### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASH IN GTON, D

. C

. 20460

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

MEMORANDUM

DATE:

SUBJECT:

PC Code: 23-J AN -20 14

Saflufenacil. Human-Health Risk Assessment in Support of Tolerances for Re s idues in/on F i sh, Crayfish, and Imported S ugarcan e.

118203 DP Barcodes: D405506 & D413071 Decision Nos.: 467996 & 473447 Registration No.: 7969-278 Petition Nos.: 2E8065 & 2F8129 Regulatory Actions: Sec. 3 Registration and Tolerance With No U.S. Registration Risk Assessment Type: Single Chemical / Case No.: 7277 Aggregate TXRNo. : NA CAS No.: 372 137-3 5-4 MRID No.: NA 40 CFR: § 180.649

FROM: George F. Kramer, Ph.D

., Senior C h emis Chester E. Rodriguez

, Ph.D., Toxicologist

## ~ 

# _;t**~k-1** 

# r/

Cha rl es W. Smith III, Senio r Environmental Scienti C**~** Ri sk Assessment Branch 1 (RAB 1 ) Health Effects Division (HE D

, 7509P)

THROUGH: Dana M. Vogel, Associate Division Director As soc iate Division Dir ecto r , HED (75 09P)

TO: Kathryn Montague / Bethany Benbow

, PM T eam 23 Re gist ration Division (RD; 7505P)

The HED of the Office of P esticide Programs (OPP) is c h arged with est i mating the risk to human health from exposu r e to pesticides. The RD of OPP has requested th at HED evaluate hazard and
expos ur e data and conduct dietary, occupational, r es idential

, and aggr egate expo s ure assessments, as needed

, to estima te the ri sk to human hea lth that wi ll result from the propo se d tolerance s for r esidues i n/on crayfish, fish, and imp orted sugarcane. T he petitioner is BAS F.

A su mm ary of the findings and an assessment of human-health risk resulting from the proposed / registered uses of sa flufen acil are provided in thi s document. The risk assessment and dietary exposure assessment were provided by George Kram er (RAB 1 ), the ha za rd characterization by Chester Rodriguez (RAB 1 ), th e residu e chemistry data review by Geor ge Kramer ( RAB 1 ), the occupational/reside ntial exposure assessment by Cha rle s Smith (RAB I ), and the d r inking wate r assessment by Mohammed Ruhman of th e En v irorunental Fat e and Effects Division ( E FED).

Pag e I of 32Saflufenacil Human-Health Risk Ass essme nt DP N umb e r 405506



### Table of Contents 1.0 Executive Summary

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

### 2.0 HED Recommendations

.... . .. .. .. .. .. ...... . .. .. .. . . ....................... . ...... ... ... . . ................... .. . ......... 6 2.1 Data Defic i encies

...... . ........................... .. ... ...... ..... . ............................. . .............. . .. . 7 2.2 Tolerance Considerations

. ... ... .... .. ................. .. .. ... . .. . ... ... . ..... ... . .. .......................... 7 2.2.1 Enforcement Analytical Method

.......... . ........ .. ..... .. .................. . .. .. ................ .. .... 7 2.2.2 Recommended Tolerances

................................. . . . ..... . . ..... . ..... ...... .. ...................... 7 2.2.3 Revisions to Petitioned-For Tolerances

.................. . ................ . .... .. ............. . ...... 8 2

. 2.4 International H armonization

........... .. . .. ... . . ....... . ....... ........ . ...... . .............. . ............. 8 2.3 Label Recommendations

... ... ........................... ......... ............... . .. .. ... . ..... .. ............. 8 3

. 0 Introduction

. ...... . ...... . .. .. . .............. . .... ........... ........................................................... .......... 8 3.1 Chemical Identity

. . .............. .. ... . . . . . .. .. . .. .. ....... .. ...... .. ... ... ..................... ......... . ......... 8 3.2 Ph y sical/Chem i cal Characteristics

......... .......................... . .. .. ... . .. .. ... . .. ..... . . . . ....... 9 3.3 Pes ti cide Use Pattern

............................................................. ........ .. .......... ... ... ..... 9 3.4 Anticipated Exposure Pathways

.......................................................... ... ........... 10 3

. 5 Consideration of Environmental Justice

..... . . ..... .. .. ..... .. ..... . . . ... . ............... ........ 10 4

. 0 Hazard Characterization and Dose-Response Assessment.

.. . . ......... ... ........................ 11 4

. 1 Toxicology Studies Available for A nalysis

... . ... . ..... ................................... .. ...... 11 4.2 Absorption, Distribution, Metabolism, and Excretion (ADM E )

.. . ... ..... ... ...... 11 4

. 2.1 Dermal Absorption

....... ... . ... .. ......................................... ........................ . ........ . .. 12 4.3 Toxicological Effects

.............. . ....... .. .. .. ..... . . . . . ........................... . ... . . ..... . .... . ... ...... 12 4.3.1 Summary of Toxico l ogical Eff ects

...... .. ........... ... .. .... . . .. .... . . .. ... . ......................... 12 4.4 Safety Factor for Infants and Children (FQPA SF)

........................................ 1 3 4.4.1 Comp lete ness of the Toxicology Database

..... . .... ... .. ....... . ................................. 13 4.4

. 2 Evidence o f Neurotoxicity

........... .... ...... . ... . ...... ...................... . ... . ....................... 13 4.4.3 Ev id ence of Sensitivity/Susceptib ility in the Developing or Young Animal.. 14 4.4.4 Residual U ncertainty in 

### the E xposure Database

.......... .... . ... . ... ........................ 14 4.5 T oxicity E ndpoint and Point of Departure Selections

..................................... 14 4.5.1 Dose-Response Assessment

... ............................................................................. 14 4.5 .2 Recommendation for Combining Routes of E xposures for Risk Assessment15 4.5.3 Cancer Classification and Risk Assessment Recommenda t ion

. ........... ..... ... . . 1 5 4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment

... ........ . ...... . ... . ... . .. ..... ... .. .. . ... .. .. . ... .. ..... . ........... . . ..... ..... . . ..... . . .. ............ . .. 16 5.0 Dietary E xposure and Risk Assessment

. .......... ........ ... ... . ... . ..... .. ...... .. ...... . ........ .. ...... . .. . 17 5

. 1 Residues of Co n cern Summary and Rationale

............................................. . ... 17 5.2 Food Residue Profile

................................................................ ... ..... .. ................. 19 5.3 Water Residue Profile

.. . . . .... .. . .. ..... . ............. . . .. ........... . .. .. .................................... 20 5.4 Dietary Risk Assessment

...... ... .......... ... ................. ..... . ... ......... . .... .... ........ .. .. .. .. . . 20 5.4. 1 Description of Residue Data Used in Dietary Assessment

... .. ... . . ... ... .......... . . .. 20 5

. 4.2 Percent Crop Treated Used in Dietary Assessment

.. .. ... . . ... .. .. ... . ....... . ............. 21 5.4.3 Acute Dietary Risk Assessment

......................................................................... 21 5.4.4 Chronic Dietary Risk Assessment

.......... . .. . ........................................ . . .. ... . ... . ... 21 5.4.5 Cancer Dietary Risk Assessment.

..... ....... ... .... . ................. .. ..... . ...... ... .. ......... ... .. 21 6.0 Residential ( N on-Occupational) Exposure/Risk

...... . .............. . .................................... 22 6.1 R es idential Exposure/Risk Characteriza tion

................. . .. ... ... . . . ........ ..... .... ...... . ... ....... 22 6.2 Resident ia l Bystander Post

- Application Inhalation E xposure

................................... 22 6.3 Spray Drift

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

### 7.0 Aggregate Ex posure/Risk Characterization

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

Page 2 of32Saflufenacil Human

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### 7.1 Acute Aggregate Risk

................................ ................................ ......................... 23 7.2 Chro nic Aggregate Risk

................................ ................................ ..................... 23 8.0 Cumulative Risk Characterization/Assessment

................................ ........................... 23 9.0 Occupational Exposure/Risk Characterization

................................ ........................... 23 9.1 Short

- and Intermediate

- Term Handler Risk

................................ .................. 23 9.2 Short

- and Intermediate

- Term Post

- Application Risk

................................ .... 24 9.2.1 Dermal Post

- Application Risk

................................ ................................ ........... 24 9.2.2 Inhalation Post

- Application Risk

................................ ................................ ...... 24 9.3 REI

................................ ................................ ................................ ....................... 24 10.0 References

................................ ................................ ................................ ........................ 24 Appendix A. Toxicology Assessment

................................ ................................ ........................ 26 A.1 Toxicology Data Requirements for Saflufenacil

................................ .................. 26 A.2 Toxicity Profiles

................................ ................................ ................................ ....... 26 Appendix B. Physical/Chemical Properties

................................ ................................ ............. 31 Appendix C. Review of Human Research

................................ ................................ ................ 32Saflufenacil Human

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### 1.0 Executive Summary

Saflufenacil is a pre

- and post

- emergence herbicide that acts by inhibiting protoporphyrinogen IX oxidase (PPO) , which leads to chlorophyll destruction by photooxidation and causes bleaching of emerging foliar tissue. PPO is one of the key enzymes in the porphyrin biosynthesis for the production of chlorop hyll in plants and heme in mammals.

