 2004.

Brunsman, L. (2004). Trifluralin: Quantitative Risk Assessment (Q 1 * 

### ) based on Fischer 344 Rat

Dietary Studies With 3⁄4’s Scaling Factors, dated May 8, 2003. TXR No.

0051890. Brunsman, L. (2004). REVISED Trifluralin: Quantitative Ri sk Assessment (Q 1 * 

### ) based on

Fischer 344 Rat Dietary Studies With 3⁄4’s Scaling Factors, dated May 11,

2004. TXR No. 0052534.

### Page 41 of 56

Copley, M. (2007). Trifluralin: Corrected DERs and Executive Summaries, dated August 27,

2007. TXR No. 00547000. Rury, K. (2013). Trifluralin: Summary of Hazard and Science Policy Council

(HASPOC) Meetings of March 6, 2012: Recommendations on the need for the neurotoxicity battery (acute and subchronic neurotoxicity studies) TXR No. 0055275.

Appendix A. Toxicology Pro file 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 Trifluralin are in Table A.1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols

were used.



### Table A.1 Toxicology Data Requirements for Trifluralin

Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity

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

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

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

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

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

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

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

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

................................ ........ 870.3200 21/28

- Day Dermal

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

- Day Dermal

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

- Day Inhalation

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

yes

yes

no

no yes a

yes b

yes

--- Waived/Yes (c)

870.3700 Developmental Toxicity (rodent)

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

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

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

yes

yes yes

yes

yes

870.4100 Chronic Toxicity (rodent)

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

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

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

................................ .................. 870.4300 Chronic/Oncogenicity (mouse)

................................ .... 870.4500 Chronic/Oncogenicity (rat)

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

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

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

— Gene Mutation

- mammalian

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

yes yes

yes

870.5375 Mutagenicity

— Structural Chromosomal Aberrations

.. 870.5385 Mutagenicity

— Structural Chromosomal Aberrations

.. 870.5395 Mutagenicity

— Other Genotoxic Effects

...................... 870.5550 Mutagenicity

— Other Genotoxic Effects

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

yes

yes

yes Yes

yes

yes

yes

870.6100 Acute Delayed Neurotox. (hen)

................................ .... 870.6100 90

- Day Neurotoxicity (hen)

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

...................... 870.6200 Chronic Neurotox. Screening Battery (rat)

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

no

yes

yes Yes

--- Waived/yes c Waived/yes c

### Page 42 of 56

Test Technical

Required Satisfied

870.6300 Develop. Neuro

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

---

870.7485 General Metabolism

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

................................ ....................... 870.7800 Immunotoxicity yes

no

yes Yes

---

no

a Guideline satisfied by the findings of the 24

- month carcinogenicity study in mice (MRID 40392313).

b Guideline satisfied by the findings of the 1

- year oral study in dogs (MRID 42447001).

c Data requirement waived by HASPOC , March 6, 2013 ( TXR No. 0055275).

### Page 43 of 56

A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Studies for Trifluralin, Technical

Guideline

No. Study Type MRID No. Results Toxicity Category

870.1100 Acute Oral (Rat) 00157486 (1985)

Acceptable/Guideline LD50 > 5000 mg/kg

IV

870.1200 Acute Dermal (Rat) 00157482 (1985)

Acceptable/Guideline LD50 > 2000 mg/kg

III

870.1200 Acute Dermal (Rabbit) 00158820 (1985)

Acceptable/guideline LD50 > 2000 mg/kg

III

870.1200 Acute Dermal (Rabbit) 40822202 (1988)

Acceptable/guideline LD50 > 5000 mg/kg

IV

870.1300 Acute Inhalation (Rat) 00155261 (1982)

Acceptable/guideline LC50 > 4660 mg/m 3 , 4.66 mg/L

IV

870.2400 Primary Eye Irritation

(Rabbit) 00157483 (1985)