Saflufenacil is currently registered for use on legume vegetables (Crop Group 06), the foliage of legume vegetables (Crop Group 07), cereal grains (Crop Group 15, pre

- plant/pre

- emergence application only), the forage, fodder, and straw of cereal grains (Crop Group 16, pre

- plant/pre

emergence application only), cotton, and sunflower . BASF has submitted a tolerance petition for residues in/on imported sugarcane (PP# 2E8065) . In addition, BASF has submitted a proposal to allow post

- emergence application of saflufenacil to rice in the U.S. and to permit crayfish and fish to be grown in the treated rice fields (PP#2F8129 )

. There are no residential uses proposed or currently registered for saflufenacil.

Hazard Assessment: Saflufenacil was well absorbed and rapidly excreted via the oral route in rat metabolism studies. Maximum blood concentrations were reached within one hour and declined rapidly thereafter. Elimination was primarily urinary in female rats and via the fec es in male rats. The sex

- dependent excretion resulted in male rats having up to 3 X higher internal levels and being

, in some cases

, more sensitive to toxicity than females.

Saflufenacil exhibited low acute toxicity via the oral, dermal

, and inhalation ro utes of exposure (Category III or IV). It was slightly irritating to the eye (Category III), but neither a dermal irritant nor dermal sensitizer.

Subchronic and chronic toxicity studies in rats, mice

, and dogs identified the hematopoietic system as the primary target of saflufenacil. Consistent with its proposed mode of toxicity involving PPO inhibition and subsequent disruption of heme biosynthesis, decreased hematological parameters [red blood cells (RBC), hematocrit (Ht), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC)] were seen at about the same dose level [lowest

- observed adverse

- effect levels (LOAELs) of 13

- 39 mg/kg/day] across s pecies, except in the case of the dog, where the effects were seen at a slightly higher dose (LOAELs of 50

- 100 mg/kg/day). These effects occurred around the same dose level from short

- through long

- term exposures without increasing in severity. Effects w ere also seen in the liver (increased weight, centrilobular fatty change, lymphoid infiltrate) in mice, the spleen (increased spleen weight and extramedullary hematopoiesis) in rats, and in both of these organs (increased iron storage in the liver and
extr amedullary hematopoiesis in the spleen) in dogs. These effects also occurred around the same dose level from short

- through long

- term exposures without increasing in severity.

Increased fetal susceptibility was observed in the developmental toxicity st udies in the rat and rabbit and in the two

- generation reproduction study in the rat. Developmental effects ( decreased fetal body weights and increased skeletal variations in rats and increased liver porphyrins in rabbits) occurred at doses that were not m aternally toxic in the developmental stud ies , indicating increased quantitative susceptibility. In the two

- generation reproductive toxicity study in rats, the reported offspring effects were more severe than the maternal effects at the same dose level, in dicating evidence for increased qualitative susceptibility. A n increased number of stillbornSaflufenacil Human

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### pups, decreased viability and lactation indices, decreased pre

- weaning body weight and/or body

weight gain, and changes in hematological parameters occurred at th e same dose level as maternal decrements in food intake, body weight, body

- weight gain, and changes in hematological parameters and organ weights indicative of anemia.

Saflufenacil was weakly clastogenic in the in vitro chromosomal aberration assay in V7 9 cells in the presence of S9 activation; however, the response was not evident in the absence of S9 activation. It was neither mutagenic in bacterial cells nor clastogenic in rodents in vivo. Carcinogenicity studies in rats and mice showed no evidence o f increased incidence of tumors at the tested doses. Saflufenacil is classified as “not likely carcinogenic to humans.”

Saflufenacil displayed no evidence of neurotoxicity in acute and subchronic neurotoxicity studies, did not produce any dermal or syste mic effects in a 28

- day dermal toxicity study, and failed to induce toxicity specific to the immune system in a recently submitted immunotoxicity study.

Dose

- Response and Food Quality Protection Act (FQPA) Assessments: The RAB1 risk assessment team for s aflufenacil determined that the FQPA Safety Factor (SF) should be reduced to 1X for all exposure scenarios for the following reasons (see Section 4.4 for a full discussion): the toxicological database is adequate for FQPA assessment, there is no evidence of neurotoxicity, there is low concern for offspring susceptibility, and there is no uncertainty in the exposure database.

A 100 X uncertainty factor (UF) (10X for interspecies extrapolation and 10X for intraspecies variation) was incorporated into the acu te reference dose (aRfD, 5.0 mg/kg) and chronic RfD (cRfD, 0.046 mg/kg/day). The acute population

- adjusted dose (aPAD) and the chronic PAD (cPAD) are equal to the acute and chronic RfDs, respectively, divided by the FQPA SF (1X). Saflufenacil is classifi ed as “not likely carcinogenic to humans” by all relevant routes of exposure based on adequate studies in two animal species; therefore, cancer risk assessments are not required. In estimating margins of exposure (MOEs), the level of concern (LOC) is for MOEs < 100 for the dermal and inhalation risk assessments. A 6 % dermal

- absorption factor (DAF) and a 100% inhalation

- absorption factor were used in route

- to

- route extrapolation s

. Food Residue Profile: The nature of the residue in plants is adequately u nderstood in the subject crops. Organization for Economic Co

- operation and Development (OECD) tolerance

calculation procedures and the submitted residue data sets were used to calculate the HED

recommended tolerances. Provided that issues related to stor age stability in crayfish are resolved, the submitted magnitude of the residue data are adequate and there are no residue chemistry issues that would preclude establishing unconditional tolerances for residues of saflufenacil , as outlined in Table 2.2.2.

Exposure/Risk Assessment Characterization: Acute and chronic dietary risk assessments were conducted using the Dietary Exposure Evaluation Model

- Food Consumption Intake Database (DEEM

- FCID, ver. 3.16) which incorporates consumption data from United Stat es Department of Agriculture (USDA) National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA; 2003

- 2008) . The acute and chronic analyses assumed 100% crop treated (CT) , DEEM 7.81 default processing factors, and tolerance

- lev el or higher residues for all foods. Drinking water was incorporated directly into the dietary assessment s using theSaflufenacil Human

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### concentration for surface water generated by Tier I Rice modeling

. The resulting acute dietary (food + drinking water) risk estimates usi ng the DEEM

- FCID model at the 95 th 

### percentile [ <1% aPAD for all infants (<1 year old), the most highly exposed population subgroup] are not of concern (<100% aPAD). The chronic dietary risk assessment shows that the chronic dietary risk estimates are not of concern (i.e., <100% cPAD). The chronic dietary risk estimate for the highest exposed population subgroup, all infants (<1 year old), is 18 % of the cPAD.

There are no residential uses proposed or currently registered for saflufenacil. Therefore, a residential risk assessment was not conducted.

Since t here are no residential exposures expected from the proposed or registered saflufenacil

uses , the aggregate exposure assessment takes into consideration dietary food + drinking water exposure only. Th e acute and chronic dietary estimates represent acute and chronic aggregate risk, respectively.

There is potential for occupational handler short

- and intermediate

- term exposure resulting from the proposed use of saflufenacil on rice. Potential occupatio nal handler exposure scenarios include mixing/loading liquids for aerial and ground applications, applications via aerial and ground equipment, and flagging. The proposed label has proposed maximum rates of 0.089 and 0.044 lbs ai/A for pre

- plant / pre

- emerg ent and post

- emergent applications, respectively. The 2009 saflufenacil risk assessment ( L. Austin, et al. , 22

- JUL

- 2009; D367317 ) assessed application rates up to 0.35 lbs ai /A with applications made via aerial and ground equipment. This assessment showed that all risks for occupational handlers are above the target MOE of 100 with the use of gloves, and do not exceed the LOC. Since the proposed label includes applications m ade using similar application equipment and lower maximum application rates than those previously assessed for saflufenacil; no new occupational handler assessment has been performed at this time.

Occupational post

- application exposures associated with the proposed use on rice are expected to be negligible as the proposed label allows applications to be made prior to planting, prior to crop emergence, or from the two

- leaf stage up to internode elong ation. Saflufenacil is classified as Toxicity Category III for acute oral toxicity, acute dermal toxicity, and acute eye irritation. It is classified as toxicity Category IV for acute inhalation toxicity and acute dermal irritation. It is not a dermal s ensitizer. The restricted

- entry interval (REI) of 12 hours on the Sharpen ® 

### label complies with the Worker Protection Standard (WPS).

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. Please refer to Appendix C for a discussion of the human study data used in this risk assessment.

2.0 HED Recommendations

Provided that issues related to storage stability in crayfish are resolved, and p ending submissio n of revised Section F s , there are no other residue chemistry, occupational, or toxicology data deficiencies that would preclude the establishment of permanent tolerances for residues of saflufenacil and it metabolites and degradates as outlined in Table 2 .2.2.Saflufenacil Human

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### 2.1 Data Deficiencies

860.1380 Storage Stability (PP# 2F8129)

Actual analysis dates of the samples from the submitted magnitude of residue study in freshwater crayfish were not provided. No supporting storage stability data were submitted. Sa mple analysis dates are required to determine the duration of storage. Ruminant storage stability data are available which show that saflufenacil is stable for up to 35 days in ruminant matrices (47128015.der.doc). These data can be translated to crayfis h. However, if crayfish samples were stored for more than 3 5 days, then storage stability data may be required for saflufenacil in crayfish.

860.1550 Proposed Tolerances (PP#s 2F8129 & 2E8065 )

The petitioner is requested to submit revised Section Fs spe cifying r evised tolerances, as presented in Table 2.2.2.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

The petitioner has submitted two liquid chromatography/mass spectroscopy/mass spectroscopy (LC

- MS/MS) analytical methods for the determination of residues of the parent and its metabolites in/on plant and livestock commodities. BASF Method D0603/02 was developed for det ermination of residues of saflufenacil and its metabolites M800H11 and M800H35 in different plant matrices using LC

- MS/MS. The limit of quantitation (LOQ) was 0.01 ppm for each analyte in food matrices and 0.025 ppm for each analyte in feed matrices. BAS F analytical Method No. L0073/01 was developed for determination of saflufenacil in livestock matrices using LC

- MS/MS. The LOQ was 0.01 ppm in all matrices. These methods were used as the data

- collection methods in the analysis of samples for residues of concern from the various studies associated with the current petitions. Each method has been adequately validated by the petitioner as well as by independent laboratories and were adequately radiovalidated using weathered samples obtained from metabolism studies.

HED has determined that Methods D0603/02 and L0073/01 are suitable enforcement methods for the plant and livestock commodities associated with this petition , respectively, as defined in SOP No. ACB

- 019 (9/15/08).

2.2.2 Recommended Tolerances

The proposed uses and the submitted data support the following permanent tolerances for residues of saflufenacil in or on the commodities summarized in Table 2.2.2.

Table 2.2.2. Tolerance Summary for Saflufenacil.

Commodity Proposed Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Comments; Correct Commodity Definition 40 CFR §180.649(a)(1) Sugarcane, cane 0.03 ppm 0.05 1

- Sugarcane, molasses 0.075 ppm 0.08 1

-Saflufenacil Human

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Page 8 of 32 Table 2.2.2. Tolerance Summary for Saflufenacil.

Commodity Proposed Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Comments; Correct Commodity Definition Sugarcane, refined sugar 0.045 ppm

- - Grain, cereal, forage, fodder and straw group 16 (except rice straw) 0.1

- -

Rice, straw 0.30

- - 40 CFR §180.649(a)(2) Fish

- freshwater finfish 0.01 0.01

- Fish

- shellfish, crustacean 0.01 0.01

- 1 Note to RD: These tolerances should include a footnote stating “No U.S. registrations as of [date of FR notice].”



### 2.2.3 Revisions to Petitioned

- For Tolerances

The residue data for sugarcane were analyzed using the OECD tolerance calculation procedures, resulting in a value for sugarcane, cane (0.05 ppm) higher than that proposed (0.03 ppm). Multiplication of the sugarcane highest

- average field trial (HAFT) resi due (0.04 ppm) by the observed molasses processing factor of 2.0X yields a value (0.08 ppm) which is significantly greater than the recommended raw agricultural commodity (RAC) tolerance (0.05 ppm); therefore, a separate tolerance of 0.08 ppm is required f or residues in/on sugarcane, molasses. Residues did not concentrate in refined sugar, so the tolerance proposed for this commodity should be withdrawn. In addition, the proposed tolerances for rice straw and grain, cereal, forage, fodder and straw group 16 (except rice straw) should be withdrawn since rice straw is not a regulated commodity.

2.2.4 International Harmonization

There are no Canadian or Codex maximum residue limits (MRLs) established for residues of saflufenacil and its metabolites in sug arcane commodities, fish

- freshwater finfish , or fish

shellfish, crustacean . Harmonization is thus not an issue at this time.

2.3 Label Recommendations

None

3.0 Introduction

3.1 Chemical Identity

TABLE 3.1. Saflufenacil Nomenclature.

Chemical Structure

Common name Saflufenacil Company experimental name BAS 800 H (synonyms: AC 433 379, BASF Reg. No. 4054449)Saflufenacil Human

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Page 9 of 32 TABLE 3.1. Saflufenacil Nomenclature.

IUPAC name N '

- [2

- chloro

- 4

- fluoro

- 5

- (3

- methyl

- 2,6

- dioxo

- 4

- (trifluoromethyl)

- 3,6

- dihydro

- 1(2 H )

- pyrimidinyl)benzoyl]

- N

- isopropyl

- N

- methylsulfamide
CAS name 2

- chloro

- 5

- [3,6

- dihydro

- 3

- methyl

- 2,6

- dioxo

- 4

- (trifluoromethyl)

- 1(2 H )

- pyrimidinyl]

- 4

- fluoro

- N

- [[methyl(1

- methylethyl)amino]sulfonyl]benzamide CAS registry number 372137

- 35

- 4
End

- use product (EP) BAS 800 04 H (342 g ai/L SC formu lation)
Chemical Structure

Common name M800H11
Chemical name N

- [2

- chloro

- 5

- (2,6

- dioxo

- 4

- (trifluoromethyl)

- 3,6

- dihydro

- 1(2 H )

- pyrimidinyl)

- 4

- fluorobenzoyl]

- N

'

- isopropylsulfamide
Chemical Structure

Common name M800H35
Chemical name N

- [4

- chloro

- 2

- fluoro

- 5

- ({[(isopropylamino)sulfonyl]amino}carbonyl)phenyl]urea



### 3.2 Physical/Chemical Characteristics

Saflufenacil (BAS 800 H) is a broad

- spectrum herbicide developed by BASF. It belongs to the herbicide mode

- of

- action Group 14 (cell membr ane disruptors). Saflufenacil acts through the inhibition of PPO, resulting in cell membrane damage and subsequent plant death. Saflufenacil is a uracil herbicide that is expected to be mobile to highly mobile. Its major routes of degradation are alkali ne hydrolysis and biodegradation in aerobic soil. The compound is expected to degrade with a half

- life of 1 to 5 weeks in aerobic soil environments and a half

- life of 7 to 15 weeks (2 to 4 months) in aerobic aquatic environments. Its vapor pressure is 4. 5 x 10 - 15 

### Pa at 20 oC. Because it is a low

- volatile herbicide, saflufenacil could be less prone to atmospheric transport than more

- volatile herbicides. A summary of the physicochemical properties can be found in Appendix B.

3.3 Pesticide Use Pattern

Sharpen ® 

### Powered by Kixor Herbicide (EPA Reg. No. 7969

- 278), a 2.85 lb ai /gal suspension

concentrate (SC) formulation, is currently registered for use on legume vegetables (Crop Group 06), the foliage of legume vegetables (Crop Group 07), cereal grains (Crop Group 15, pre

plant/pre

- emergence application only), the forage, fodde r, and straw of cereal grains (Crop Group 16, pre

- plant/pre

- emergence application only), cotton, and sunflower. BASF has submitted a tolerance petition for residues in/on imported sugarcane (PP# 2E8065) . In addition, BASF has submitted a proposal to allow post

- emergence application of saflufenacil to rice in the U.S. and to permit crayfish and fish to be grown in the treated rice fields (PP#2F8129 ) . Example labels were provided and the proposed use directions are summarized in Table 3.3.1.Saflufenacil Human

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Page 10 of 32 Table 3.3.1

. Summary of Directions for Use of Saflufenacil.

Applic. Timing, Type, and Equip. Formulation App. rate (lb ai/acre) Max. No.

App. per Season Max. Seasonal

App. Rate (lb ai/acre) PHI

(days) Use Directions and Limitations
Rice

Ground, Air Sharpen ®

Powered by Kixor Herbicide 0.045

- 0. 0 90 2 0.135

- - A maximum of 0.045 lb ai/A applied post

- emergence between the two

- leaf stage and internode elongation.

- Minimum retreatment interval (RTI) = 14 days.

- May be applied to fields used for crayfish and fish production.

- May not be applied to fields used for mollusc production.

- Flood water from treated fields must be held at least 7 days prior to release.

- A crop

- oil concentrate is required for optimum activity. Sugarcane

Ground, Air Heat ® 0.022

- 0.075 1 0.075 7 Applications are to be made in 16

- 43 gal/acre (ground) or 4.3

- 5.3 gal/acre (air)



### Conclusions: The proposed use patterns are adequate to allow evaluation of the residue data submitted in support of these petitions.

3.4 Anticipated Exposure Pathways

RD has requested that HED evaluate hazard and exposure data and conduct dietary, occupational, residential, and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from the tolerance petitions for residues in/on fish, crayfish, and sugarcane. Humans may be exposed to saflufenacil in food and drinking water, since saflufenacil may be applied directly to growing crops and application may result in saflufenacil reaching surface and ground water sources of drinking water. There are no residential uses of saflufenacil, so exposure in residential or non

- occupational settings is not likely. In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during appli cation. There is also a potential for post

- application exposure for workers re

- entering treated fields.

This risk assessment considers all of the aforementioned exposure pathways based on the proposed new uses of saflufenacil , but also considers the ex isting registered uses as well.

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://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf ). As a part of everySaflufenacil Human

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### pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patte rns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture (USDA) under the N ational Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA; 2003

- 2008) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based
on age, s eason 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 developme nt 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 Characte rization and Dose

- Response Assessment

Saflufenacil is a pre

- and post

- emergence herbicide that acts by inhibiting the enzyme PPO, leading to disruption of chlorophyll biosynthesis, and ultimately bleaching of emerging foliar tissue. PPO is a key enzyme i n porphyrin biosynthesis for the production of chlorophyll in plants and heme in mammals. When PPO is inhibited in mammals, hemoglobin biosynthesis is reduced, resulting in anemia and accumulation of different porphyrins and their precursors in various or gans.

4.1 Toxicology Studies Available for Analysis

The toxicology database for saflufenacil is adequate for hazard characterization, toxicity endpoint selection, and FQPA SF evaluation. In previous risk assessments (Kramer et al ., DP# 384602; 04

- AUG

- 2011) and in the current assessment , an oral toxicity study i s used for the inhalation endpoint. The HED Hazard and Science Policy Council ( HASPOC) concluded, based on a weight

- of

- evidence approach, that a 28

- day inhalation toxicity study is not required at this time (TXR #056720).