Acceptable/Guideline Conjunctival redness at 24hr, cleared by 4 days

III

870.2500 Primary Skin Irritation 00157485 (1985)

Acceptable/Guideline Not an irritant

IV

870.2600 Dermal Sensitization 00157484 (1985)

Acceptable/Guideline Sensitizing agent

N/A

### Page 44 of 56

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

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

/Doses Comments

870.3100

2

- Week R

- F Feeding

- Rats (male) 00157154 (1983)

0, 6500 ppm

range

- finding study for 00157156 (1985), 41038301 (1986)

Acceptable/Nonguideline NOAEL = not achieved LOAEL = 6500 ppm based on renal epith damage, urine triple phosphates crystals and urinary

sediment

870.3100

90

- Day Oral toxicity

- Rat 00151906 (1980)

0, 800, 2000, or 5000 ppm M: 0, 59, 154, and 392 mg/kg/day F: 0, 69, 168, and 421 mg/kg/day

Acceptable/Guideline NOAEL = 2000 ppm (154/168 mg/kg/day, M/F) LOAEL = 5000 (392/421 mg/kg/day, M/F) Based on minor decreases in overall body weight gains and food consumption in males and females, decreased hemoglobin, alkaline phosphatase, and alanine aminotransferase in the males, and increased absolute and relative (to body) liver weights in males and females.

870.3200

21/28

- Day dermal toxicity

- rabbit 41993810 (1991)

0, 100, 500, or 1000 mg/kg /day,
[ formulation containing 35.8%

trifluralin and 2.6% XRD

- 498]

Acceptable/Guideline Systemic NOAEL =1000 mg/kg/day Systemic LOAEL = Not achieved

Dermal NOAEL = Not achieved Dermal LOAEL = 100 mg/kg/day, edema, and/or scaling and fissuring 100 mg/kg/day based skin

irritation

870.3200

31

- Day dermal toxicity

rat 00153171 (1982)

0, 40, 200, or 1000 mg/kg/day

Acceptable/Guideline Systemic NOAEL = 1000 mg/kg/day (limit dose) Systemic LOAEL = not achieved

Dermal NOAEL = 40 mg/kg/day. Dermal LOAEL = 200 mg/kg/day based on sub

epidermal inflammation and ulcerations in males

and females.

870.3200

21/28

- Day dermal toxicity

- rat 00152888 (1985)

0, 1000 mg/kg/day (limit dose)

Acceptable/Guideline Systemic NOAEL = 1000 mg/kg/day. Systemic LOAEL = Not achieved

Dermal NOAEL= Not achieved Dermal LOAEL = 1000 mg/kg/day (limit dose) based on erythema, edema, and desquamination of the treated skin.

870.3465

30

- Day inhalation toxicity 40392312 (1987) reformat of 00151904 (1982)

0, 100, 301, 1006 mg/m 3
(6 hours/day 5 days/week for up to 30 days)

Acceptable/Nonguideline NOAEL = 301 mg/m 3 (81 mg/kg/day) LOAEL = 1006 mg/m 3 (300 mg/kg/day) based on increased methemoglobin and bilirubin in females and incidences of dyspnea and ruffled fur in males

and females.

### Page 45 of 56

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

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

/Doses Comments

870.3700 [83

- 3(a)]

Developmental Toxicity Study

- Rat 00151899 (1983), 00159620 (1986), 40392310 (1987)

0, 20, 100, 500 mg/kg/day Acceptable/Guideline Systemic Maternal NOAEL = 100 mg/kg/day Systemic Maternal LOAEL = 500 mg/kg/day based on mortality, clinical signs, decreased body weight gains, decreased food consumption, and increased liver and spleen weights, Developmental NOAEL =100 mg/kg/day. Developmental LOAEL = 500 m g/kg/day based on

reduced ossification of the vertebrae and ribs and thickened, wavy or bent ribs and increased of incidences of total resorptions

870.3700 [83

- 3(a)]

Developmental Toxicity Study

- Rat 00152419 (1984) 0, 100, 225, 495, or 1000 mg/kg/day Acceptable/Guideline Maternal NOAEL = 495 mg/kg/day Maternal LOAEL = 1000 mg/kg/day based decreased body weights and decreased food consumption.