4.2 Absorption, Distribution, Metabolism, and Excretion (ADME)

In rat metabolism/pharmacokinetic studies via the oral route, radiolabeled saflufenacil was well absorbed and rapidly excreted. Following a single dose and r egard less of the dose administered, maximum blood concentrations were reached within 1 hour of dosing and declined rapidly thereafter ; e xcretion of saflufenacil was essentially complete within 96 hours, with the majority eliminated within the first 24

- 48 hours. The blood and plasma data demonstrated that the majority of the saflufenacil residues occurred in the plasma and were not bound t o cellular elements of the blood such as red blood cells. Following single or repeated low

- and high

- dose administration, the main route of elimination in male rats was via the feces, whereas urinary excretion was the major route of elimination in females

. There was significantly higher biliary excretion of saflufenacil residues in males than in females. This sex

- dependent difference inSaflufenacil Human

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### excretion was more pronounced at the low

- dose level and resulted in males having up to 3 X higher internal exposures tha n females as measured by the plasma area under the concentration

time curve (AUC). Increasing the administered dose by a factor of 25 resulted in less than proportional increases in plasma AUC values at 6.1 in males and 12.4 in females. Saflufenacil resi dues remained very low in tissues at 168 hours after dosing, occurring mainly in carcass, liver, skin, and gut contents.

4.2.1 Dermal Absorption

A DAF of 6% was estimated for saflufenacil based on the highest degree of skin penetration at the lowest dose tested in a rat dermal absorption study. Immediately after a 10

- h exposure, the estimated DAF was 3.4%. However, about 50% of the radioactivity remaining at the end of exposure penetrated through the skin during a 120

- hour ( 5

- day) observational period, indicating that skin

- bound residues of saflufenacil are available for dermal absorption. When skin

- bound residues were included, a DAF of 6% will assess the potential risk associated with dermal exposures to saflufenacil from the proposed uses.

4.3 Toxicological Effects

4.3.1 Summary of Toxicological Effects

The effects observed following repeated oral exposures to saflufenacil are consistent wit h the proposed mode of toxicity involving inhibition of PPO in mammals, resulting in disruption of heme biosynthesis. Toxicological effects from subchronic and chronic toxicity studies in rats, mice and dogs consisted of decreased hematological parameters (RBC, Ht, MCV, MCH, and MCHC) at approximately the same dose level (13

- 39 mg/kg/day), except in the case of the dog, where the effects were seen at a slightly higher dose (50

- 100 mg/kg/day). In line with the ADME findings suggesting that male rats achiev e a greater systemic exposure than females, males were the most sensitive sex in mice and rats, with LOAELs approximately 3

- 4 X lower than their female counterparts. The hematological effects resulting from oral exposures to saflufenacil occurred around th e same dose level from short

- through long

- term exposures without increasing in severity. Toxic effects were also seen in the liver (increased organ weight, centrilobular fatty change, lymphoid infiltrate) in mice, the spleen (increased organ weight and

e xtramedullary hematopoiesis) in rats, and in both of these organs (increased iron storage in the liver and extramedullary hematopoiesis in the spleen) in dogs. These effects also occurred around the same dose level from short

- through long

- term exposures without a progression in severity.

Evidence for increased pre

- and/or postnatal susceptibility was noted from the developmental toxicity studies in the rat and rabbit and in the two

- generation reproduction study in the rat. Decreased fetal body weights and increased skeletal variations occurred at doses (20 mg/kg/day) that were not maternally toxic in the developmental study in rats. Similarly, in rabbits, increased liver porphyrins in fetuse s were observed at doses (200 mg/kg/day) that were not maternally toxic. In the two

- generation reproductive toxicity study in rats, there was evidence of increased qualitative susceptibility based on an increased number of stillborn pups, decreased pup vi ability and lactation indices, decreased pre

- weaning body weight and/or body

- weight gain, and changes in hematological parameters at the same dose level as less severe maternal effects consisting of decrements in food intake, body weight, body

- weight gain, and changes in organ weights andSaflufenacil Human

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### hematological parameters indicative of anemia.

In an acute neurotoxicity (ACN) study in rats, a decrease in motor activity was observed on the day of dosing at the limit dose (2000 mg/kg/day) in males only. However, the finding was not accompanied by any neuropathological changes and was considered a reflection of a mild and transient general systemic toxicity and not a substance

- specific neurotoxic effect. In the subchronic neurotoxicity (SCN) study, systemic toxicity (anemia) was seen at 1000 ppm (66.2 mg/kg/day) and 1350 ppm (101 mg/kg/day) in males and females, respectively. There was no evidence of neurotoxicity or neuropathology in either the acute or subchronic neurotoxicity study.

In a 28

- day dermal toxicity st udy in rats, saflufenacil did not induce any type of dermal or systemic toxicity up to the limit dose of 1000 mg/kg bw/day.

Based on the results of acute toxicity studies, saflufenacil was ranked low for acute toxicity (Category III or IV) via the oral, d ermal, and inhalation route of exposure. It was not classified

as a dermal irritant or dermal sensitizer.

In a 28

- day immunotoxicity study in mice, saflufenacil failed to induce toxicity specific to the immune system at the highest dose tested (i.e., 52 mg/kg bw/day).

Saflufenacil was weakly clastogenic in the in vitro chromosomal aberration assay in V79 cells in the presence of S9 activation; however, the response was not evident in the absence of S9 activation. It was neither mutagenic in bacterial cells nor clastogenic in rodents in vivo. Carcinogenicity studies in rats and mice showed no evidence of increased incidence of tumors at the tested doses. Saflufenacil is classified as “not likely carcinogenic to humans.”

4.4 Safety Factor for Infants and Children (FQPA SF)

The saflufenacil risk assessment team recommends that the FQPA SF be reduced to 1X for all exposure scenarios based on the following rationale : the toxicological database is adequate for FQPA assessment, there is no evidence of neurotoxicity, there is low concern for offspring susceptibility, and there is no uncertainty in the exposure database

.

4.4.1 Completeness of the Toxicology Database

The toxicology database for saflufenacil is adequate for FQPA SF consideration. The fol lowing acceptable studies are available for evaluation: developmental toxicity study in rats and rabbits,
two

- generation reproduction study in rats, ACN and SCN studies in rats.

4.4.2 Evidence of Neurotoxicity

There was no evidence of neurotoxicity or n europathology in the acute and subchronic neurotoxicity study. The decrease in motor activity observed in the ACN study on the day of dosing at the limit dose (2000 mg/kg/day) in males is considered a reflection of a mild and transient general systemic to xicity and not a substance

- specific neurotoxic effect. No neurotoxicity effects were seen in the S C N study

. The systemic toxicity (anemia) observed is in line with the mode of toxicity proposed for saflufenacil as a PPO inhibitor.Saflufenacil Human

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### 4.4.3 Evidence of Sens itivity/Susceptibility in the Developing or Young Animal

The concern for increased susceptibility following prenatal or postnatal exposure is low because clear no

- observed adverse

- effect levels (NOAELs) /LOAELs were established for the developmental effect s seen in rats and rabbits as well as for the offspring effects seen in the two

generation reproductive toxicity study. Further, the dose

- response relationship for the effects of concern are also well characterized and being used for assessing risks. The point of departure for risk assessments would be protective of the developmental and offspring effects.

4.4.4 Residual Uncertainty in the Exposure Database

There are no additional residual uncertainties with respect to exposure data. The dietary food exposure assessment utilizes recommended tolerance

- level residues and 100% CT information for all commodities. By using these screening

- level assessments, acute and chronic exposures/risks will not be underestimated. The dietary drinking water assessmen t utilizes values generated by model s and associated modeling parameters that are designed to provide conservative, health

- protective, high

- end estimates of water concentrations. There are no registered residential uses of saflufenacil; therefore, residen tial exposures are not anticipated.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose

- Response Assessment

Acute Dietary Endpoint (General population including infants and children): An acute dietary endpoint was established for this population group based on decreased motor activity observed at the LOAEL of 2000 mg/kg bw in male rats in the ACN study

. The NOAEL was 500 mg/kg bw. A combined UF of 100 was applied to account for interspecies (10X) and intraspecies (10X) extrapolation. The FQPA SF was reduced to 1X for this exposure scenario since the toxicology database is complete and there were no residual uncertainties for pre

- and or postnatal susceptibility. Thus, the aPAD is estimated at 5.0 mg/ kg bw.

Acute Dietary Endpoint (Females 13

- 49 years old): An acute dietary endpoint , separate from that defined above, was not established for this population group

. The developmental effects following saflufenacil exposure are unlikely to be the result of a single dose event. The skeletal variations (e.g., misshapen bones, delays in ossification, and wavy ribs) observed in the prenatal developmental study in the rat are not considered to be the result of a single dose. The process of bone deposition be gins with cartilage deposition followed by calcification and does not occur during a single day. Unlike supernumerary ribs or missing bones, which may be caused by the activation or inactivation of genes and could be the outcome of a single exposure, the process of bone deposition occurs over several days and, therefore, is not considered appropriate for this endpoint.