Offspring NOAEL = 495 mg/kg/day Offspring LOAEL = 1000 mg/kg/day based on

decreased fetal body weights.

Developmental NOAEL = 1000 mg/kg/day
Developmental LOAEL was not established



### .

870.3700 [83

- 3(b)]

Developmental Toxicity

- Rabbit 00152421 (1984)

0, 100, 225, 500 mg/kg/day

Acceptable/Guideline Maternal NOAEL = 100 mg/kg/day Ma Maternal LOAEL = 225 mg/kg/day based on abortions, macroscopic changes in the liver and lungs, and decreased food consumption abortions, macroscopic changes in the liver and lungs, and decreased food consumption.

Developmental NOAEL = 100 mg/kg/day Developmental LOAEL = 225 mg/kg based on

abortions.

### Page 46 of 56

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

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

/Doses Comments

870.3800 [83

- 4]

2

- Gen Repro

- Rat 00151901 (1984) 00151902 (1984) Feed analysis 00151903 (1984) Path 00159619 (1985) Supplement

0, 200, 650, 2000 ppm 0, 20, 32.5, 200 mg/kg/day (1 ppm = 0.5 mg/kg/day)

Acceptable/Guideline Parental NOAEL = 200 ppm (10 mg/kg/day). Parental LOAEL = 650 ppm (32.5 mg/kg/day)

based on mortality due to acute renal failure and increased lesions of the renal proximal tubules in the F1 females; increased relative (to body) weights of the liver, kidney (males), and testes in both generations.

Offspring NOAEL = 200 ppm (10 mg/kg/day)

Of fspring LOAEL = 650 ppm (32.5 mg/kg/day) based on decreased pup weights in both generations and increased relative to body liver weights in the F2b females

Repro NOAEL = 2000 ppm (100 mg/kg/day) Repro LOAEL = Not established.

870.3800 [83

- 4]

2

- Gen Repro

- Rat 00162543 (1986) 44135107 (1996)

0, 200, 630, 2000 ppm 0, 15, 47, 148 mg/kg/day

Acceptable/Guideline Parental NOAEL = 200 ppm (15 mg/kg/day) Parental LOAEL = 630 ppm (47 mg/kg/day), based on decreased BWG and food consumption

Offspring NOAEL = 200 ppm (15 mg/kg/day) Offspring LOAEL = 630 ppm (47 mg/kg/day) based on small pup size in 3 litters

Repro NOAEL = 2000 ppm (148 mg/kg/day) Repro LOAEL = Not established

870.3800 [83

- 4]

2

- Gen Repro

- Rat 40405007 (1987)

0, 50, 450, 4000 ppm M: 0, 3.9, 35, 295 mg/kg/day F: 0, 4.7, 42, 337 mg/kg/day

Acceptable/Guideline Parental NOAEL = 450 ppm [35/42 mg/kg/day M/F] Parental LOAEL = 4000 ppm [295/337 mg/kg/day M/F] based on decreased body weights, body weight gains, food consumption, and food efficiency in males and females of both generations; decreased ovary weights in both generations; colon distension in the F1 m ales; and uterine atrophy in the females of both generations.

Offspring NOAEL = 450 ppm (35/42 mg/kg/day M/F] Offspring LOAEL = 4000 ppm [295/337mg/kg/day M/F] based on decreased pup weight

in F1a litters

Repro NOAEL = 450 ppm (35/42 mg/kg/day) Repro LOAEL = 4000 ppm [295/337 mg/kg/day , M/F), based on decreased fetal, neonatal, and litter viability and decreased lactation index in the F1a pups; and decreased number of implantation sites, newborn pups, litter size, and pup weights in both gener ations.