Chronic Dietary Endpoint: This endpoint was based on decreases in red blood cells, hemoglobin, and hematocrit as well as porphyria observ ed in males in the satellite group (sacrificed at 10 months) at the LOAEL of 13.8 mg/kg bw/day in a mouse chronic/carcinogenicity study. The NOAEL is 4.6 mg/kg bw/day

. A combined UF of 100 was applied to account for interspecies (10X) and intraspecies (1 0X) extrapolation. The FQPA SF was reduced to 1X for this exposure scenario since the toxicology database is complete and thereSaflufenacil Human

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### were no residual uncertainties for pre

- and or postnatal susceptibility. Thus, the cPAD is estimated at 0.046 mg/kg bw/day. Th is point of departure is protective of the developmental and offspring effects.

Incidental Oral (Short

- and Intermediate

- Term): Selection of this endpoint is not warranted since there are no registered or proposed uses of saflufenacil.

Dermal (Short

- and Intermediate

- Term): Although a 28

- day dermal toxicity study with non

pregnant adult rats yielded no evidence of toxicity (dermal or systemic), there is concern for developmental toxicity following exposure to saflufenacil. Decreased fe tal weights and increased skeletal variations were observed in the rat oral prenatal developmental toxicity study at the LOAEL of 20 mg/kg/day (NOAEL of 5 mg/kg/day). The concern for developmental toxicity is also supported by findings at higher doses fro m the rabbit developmental toxicity study and the rat two

- generation reproductive toxicity study. A DAF of 6% was estimated based on a dermal penetration study in rats. Thus, the equivalent dermal NOAEL based on the rat prenatal developmental toxicity st udy can be estimated at 83.3 mg/kg/day. The LOC is 100 based on a combined UF of 100 applied to account for interspecies (10X) and intraspecies (10X) extrapolation.

Inhalation (Short

- and Intermediate

- Term): The inhalation risk for saflufenacil is being assessed using the rat prenatal developmental toxicity study with 100% absorption assumed via the inhalation route

. The HASPOC ( TXR # 056720) decided, based on a weight

- of

- evidence approach, that a 28

- day inhalation toxicity study is not required at this time. The effects in the rat prenatal developmental toxicity study consisted of decreased fetal weights and increased skeletal variations at the LOAEL of 20 mg/kg/day (NOAEL of 5 mg/kg/day). The LOC is 100 based on a combined UF of 100 applied to account for interspecies (10X) and intraspecies (10X) extrapolation

.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

For occupational risk, dermal and inhalation exposures are of concern and should be combined since the dermal and i nhalation endpoints are the same . Currently, there are no registered residential uses of saflufenacil.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Carcinogenicity studies in rats and mice showed no evidence of increased incidence of t umors at the tested doses. Saflufenacil is classified as “not likely carcinogenic to humans” ; therefore, a cancer risk assessment is not required.Saflufenacil Human

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

Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Saflufenacil for Use in Dietary Human

- Health Risk Assessments. Exposure Scenario Point of

Departure UFs /

FQPA SF RfD and PAD Study and Toxicological Effects
Acute Dietary (General Population, including Infants and Children) NOAEL = 500

mg/kg bw UF A = 10X

UF H = 10X

FQPA SF = 1X aRfD = 5.0

mg/kg

aPAD = 5.0 mg/kg Acute Neurotoxicity Study

- rats

NOAEL = 500 mg/kg bw. LOAEL = 2000 mg/kg bw based on decreased motor activity representing mild and transient systemic toxicity in males.

Chronic Dietary (All Populations) NOAEL = 4.6

mg/kg/day UF A = 10X

UF H = 10X

FQPA SF = 1X cRfD = 0.046

mg/kg/day

cPAD = 0.046 mg/kg/day Chronic/Carcinogenicity (mouse)

NOAEL = 4.6 mg/kg bw/day

. LOAEL = 13.8 mg/kg bw/d based on decreased red blood cells, hemoglobin, hematocrit, and porphyria observed in the satellite group. Cancer (oral, dermal, inhalation) Classification: Not likely carcinogenic to humans based on the lack of tumors in the mouse and rat

carcinogenicity studies and lack of mutagenicity.

NOAEL = no

- observed adverse

- effect level. LOAEL = lowest

- observed adverse

- effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. FQPA SF = FQPA Safety Factor. PAD = population

- adjus ted dose (a = acute, c = chronic). RfD = reference dose.

Table 4.5.4.2. Summary of Toxicological Doses and Endpoints for Saflufenacil for Occupational Human

- Health Risk Assessment. Exposure/ Scenario Point of

Departure UFs/

FQPA SF LOC for Risk

Asses sment Study and Toxicological Effects

Dermal Short

and Intermediate

Term (1

- 30 days and 1

- 6 months, respectively) NOAEL = 5

mg/kg/day

Dermal absorption factor = 6% UF A = 10X

UF H = 10X

FQPA SF = 1X Occupational LOC

for MOE = 100 Developmental study

- Rat

NOAEL = 5 mg/kg bw/day

. LOAEL = 20 mg/kg bw/day based on decreased fetal bodyweight and increased skeletal variations.

Inhalation Short

- and Intermediate

Term (1

- 30 days and 1

- 6 months, respectively) NOAEL = 5

mg/kg/day

Inhalation

absorption = 100% UF A = 10X

UF H = 10X

FQPA SF = 1X Occupational LOC

for MOE = 100 Developmental study

- Rat

NOAEL = 5 mg/kg bw/day

. LOAEL = 20 mg/kg bw/day based on decreased fetal bodyweight and increased skeletal variations.

Cancer (oral, dermal, inhalation) Classification: Not likely carcinogenic to humans based on the lack of tumors in the mouse and rat

carcinogenicity studies and lack of mutagenicity.

No long term uses are expected for saflufenacil

NOAEL = no

- observed adverse

- effect level. LOAEL = lowest

- observed adverse

- effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = leve l of concern.Saflufenacil Human

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### 5.0 Dietary Exposure and Risk Assessment

An overview of the metabolism and environmental degradation of saflufenacil can be found in the 22

- JUL

- 2009 human

- health risk assessment ( L. Austin, et al. , D 367317 ).

5.1 Residues of Concern Sum mary and Rationale

Plants (Primary Crops): The previously submitted metabolism data for corn, soybean, and tomato were adequate to elucidate the nature of the residue in plants resulting from pre

- plant/pre

emergence application. The main reactions involved in the metabolic pathway of saflufenacil

were N

- demethylation at the uracil ring, stepwise degradation ( N

- dealkylation) of the N

- methyl

N

- isopropyl group, hydrolytic cleavage of the uracil ring generating a urea s ide chain, and hydroxylation of the phenyl ring. The HED ROCKS determined that residues of concern for the tolerance expression and risk assessment consist of saflufenacil, M800H11, and M800H35 (Memo, B. Daiss, 1/6/09; D 359645 ). The metabolic pathway of radiolabeled saflufenacil in soybean following a late

- season post

- emergence treatment follows the same initial pathways, but is not as extensive. No new metabolites were observed following post

- emergence treatment; however, an additional major metabolite (M800H02), that is not included in the tolerance expression, was observed in soybean seed. As the structure of M800H02 is closely related to the parent compound and it is the precursor of the regulated metabolite M800H11, HED conclude d that M800H02 is a r esidue of concern for risk

- assessment purposes in seed crops following late

season post

- emergence treatment.

BASF Corporation has submitted a study investigating the metabolism of uniformly phenyl ring

labeled [phenyl

- U

14 

### C]saflufenacil (PH label) and pyr imidine ring

- labeled [uracil

- 4

- 14 

### C]saflufenacil (UR label) following early post

- emergence foliar application to rice. The radiolabeled test substances were applied to rice plants (BBCH growth stages 22

- 24) grown in growth chambers as a single broadcast fo liar spray at a nominal rate of 0.089 lb ai/A (2X the proposed post

- emergence use rate).

Metabolism of saflufenacil in rice is consistent with the other crops studied. The combined residues of saflufenacil, M800H11, and M800H35 (the current residues of concern for the tolerance expression and risk assessment) in rice forage were 71

- 89% of the total radioactive residue (TRR). The only other major metabolite was M800H02, which accounted for 4

- 16% of the TRR in forage. In rice gr ain , the combined residues of saflufenacil and all metabolites was <10% of the TRR (≤0.01 ppm). HED thus concludes that current tolerance expression adequately accounts for the residues of concern following post

- emergence foliar application to rice and su garcane. Additional metabolism data may be required to support foliar application to

non

- grass crops.

Plants (Rotational Crops): The metabolism of saflufenacil in rotational crops appears to be consistent with the pathway observed in the plant metabolis m studies. The previously submitted confined and field rotational crop data are adequate to satisfy data requirements for application rates up to 0.137 lb ai/A (1X). The available data indicate that residues of saflufenacil and its metabolites M800H11 an d M800H35 were each <LOQ in/on all rotational crop matrices at a 120

- day plantback interval (PBI) . These data support the labeled rotational crop restriction of 4 months for all non

- labeled crops. Unless the petitioner requests PBIs shorter than 120 days , no additional data are required, and tolerances for inadvertent residues in/on rotational crops needSaflufenacil Human

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Page 18 of 32 

### not be established in conjunction with the currently proposed uses.

Livestock: The nature of the residue in livestock is adequately understood based on acceptable metabolism studies conducted on lactating goats and laying hens. Saflufenacil was metabolized by several dealkylation steps occurring at two different sites in the molecule ( N

- isopropyl

- N

methylsulfamide side chain and at the uracil ring) an d via hydrolytic opening of the uracil ring (goat only). In the ruminant metabolism study, saflufenacil was a major residue in all matrices. M800H04, a ring opening product, was the only significant metabolite (>10% total radioactive residue, TRR) found (liver). In the poultry metabolism study, saflufenacil was a major residue in all matrices and no significant metabolites were found. The HED ROCKS determined that saflufenacil per se is the only residue of concern for the tolerance expression and risk a ssessment (Memo, B. Daiss, 1/6/09; D 359645 ).