870.4100 [83

- 1(b)]

1

- Year Oral (capsule) Study

- Dog 42447001 (1992)

0, 0.75, 2.4, 40 mg/kg/day Systemic NOAEL = 2.4 mg/kg/day Systemic LOAEL = 40 mg/kg/day, based on increased frequency of abnormal stool, decreased body weights and body weight gains, and on

### Page 47 of 56

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

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

/Doses Comments

Acceptable/Guideline decreased erythrocytes and hemoglobin and increased thrombocytes in males.

870.4300 [83

- 5(a)]

24

- Month Chronic Toxicity/ Carcinogenicity Study

- Rat 00162457 (1985), 00162458 (1985)

0, 200, 800, or 3200 ppm M: 0, 10, 40, and 169 mg/kg/day F: 0, 13, 53, and 219 mg/kg/day

Unacceptable/guideline NOAEL = 800 ppm (40/53 mg/kg/day M/F). LOAEL = 3200 ppm (169/219 mg/kg/day M/F) based on decreases in body weight and body weight gains.

At the doses tested, the carcinogenic potential of trifluralin was negative. Dosing was considered adequate, based on the differences in body weight and body weight gain.

870.4300 [83

- 2(a)]

24

- Month Carcinogenicity Study

- Mouse 00158935 (1986), 40392313 (1987)

0, 50, 200, or 800 ppm M: 0, 7.5, 29, and 118 mg/kg/day F: 0, 10.5, 41, and 165 mg/kg/day

Unacceptable/guideline Systemic NOAEL = 800 ppm (118/165 mg/kg/day in males/females) Systemic LOAEL = Not achieved

At the doses tested, the c arcinogenic potential of trifluralin was negative. Dosing was considered inadequate as a toxic effect was not observed, and

the limit dose was not tested. The LOAEL was not observed and the range

- finding study indicated that dosing was adequate. The NOA EL for the range finder was 2500 ppm (equivalent to 375 mg/kg/day), the highest dose tested.

870.5100 Bacterial reverse gene mutation assay MRID 00148345 (1984) Acceptable/Guideline Trifluralin was tested up to the limit of solubility (400 μg/plate

- S9; 800 μg/plate +S9). No cytotoxicity was observed in any strain at up to 800 (+S9) or 400 (

- S9) μg/plate. No treatment

- related increases in revertant colonies were observed at any

dose in any strain (±S9). The positive controls induced the appropriate responses. There was no

evidence of induced mutant colonies over background

### Page 48 of 56

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

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

/Doses Comments

870.5100 Bacterial reverse gene mutation assay MRID 40334707 (1987) Acceptable/Guideline In a reverse gene mutation assay in bacteria (MRID 40334707), Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538 were exposed to trifluralin (96.8% a.i., Lot/Batch #: 335/336) in dimethyl sulfoxide (DMSO) at concentrations of 30, 100, 300, 1000, 3000, or 10,000 μg/plate in the presence and absence of mammalian metabolic activation (S9). The standard plate incorporation method was used.

Standard strain

- specific mutagens served as positive controls.

Trifluralin was tested up to the lim it of solubility (3000 μg/plate, +/

- S9). No cytotoxicity was observed in any strain at up to 3000 μg/plate (+/

- S9). No treatment

- related increases in revertant colonies were observed at any dose in any strain (+/

- S9). The positive controls induced the

a ppropriate responses. There was no evidence of induced mutant colonies over background.

870.5100 Bacterial reverse gene mutation assay MRID 00153173 (1979)

Acceptable/Guideline In a reverse gene mutation assay in bacteria (MRID 00153173), Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538 were exposed to HOE 38474 (trifluralin; purity not reported; Lot/Batch #: OH AT204) in DMSO at concentrations of 0, 4, 20, 100, 500, 2500, or 10,000 μg/plate (+/

- S9). Standard strain

- s pecific positive controls were used.