The HED ChemSAC waived the data requirement for metabolism studies in fish (Memo G. Kramer, 4/5/12; D396260) based on the results of a bioaccumulation study in bluegill sunfish ( conducted for EFED ) in which t he concentration of saflufenacil in the edible tissue of the fish was only 0.35 ppb at the 10

- ug/L dose level (~2X).

Drinking Water: Saflufenacil is slowly photolyzed in water (half

- life of 57 days at pH 5) and on soil (half

- lives of 83 and 87 days) at 2 2 °C. In addition, the compound is relatively stable to hydrolysis at pH 5, almost stable at pH 7 (half

- life of 248 days), and readily hydrolyzed at pH 9 (half

- life of 4.9 days). Therefore, alkaline hydrolysis is a major degradation route for saflufenaci l in high pH environments.

Saflufenacil biodegrades in 1 to 5 weeks in aerobic soil (half

- lives of 8.5

- 34 days) and less quickly in aerobic aquatic environments of pH 5.6 to 6.4 (half

- lives of 50 and 107 days). Therefore, aerobic soil metabolism is anoth er major degradation route for saflufenacil that will operate in the environment at any pH value.

Dissipation occurred with half

- lives of 2.4 to 22 days in terrestrial field dissipation studies conducted in the continental U.S., which is consistent with t he submitted, laboratory

- derived data. Dissipation was slower in Canadian field plots (half

- lives of 25 days and >>20 days).

Major degradates that are structurally similar to the parent compound include M01, M02, M04, M07, M08, M15, M22, and the soil pho tolysis product number 8. Major cleavage products of saflufenacil include M26, trifluoroacetic acid, M31, M33, and TFP. Another major aqueous photolysis product was isolated as well (unknown 3/4/7/6), but not identified. Major degradates that did not de cline in amount in unsterile study conditions include M7, M29, and product 8 (see Appendix B: Metabolism Assessment, Table B.1.2 of L. Austin, et al.

, 22

- JUL

- 2009 ; D367317 ).Saflufenacil Human

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Page 19 of 32 Table 5.1. Summary of Metabolites and Degradates to be Included in the Toleranc e Expression and Risk Assessment.

Matrix Residues Included in Risk Assessment Residues Included in Tolerance Expression

Plants Primary Crops ( pre

- plant

application) Saflufenacil + M800H11, M800H35 Saflufenacil + M800H11, M800H35 Primary Crops ( late

season preharvest application)* Saflufenacil + M800H11, M800H02, M800H35

Rotational Crops Saflufenacil + M800H11, M800H35

Livestock Ruminants Saflufenacil Saflufenacil

Poultry

Drinking Water Saflufenacil + M800H01, M800H02, M800H07, M800H08

, M800H15, M800H22, Product 8 Not Applicable

* Excluding rice and sugarcane.



### 5.2 Food Residue Profile

The submitted rice field trial data are adequate to fulfill data requirements. Following two broadcast applications of the 342 g ai /L SC formulation of saflufenacil at 0.131

- 0.139 lb ai/A, combined residues (and per

- trial averages) of saflufenacil, M800H11, and M800H35 in/on rice grain harvested at a 54

- to 103

- day PHI were all <LOQ (<0.03 ppm). The available data will thus support t he proposed use pattern. Since the existing tolerance of 0.03 ppm for residues in/on rice grain (as a member of cereal grains Crop Group 15) is supported by the residue data reflecting the post

- emergent use pattern, no changes in the existing tolerances f or Crop Group 15 are needed. However, a tolerance is not required for rice straw since it is not a regulated commodity.

The submitted magnitude of the residue data for sugarcane are also adequate. There are also adequate storage stability data to vali date the storage conditions and intervals of samples collected from the field trials. Using the OECD tolerance

- calculation procedures for the residue data sets indicate that the requested tolerance levels are too low.

The actual analysis dates of the s amples from the submitted magnitude of residue study in freshwater crayfish were not provided. Based on the sample collection dates and the final report date, the estimated storage duration for frozen samples is <125 days. No supporting storage stability data were submitted. Sample analysis dates are required to determine the duration of storage. Ruminant storage stability data are available which show that saflufenacil is stable for up to 35 days in ruminant matrices (47128015.der.doc). These data can be translated to crayfish. However, if crayfish samples were stored for more than 35 days, then storage stability data may be required for saflufenacil in crayfish. Provided issues related to storage stability are resolved, the submitted magnitude of sa flufenacil residue study in freshwater crayfish will support the proposed tolerance for residues in/on f ish

- shellfish, crustacean

. In addition, the crayfish magnitude of saflufenacil residue data can be translated to support the proposed tolerance for

res idues in/on fish

- freshwater finfish.

The submitted rice processing data are adequate to fulfill data requirements. As the residues inSaflufenacil Human

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### the RAC were <LOQ after treatment at a 5X rate, a separate tolerance for hulls and bran will not be required. The submi tted sugarcane processing study is also adequate. Concentration following processing was observed in molasses, but not in refined sugar. Multiplication of the sugarcane HAFT residue (0.04 ppm) by the molasses processing factor of 2.0X yields a value (0.0 8 ppm) which is significantly greater than the recommended RAC tolerance (0.05 ppm); therefore, a separate tolerance of 0.08 ppm is required for residues in/on sugarcane, molasses.

The previously submitted confined and field rotational crop data are adequ ate to satisfy data requirements for application rates up to 0.137 lb ai/A (1X). The available data indicate that residues of saflufenacil and its metabolites M800H11 and M800H35 were each <LOQ in/on all rotational crop matrices at a 120

- day PBI. These d ata support the labeled rotational crop restriction of 4 months for all non

- labeled crops.

5.3 Water Residue Profile

The Estimated Drinking Water Concentrations (EDWCs) used in the dietary exposure risk assessment were provided by EFED in a memorandum dated 1 2

- A U G

- 2013 (Memo, M. Ruhman; DP# 413592) . Water residues were incorporated directly into the DEEM

- FCID in the foo d categories “water, direct, all sources” and “water, indirect, all sources.”

Screening EDWCs ( Table 5.1.9 ) of saflufenacil were generated by Tier I Rice modeling for surface water and with Pesticide Root Zone Model

- Ground Water (PRZM

- GW) for ground
water . Modeled application rates represent the maximum use patterns for dry

- seeded rice: the 1 st 

### application at planting, the second application 14 days after planting and flooding at 45 days after planting . Remaining model input parameters were chosen accor ding to current guidance (USEPA, 2002). EDWCs reflect exposure to saflufenacil and all degradates of concern in drinking water ( Table 5.1.8 ).

Table 5.3. Tiered EDWCs for Proposed Saflufenacil Uses.

Source (Tier: Model) 1

- in

- 10

- year Peak Exposure (ppb) 1

- in

- 10

- year Annual Mean Exposure (ppb) Surface water (Tier I: Rice Model) 13 3 (used in acute analysis) 12 0 (used in chronic analysis) Ground water (Tier II: PRZM GW) 69.2 51.5



### 5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

The unrefined acute and chronic analyses assumed DEEM 7.81 default concentration factors and tolerance

- level residues for all commodities [except for cottonseed; sunflower subgroup 20B; soybean, seed; vegetable, legume, subgroup 6C, pea and bean (except soybean); and rapeseed subgroup 20A for which the recommended tolerance levels were multiplied by a correction factor to account for a metabolite of concern which is not included in the tolerance expression]. Drinking water was incor porated directly into the dietary assessment using the concentration for surface water generated by Tier I Rice modeling

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### 5.4.2 Percent Crop Treated Used in Dietary Assessment

The acute and chronic dietary analyses assumed 100% CT for all commodities

.

5.4.3 Acute Dietary Risk Assessment

The acute dietary risk for food and drinking water utilized <1% of the aPAD for the U.S. population. The acute dietary risk for the highest exposed population subgroup, all infants (<1 year old), is <1% of the aPAD at the 95 th 

### percentile. A summary table of acute dietary exposure and risk for saflufenacil can be found in Section 5.4.6. Although further refinement to the analysis is not required at this time, future assessments could be refined using average fi eld trial values, use of empirical processing factors, incorporation of %CT data, or monitoring data.

5.4.4 Chronic Dietary Risk Assessment

The chronic dietary risk for food and drinking water utilized 6.7 % of the cPAD for the U.S. population. The chr onic dietary risk for the highest exposed population subgroup, all infants (<1 year old), is 18 % of the cPAD. A summary table of chronic dietary exposure and risk for saflufenacil can be found in Section 5.4.6. Although further refinement to the analysis is not required at this time, future assessments could be refined using average field trial values, use of empirical processing factors, incorporation of %CT data, or monitoring data.

5.4.5 Cancer Dietary Risk Assessment

Saflufenacil is classified as “not likely carcinogenic to humans.” Therefore, cancer risk is not a concern for this chemical.

5.4.6 Summary Table

Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure Risk for Saflufenacil.

Population Subgroup Acute Dietary (95 th Percentile) Chronic Dietary
Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/day) % cPAD
General U.S. Population 0.008199 <1 0.003105 6.7 All Infants (<1 year old) 0.026256 <1 0.008506 18 Children 1

- 2 years old 0.014271 <1 0.005786 13 Children 3

- 5 years old 0.011052 <1 0.004637 10 Children 6

- 12 years old 0.008171 <1 0.003098 6.7 Youth 13

- 19 years old 0.006825 <1 0.002347 5.1 Adults 20

- 49 years old 0.007652 <1 0.002943 6.4 Adults 50

- 99 years old 0.006909 <1 0.002867 6.2 Females 13

- 49 years old 0.007849 <1 0.002923 6.4 *The values for the highest exposed population for each type of risk assessment are bolded.Saflufenacil Human

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### 6.0 Residential (Non

- Occupational) Exposure/Risk

6.1 Residential Exposure/Risk Characterization

Saflufenacil has no registered or proposed residential uses; therefore, a quantitative non

occupational exposure assessment was not performed.

6.2 Residential Bystander Post

- Application Inhalation Exposure

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

- applica tion inhalation exposure assessment was not performed for saflufenacil at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV) and the low use rate (0.13 lb ai/A). 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 (FIFRA) Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 1 

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

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

- application inhalation exposure assessment for saflufe nacil.

6.3 Spray Drift

Spray drift is always a potential source of exposure to residents nearby spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the gr ound application method employed for saflufenacil. 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 the best spray

- drift

- management practices. On a chemical

- by

- chemical basis, the Agency is now requiring interim mitigation measures for aerial 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 appropriately apply the data and the AgDRIFT ® 

### computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. Aft er the policy is in place, the Agency may impose further refinements in spray

- drift

- management practices to reduce off

- target drift with specific products with significant risks associated with drift.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compar ed to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and

1 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlSaflufenacil Human

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### duration of exposure.

For saflufenacil , aggregate exposu re and risk assessments were assessed by incorporating the drinking water directly into the dietary

- exposure assessment for the following scenarios: acute and chronic aggregate exposure (food + drinking water). Short

- , intermediate

- , and long

- term aggreg ate

- risk assessments were not performed because there are no registered or proposed uses of saflufenacil that result in residential exposures. A cancer aggregate

- risk assessment was not performed because saflufenacil is not a carcinogen and cancer risk is not a concern.

7.1 Acute Aggregate Risk

The acute aggregate risk assessment takes into account average exposure estimates from dietary consumption of saflufenacil (food and drinking water). The acute dietary exposure estimates are not of concern to HED (<100% cPAD) for the general U.S. population and all population subgroups (see Table 5.4.6).

7.2 Chronic Aggregate Risk

The chronic aggregate risk assessment takes into account average exposure estimates from dietary consumption of saflufenacil (food and drinking water). The chronic dietary exposure estimates are not of concern to HED (<100% cPAD) for the general U.S. population and all population subgroups (see Table 5.4.6).

8.0 Cumulative Risk Characterization/Assessment

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 saflufenacil and any other substances and saflufenacil does not appear to p roduce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that saflufenacil has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to deter mine 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 concerning common mechanism determinations and procedures for cumula ting effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

9.1 Short

- and Intermediate

- Term Handler Risk

There is potential for occupational handler short

- and intermediate

- term exposure resulting from the proposed use of saflufenacil on rice. Potential occupational handler exposure scenarios include mixing/loading liquids for aerial and ground applications, applications via aerial and ground equipment, and flagging. The proposed label has proposed maximum rates of 0.089 and 0.044 lbs ai/A for pre

- plant/pre

- emergent and post

- emergent applications, respectively. The 2009 saflufenacil risk assessment (L. Aust in, et al. , 22

- JUL

- 2009; D367317 ) assessedSaflufenacil Human

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### application rates up to 0.35 lbs ai/A with applications made via aerial and ground equipment. This assessment showed that all risks for occupational handlers are above the target MOE of 100 with the use of gloves , and do not exceed the LOC. Since the proposed label includes applications made using similar application equipment and lower maximum application rates than those previously assessed for saflufenacil; no new occupational handler assessment has been perfo rmed at this time.

9.2 Short

- and Intermediate

- Term Post

- Application Risk

9.2.1 Dermal Post

- Application Risk

Occupational post

- application exposures associated with the proposed use on rice are expected to be negligible as the proposed label allows appl ications to be made prior to planting, prior to crop emergence, or from the two

- leaf stage up to internode elongation.

9.2.2 Inhalation Post

- Application Risk

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

- application inhalation exposure assessment was not performed for saflufenacil at this time. However, there are multiple potential sources of post

- application inhalation exposure to individuals performing post

application activities in previously treated fields. These potentia l sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA SAP in December 2009. The Age ncy 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 as well as available post

- application inhalation exposure data generated by t he Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the Agency's risk assessments. If new po licies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post

- application inhalation exposure assessment for saflufenacil

.

9. 3 REI

Saflufenacil is classified as Toxicity Category III for acute oral toxicity, acute dermal toxicity, and acute eye irritation. It is classified as toxicity Category IV for acute inhalation toxicity and acute dermal irritation. It is not a dermal sensitizer. The REI of 12 hours appearing on the Sharpen ® 

### label complies wi th the WPS.

10.0 References

Previous Risk Assessments: L. Austin, et al.

, 22

- JUL

- 2009 ; D367317 . G. Kramer, et al. ; 19

- APR

- 2011 ; D380636

HASPOC Memo: 02

- A UG

- 2013 ; TXR# 056720

Chemistry Memo s : G. Kramer

, 02

- APR

- 2013 ; D405746. G. Kramer

, 23

- JAN

- 2014 ; D407976Saflufenacil Human

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### Drinking Water Memo: M. Ruhman

, 12

- AUG

- 2013 ; D 413592

Dietary Memo: G. Kramer

, 23

- JAN

- 2014 ; D405747

List of Appendices: Appendix A. Toxicology Profile Appendix B. Physical/Chemical Properties Appendix C. Review of Human Researc h

cc: G. Kramer (RAB1) RDI: RAB1 (8/7/13 ) G.F. Kramer:S10957:PY

- S:(703)305

- 5079:7509P:RAB1Saflufenacil Human

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### Appendix A

. Toxicology Assessment

A.1 Toxicology Data Requirements for S aflufenacil

Test Technical Required Satisfied 870.1100 Acute Oral Toxicity

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

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

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

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

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

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

yes yes yes yes yes 870.3100 Oral Subchronic (rodent)

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

................................ ......... 870.3200 21

- Day Dermal

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

- Day Dermal

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

- Day Inhalation

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

no

no yes

yes yes

- yes 1 870.3700a Developmental Toxicity (rodent)

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

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

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

yes yes 870.4100a Chronic Toxicity (rodent)

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

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

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

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

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

yes yes yes yes 870.5100 Mutagenicity

— Gene Mutation

- bacterial

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

— Gene Mutation

- mammalian

................ 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations

... 870.5xxx Mutagenicity

— Other Genotoxic Effects

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

yes yes yes 870.6100a Acute Delayed Neurotox. (hen)

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

- Day Neurotoxicity (hen)

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

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

- Day Neuro. Screening Battery (rat)

.......................... 870.6300 Develop. Neuro

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

no yes yes

no -

- yes yes

no 870.7485 General Metabolism

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

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

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

yes yes 1 Waived by the HASPOC (TXR #056720).



### A.2 Toxicity Profiles

Table A.2.1

. Acute Toxicity Profile

– Saflufenacil.

Guideline No. Study Type MRID(s) Results Toxicity Category Purity 870.1100 Acute oral [rat] 47128101 LD 50 >2000 mg/kg bw III 93.8%

870.1200 Acute dermal [rat] 47128102 LD 50 >2000 mg/kg III 93.8% 870.1300 Acute inhalation [rat] 47128103 LC 50 >5.3 mg/L IV 93.8% 870.2400 Acute eye irritation [White New

Zealand rabbit] 47128105 minimal irritation III 93.8%

870.2400 Acute eye irritation [White New

Zealand rabbit] 47128104 minimal irritation III 93.8%

870.2500 Acute dermal irritation [rabbit] 47128106 slightly irritating IV 93.8% 870.2600 Skin sensitization [Guinea Pig] 47128107 not a sensitizer N/A 93.8%Saflufenacil Human

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Page 27 of 32 Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile for Saflufenacil.
Guideline No./Study Type MRID No. (year)/Classification/Doses Results

870.3100 28

- Day Oral Toxicity feeding

- mice 47128110 (2007) Acceptable/non

- guideline

0, 50, 150, 450, 1350, or 4050 ppm

M \ F: 0, 12.8/17.9, 36.6/63.4, 112/153.1, 335/446, 882/1630 mg/kg bw/day. LOAEL = 36.6 mg/kg bw/day (males) based on increased alanine aminotransferase, aspartate aminotransferase, urea and total bilirubin, decreased hemoglobin (Hb) and Ht

, and increased liver weight and centrilobular fatty change. NOAEL = 12.8 mg/kg bw/day. LOAEL = 153.1 mg/kg bw/day (females) based on moderate centrilobular fatty change in the liver. NOAEL = 63.4 mg/kg bw/day. 870.3100 28

- Day Oral Toxicity feeding

- rat 47128108 (2007)

Acceptable/non

- guideline

0, 50, 150, 450, 1350, or 4050 ppm M = 0, 4.5, 13.4, 39.2, 117, 357 F = 0, 5.0, 15.9, 43.6, 130.4, 376 mg/kg bw/day

. LOAEL = 39.2 mg/kg bw/day (males) based on decreased Hb, MCV, and MCH. NOAEL =13.4 mg/kg bw/day. LOAEL = 130.4 mg/kg bw/day (females) based on decreased Hb, Ht, MCV, and MCH. NOA EL = 43.6 mg/kg bw/day.