HOE 38474 was tested up to the limit dose (10,000 μg/plate, +/

- S9). No treatment

- related increases in revertant colonies were observed at any dose in any

strain (±S9). The positive controls induced the appropriate responses. There was no evidence of induced mutant colonies over background

.

870.5250 Gene Mutation Assay

- Yeast MRID 00151898 ((1982) Acceptable/Guideline The test material was tested up to the limit of solubility (1000 mg/L); however, no solubility data were provided. No treatment

- related increases in mutation frequency were observed at any dose with

or without S9

- activation. The positive controls induced the appropriate response . There was no concentration

- related positive response of induced mutant colonies over background

.

### Page 49 of 56

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

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

/Doses Comments

870.5300

In vitro mammalian cell gene mutation assay MRID 00126661 Acceptable/Guideline In a mammalian cell gene mutation assay at the thymidine kinase (TK) locus, mouse lymphoma L5178Y cells cultured in vitro were exposed to trifluralin (95.0% a.i.; Lot/Batch #: 00554AP2) in DMSO for 4 hours at 8 concentrations ranging from 0.5 to 20 μg/mL ( individual doses not reported) both in the presence and absence of S9

- activation.

Trifluralin was tested up to cytotoxic concentrations (20 μg/mL, +/

- S9). No treatment

related increases in mutation frequency were observed at any dose compared to control s. The positive controls induced the appropriate response.

There was no concentration

- related positive

response of induced mutant colonies over background.

870.5300

Mammalian Cell Forward Gene Mutation Assay MRID 40765601 (1988) Acceptable/Guideline In a mammalian cell gene mutation assay at the HGPRT locus (MRID 40765601), Chinese hamster ovary (CHO) cells cultured in vitro were exposed to trifluralin (97.6% a.i.; Lot/Batch #: 39) in dimethyl

sulfoxide for 4 hours at concentrati ons of 50, 100, 150, 200, 300, 400, or 500 μg/mL (Trial 1,

- S9); 50, 100, 200, 300, 500, 600, or 700 μg/mL (Trial 2,

- S9); 50, 100, 200, 250, 300, 400, or 500 μg/mL (Trial 1, +S9); and 50, 100, 200, 300, 400, 500, or 600 μg/mL (Trial 2, +S9).

Trifluralin was tested up to cytotoxic concentrations (>=200 μg/mL, +/

- S9) and the limit of solubility (>=100 μg/mL, +/

- S9). No treatment

related increases in mutant frequency were observed in either trial in the presence or absence of S9. The positive controls indu ced the appropriate

response. There was no evidence of induced mutant colonies over background in the presence or absence of S9

- activation.

### Page 50 of 56

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

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

/Doses Comments

870.5300

Mammalian Cell Forward Gene Mutation Assay MRID 00148318 (1984) Acceptable/Guideline In a mammalian cell gene mutation assay at the HGPRT locus (MRID 00148318), Chinese hamster ovary (CHO) cells cultured in vitro were exposed to triflurex technical (trifluralin; purity not reported; Lot/Batch #: not reported) in ethanol for 4 hours at

conc entrations of 10, 50, 100, 200, 300, 400, or 500 μg/mL (

- S9) and 50, 100, 200, 300, 400, 500, or 600 μg/mL (+S9).

Triflurex technical was tested up to cytotoxic concentrations (>=200 μg/mL,

- S9 and >=300 μg/mL, +S9) and the limit of solubility (>=100 μg/m L, +/

- S9). No treatment

- related increases in mutant frequency were observed in either trial in the presence or absence of S9. The positive controls induced the appropriate response. There

was no evidence of induced mutant colonies over background in the presence or absence of S9

- activation.

870.5385

In Vivo Mammalian Cytogenetics [Bone Marrow/Spermatogonial Aberration Test] MRID 40765603 (1988) Acceptable/Guideline In a bone marrow/spermatogonial chromosome aberration assay (MRID 40765603), ICR mice (10 males/dose, spermatogonial tissue; and 5/sex/dose, bone marrow) were dosed once daily via gavage (10 mL/kg) with trifluralin (97.6% a.i., Lot/Batch No 39) in corn oil at doses of 0, 62.5, 208, or 6 25 mg/kg for 5 consecutive days. Bone marrow and spermatogonial cells were harvested at 4.5 hours

after the last treatment.

Mortalities were observed in the 625 mg/kg females (2/5 treated vs. 1/5 controls), and at 62.5 mg/kg in the males (2/10 treated v s. 1/10 controls) and females (2/5 treated vs. 1/5 controls). Clinical signs of toxicity (lethargy, swollen neck, and yellow stains around the mouth and perianal area) were also observed at >=62.5 mg/kg. No statistically significant increases in the pe rcent of aberrant cells were observed at any dose in either sex in the bone marrow assay or in the males in the spermatogonial assay. Trifluralin was tested at an adequate dose based on mortalities observed at >=62.5 mg/kg. The positive control induced t he appropriate response. There was no evidence of

chromosome aberration induced over background

### Page 51 of 56

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

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

/Doses Comments

870.5385

In Vivo Mammalian Cytogenetics [Bone

Marrow Chromosome Aberration Test] MRID 00148320 Acceptable/Guideline In a bone marrow chromosome aberration assay (MRID 00148320), 5 Sprague

- Dawley (HSD:([SD] BR) rats/sex/dose/sacrifice time were treated once via oral gavage with Triflurex technical (trifluralin; 97.3% a.i.; Batch #: 5320), in corn oil at doses of 0, 500, 1650, or 5000 mg/kg. Bone marrow cell s were harvested at 6, 24, or 48 hours after treatment.

Mortality was observed at 1650 (3/15 males and 5/15 females) and 5000 (2/15 males and 1/15 females) mg/kg upon initial dosing; however, these animals were replaced and only one replacement 1650 mg/kg female in the 48 hour group died after

dosing. Triflurex technical induced minimal bone marrow toxicity (as indicated by decreased mitotic index) at 500 mg/kg in males and 1650 mg/kg in females. Dosing was considered adequate based on

bone marrow tox icity and that the animals were dosed above the limit dose (2000 mg/kg). No statistically significant increases in the percent of aberrant cells were observed at any dose or sampling time compared to concurrent controls. The positive control induced the appropriate

response. There was no evidence of chromosome aberration induced over background

.

870.5395

In vivo Mouse Erythrocyte Micronucleus

assay MRID 00151895 (1981) Acceptable/Guideline In a bone marrow micronucleus assay, 5 NMRI mice/sex/dose were treated via oral gavage with HOE 38474 (Trifluralin; 98.3% a.i., Lot/Batch #: OH AT208), in sesame oil at doses of 0, 25, 250, or 2500 mg/kg on two consecutive days (24 hours apart). Bone marr ow cells were harvested at 6

hours after the last treatment.

No unscheduled deaths occurred during the study. No clinical signs of toxicity were observed. No statistically significant differences in the number of micronucleated polychromatic erythrocyte s (MPCE) or normocytes and no decrease in polychromatic erythrocyte to normocyte (PCE:NCE) ratios were noted in the treated animals compared to controls; however, only individual data were provided. Additionally, although no evidence of cytotoxicity (decr eased PCE: NCE) was noted in the bone marrow, the animals were sufficiently dosed (the limit dose was given twice). The test material was absorbed as indicated by the presence of orange urine in the 2500

- mg/kg

### Page 52 of 56

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

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

/Doses Comments

animals. The positive control induced the

a ppropriate response. There was no significant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow compared to controls.

870.5450

Dominant Lethal

- Rat MRID 00148319 (1984) Acceptable/Guideline In a dominant lethal assay (MRID 00148319), groups of 20 male Sprague

- Dawley (CD) rats/dose were treated once daily via gavage (1.0 mL/dose) with Triflurex technical (trifluralin; 97.3% a.i.; Batch #: 5320), in corn oil for 5 consecutive days at

doses of 0, 100, 333, or 1000 mg/kg/day (total doses of 0, 500, 1665, or 5000 mg/kg). Beginning two days after the last exposure, each male was mated sequentially to two untreated female rats per week for seven weeks. At 14 days after the midpoint of each mating week, the females were killed, determined to be pregnant or not pregnant, and the number of corpora lutea, living, dead, and total implantations was determined. On the fifth day of dosing, the positive control males were given a single dose of triethylene melamine (TEM; 0.3 mg/kg, i.p. in 0.9% saline).

One 1000 mg/kg male (#8476) was found dead 72

hours after the last treatment. Triflurex technical was tested at the limit dose (5000 mg/kg = 1000 mg/kg/day X 5 days). There were no treatment

related effect s on fertility, number of implants, pre

implantation losses, number of dead implants,

number of females with 1 or 2 dead implants, or ratio of dead implants to total implants at any dose in the study. The positive control induced the appropriate respons e. There was no time

- related positive response of increased pre

- or post

implantation loss compared to controls.

### Page 53 of 56

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

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

/Doses Comments

870.5450

Dominant Lethal

- Mouse MRID 00151896 (1984) Acceptable/Guideline In a dominant lethal assay (MRID 00151896), 30 male NMRI mice were dosed once daily for 5 consecutive days via oral gavage (5 mL/kg) with HOE 38474 (trifluralin; 98.3% a.i.; Lot/Batch #: OHZD99002), in sesame oil at concentrations of 0, 10, 100, or 1000 mg /kg. After the final treatment,

each male was mated with 13 untreated females during separate 4

- day intervals over a 52 day period.

No treatment

- related mortalities were noted during the study. No treatment

- related effects on clinical signs, body weight , fertilization rate, and pre

- or post

- implantation loss were observed; however, no data were provided. The positive control

(cyclophosphamide) increased the number of post

implantation fetal losses . There was no time

related positive response of incre ased pre

- or post

- implantation loss compared to controls.

870.5550

Unscheduled DNA synthesis in mammalian

cell culture MRID 40765602 (1988) Acceptable/Guideline In an unscheduled DNA synthesis assay (MRID 40765602), primary rat hepatocyte cultures were exposed to trifluralin (97.6% a.i.; Lot/Batch #: 39)

in DMSO for 18

- 19 hours at concentrations of 0, 0.032, 0.214, 0.404, 0.917, 2.22, 4.36, 8.52, 21.3, 42.9, 88.0, 448, or 898 μg/mL. Fifteen doses ranging from 0.032

- 898 μg/mL were used in each assay; however, the three doses between 0.032 and 0.214 μg/mL were not reported.

Trifluralin was tested up to cytotoxic levels (determined by trypan blue exclusion), 88.0 μg /mL in rat #1 and 42.9 μg/mL in rat #2. There were no

marked increases observed in the mean NNG or percent cells in repair at any dose in either trial. The positive controls induced marked increases in mean NNG and the percent of cells in repair.

There was no evidence that unscheduled DNA synthesis, as determined by radioactive tracer procedures (nuclear silver grain counts), was

induced

.

### Page 54 of 56

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

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

/Doses Comments

870.5550

Unscheduled DNA synthesis in mammalian

cell culture MRID 00151894 (1982) Acceptable/Guideline In an unscheduled DNA synthesis assay (MRID 00151894), HeLa cell cultures were exposed to HOE 38474 (trifluralin, 98.3% a.i.; Lot/Batch #: OH AT 208) in DMSO for 1 hour at concentrations of 0, 50, 100 or 500 μg/mL both in the presence and

absence of S9

- act ivation.

HOE 38474 was tested up to cytotoxic concentrations (>= 50 μg/mL, +/

- S9). No statistically significant increases in mean counts per minute of the test material with hydroxyurea were noted compared to concurrent solvent controls at any dose level , either in the presence or absence of

S9

- activation. The positive controls induced the appropriate response. There was no evidence that unscheduled DNA synthesis, as determined by liquid scintillation counting procedures, was

induced

.

870.5900

In vivo Sister Chromatid Exchange (SCE) Assay MRID 00133426 (1983) Acceptable/Guideline In a mammalian cell cytogenetics assay [SCE induction] using the BrdU tablet method , groups of 3 female Chinese hamsters/dose were exposed once via gavage (10 mL/kg) to trifluralin (95.0% a.i., Lot/batch No 00554AP2) in DMSO and 10% acacia at concentrations of 200, 300, 400, or 500 mg/kg at 5 hours following BrdU tablet im plantation. Bone

marrow was collected at 21 hours after treatment.

Trifluralin was tested up to cytotoxic

concentrations (>=400 mg/kg). Cytotoxicity (as

indicated by an increase in the number of first division metaphase figures) was observed in all

an imals at >=400 mg/kg. No statistically significant increases in SCE frequency were observed at any dose compared to controls. The positive control induced the appropriate response.

There was no evidence of SCE induced over background

870.7845 (85

- 1)

Metabolism

- Rat Urinary metabolites 41218901 (1989) Acceptable/Guideline There was no sex

- dependent effect on metabolic profiles. A minimum of 20

- 30 non

- conjugated

metabolites and an additional 10

- 20 conjugated metabolites were present in the urine, but no parent compound was detected. Information on the percentage of the adm inistered dose excreted in the urine was not provided. However, no single

metabolite accounted for more than 8

- 10% of the total urinary radioactivity, and the majority of the

### Page 55 of 56

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

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

/Doses Comments

metabolites were present at 1

- 2% of the total urinary radioactivity. Thus, almo st all of the metabolites were minor (<5% of the total radioactive dose). Metabolite F1B was found at

8.2

- 8.9% of the total urinary radioactivity in both sexes, and Metabolite F2, N

- [(3

- (acetylamino)

- 2

- amino

- 5

- (trifluoromethyl)phenyl] acetamide, was

found at 4.0

- 5.2%. Metabolite F1B was partially characterized as retaining the trifluoromethyl groups, the two equivalent aromatic protons, and the two nitro groups, but the propyl groups were lost. Ten other metabolites were identified (<0.1

- 3.7% of total ur inary radioactivity, each compound in each sex). Two additional metabolites were partially characterized (0.1

- 2.6% of total urinary radioactivity, each compound in each sex).

Four metabolic pathways were identified as follows: (i) oxidative N

- dealkylati on of one or both propyl groups and metabolites which were hydroxylated on the propyl side chain; (ii) reduction of one or both nitro groups to the corresponding amine; (iii) cyclization reactions to give a variety of substituted and unsubstituted

benzimid azole metabolites; and (iv) conjugation reactions, including acetylation of the reduced nitro groups, sulfate, and glucuronic acid conjugates.

Special study

3

- Mo Feeding

- Rat with Urinalysis study 00157156 (1985), 40138301(1986) 41086101 (1989)

0, 50, 200, 800, 3200, and 6400

ppm 0, 2.6, 10.7, 42.2, 170.2, and 342.1 mg/kg/day

Acceptable/Nonguideline NOAEL = 200 ppm (10.7 mg/kg/day) LOAEL for nephrotoxicity = 800 ppm (42.2 mg/kg/day), based on the presence of cortical tubular cytoplasmic hyaline dr oplets; increased total protein, AST, and LDH in the urine; and increased urinary volume upon protein electrophoresis and urinalysis.

### Trifluralin Human Health Risk Assessment DP No. D401005

Page 56 of 56