870.3100 90

- Day Oral Toxicity feeding

- mice 47128111 (2007)

Acceptable/guideline

0, 15 (males only), 50, 150, 450, and 1350 (females only) ppm M = 0, 3.6, 12.4, 36.7, 109.1 F = 0, 17.6, 51.8, 156.6, 471.2 mg/kg bw/day LOAEL = 36.7 mg/kg bw/day (males) based on multiple hematological changes, liver weight increases with centrilobular fatty change and lymphoid infiltrate in males. NOAEL = 12.4 mg/kg bw/day. LOAEL = 156.6 mg/kg/day (females) based on increased liver weigh t with centrilobular fatty change and lymphoid infiltrate. NOAEL = 51.8 mg/kg/day. 870.3100 90

- Day Oral Toxicity feeding

- rat 47128109 (2007)

Acceptable/guideline

0, 50, 150, 450 (males), 1350, or 4050 (females) ppm M =0, 3.5, 10.5, 32.3, 94.7 F = 0, 4.3, 12.6, 110.5, 344.7 mg/kg bw/day. LOAEL = 32.3 mg/kg bw/day (M) and 110.5 mg/kg bw/day (F) based on multiple hematological effects and increased spleen weight and extramedullary hematopoiesis. NOAEL = 10.5 (M), 12.6 mg/kg bw/day (F).

870.3150 28

- Day Oral Toxicity feeding

- dog 47128112 (2005)

Acceptable/non

- guideline

0, 30, 100, or 300 mg/kg bw/day. LOAEL = 100 mg/kg bw/day based decreased mean corpuscular volume, MCH, and MCHC, bone marrow hyperplasia, increased iron storage in the liver and e xtramedullary hematopoiesis in the spleen. NOAEL = 30 mg/kg bw/day. 870.3150 90

- Day Oral Toxicity feeding

- dog 47128113 (2006)

Acceptable/guideline

0, 10, 50, or 150 mg/kg bw/day LOAEL = 50 mg/kg bw/day based on lower MCV and MCH values in both sexes. NOAEL = 10 mg/kg bw/day.

870.3200 21/28

- Day dermal toxicity (rat) 47128114 (2006) Acceptable/guideline

0, 100, 300, or 1000 mg/kg LOAEL was not established. NOAEL = 1000 mg/kg bw/day.

870.3700a Prenatal developmental in (rat) 47128115 (2007) Acceptable/guideline 0, 5, 20, or 60 mg/kg/day Maternal NOAEL = 20 mg/kg/day LOAEL = 60 mg/kg/day based on decreased Hb, Ht, MCV, and MCH. Developmental NOAEL = 5 mg/kg/day. LOAEL = 20 mg/kg/day based on decreased fetal body weights and increase in skeletal variations.Saflufenacil Human

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Page 28 of 32 Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile for Saflufenacil.
Guideline No./Study Type MRID No. (year)/Classification/Doses Results

870.3700b Prenatal developmental in (rabbit) 47128116 (2006) Acceptable/guideline 0, 50, 200, or 600 mg/kg/day Maternal NOAEL = 200 mg/kg bw/day LOAEL = 600 mg/kg bw/d based on mortality and increased necropsy findings. Developmental NOAEL = 50 mg/kg/day LOAEL = 200 mg/kg/day based on increased liver porphyrins. 870.3800 Reproduction and fertility effects (rat) 47128117 (2007) acceptable/guideline 0, 5, 15, or 50 mg/kg bw/day Parental Systemic NOAEL = 15 mg/kg/day. Parental Systemic LOAEL = 50 mg/kg/day based on decreased food intake, body weight, body

- weight gain and changes in hematological parameters and organ weights indicative of anemia. Reproduction NOAEL = M/F 50 mg/kg/day. Reproduction LOAEL was not established. Offspring NOAEL = 15 mg/kg/day. Offspring LOAEL = 50 mg/kg/day based on decreased number of live born pups, increased number of stillborn pups, decreased viability and lactation indices, decreased pre

- weaning body weight and/or body

- weight gai n and changes in hematological parameters. 870.4300b Chronic Toxicity (dog) 47128118 (2007)

Acceptable/guideline

0, 5, 20, or 80 mg/kg bw/day LOAEL = 80 mg/kg bw/day based on decreased albumin, MVH, and MCH. NOAEL = 20 mg/kg bw/day.

870.4300 Chronic/Carcinogenicity (rat) 47128120 (2007) Acceptable/guideline 0, 20, 100, 250 (males), 500 or 1000 (females) ppm

M = 0, 0.9, 4.8, 12.0, 24.2 F = 0, 1.3, 6.2, 31.4, 63.0 mg/kg bw/day. LOAEL = 31.4 mg/kg bw/day (females) based on decreased Hb , Ht, MCV

, and MCH. NOAEL = 6.2 mg/kg bw/day (females). LOAEL was not established in males. NOAEL = 24.2 mg/kg bw/day.

No evidence of carcinogenicity

.

870.4300 Chronic/Carcinogenicity (mouse) 47128119 (2007) Acceptable/guideline 0, 1 (males), 5, 25, 75, or 150 (females) ppm

M = 0, 0.2, 0.9, 4.6, 13.8 F = 0, 1.2, 6.4, 18.9, 38.1 mg/kg bw/day.

satellite groups: M = 0, 14.2 F = 0, 39.0 mg/kg bw/d NOAEL = 4.6 mg/kg bw/day (males) and 18.9 mg/kg bw/day (females). LOAELs = 13.8 mg/kg bw /day (males) and 38.1 mg/kg bw/day (females) based on decreased red blood cells, Hb , and Ht and porphyria observed in the satellite group.

No evidence of carcinogenicity.

Gene Mutation 870.5100 In vitro Bacterial Gene Mutation 47128121 (2005) Acceptable/guideline 0, 20, 100, 500, 2500, or 5000 μg/plate (saflufenacil hydrate) There was no evidence of induced mutant colonies over background.

Gene Mutation 870.5100 In vitro Bacterial Gene Mutation 47128122 (2005) Acceptable/guideline 0, 20, 100, 500, 2500, or 5000 μg/plate (saflufenacil anhydrate) There was no evidence of induced mutant colonies over background.

Gene Mutation 870.5300 In vitro Mammalian Cells Gene Mutation (Chinese Hamster Ovary Cells) 47128123 (2005) Acceptable/guideline 0, 312.5, 625, 1250, 2500, or 5000 μg/mL There was no evidence of induced mutant colonies over background.Saflufenacil Human

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Guideline No./Study Type MRID No. (year)/Classification/Doses Results
Cytogenetics 870.5375 In vitro Mammalian Cytogenetics chromosomal aberration assay

- V79 cells 47128124 (2005) Acceptable/guideline 0, 5, 10, and 20 ug/ml without S9 activation 0, 10, 20, and 40 ug/ml with S9 activation Saflufenacil was considered clastogenic in vitro in V79 cells in the presence of S9 metabolic activation. Saflufenacil was not clastogenic in th e absence of metabolic activation.

Cytogenetics

- other 870.5395 In Vivo Mammalian Cytogenetics

- Erythrocyte Micronucleus assay in mice 47128125 (2005) Acceptable/guideline 0, 500, 1000, or 2000 mg/kg bw. There was no increase in the frequency of micronucleated immature erythrocytes in mouse bone marrow.

870.5550 Other Genotoxicity

- In vivo unscheduled DNA synthesis (rat) 47128126 (2005) Acceptable/guideline single oral dose of 1000, or 2000 mg/kg bw Negative

870.6200a Acute neurotoxicity battery (rat) 47128127 (2007) Acceptable/Guideline

0, 125, 500, or 2000 mg/kg bw Systemic LOAEL was 2000 mg/kg bw (males) based on the decreased motor activity representing mild and transient systemic toxicity. Systemic LOAEL was not established for females. Systemic NOAEL = 500 (M) and 2000 (F) mg/kg bw.

There was no evidence of neurotoxicity. 870.6200b Subchronic neurotoxicity (rat) 47128128 (2007)

Acceptable/Guideline

0, 50, 250, 1000 (males), or 1350 (females) ppm

M = 0, 3.3, 16.6, 66.2 F = 0, 3.9, 19.4, 101.0 mg/kg bw/d. Systemic NOAEL = 16.6 (males), 19.4 (females) mg/kg bw/day. Systemic LOAEL = 66.2 (males) and 101 (females) mg/kg bw/day based on decreased Hb , Ht, MCV, and MCH.

There was no evidence of neurotoxicity

.

870.7485 Metabolism and pharmacokinetics (rat) 47128130, 47128129 (2007) 4, 20, or 100 mg/kg bw (single oral dose) 5 or 100 mg/kg bw (single dose) 100 mg/kg for 14 days Saflufenacil was rapidly absorbed, distributed, and excreted

. Regardless of the dose administered, maximum concentration of saflufenacil in blood and plasma was reached within 1 h of dosing and declined rapidly after 24 h. Excretion of orally dosed saflufenacil was essentially complete within 96 h; the majority was eliminated within the first 24 to 48 h. Demonstrating that the majority of the saflufenacil residues occurred in the plasma and was not bound to cellular elements of the blood. There was a sex

- dependent difference in the excretion of orally administered saflufenacil. Following single low

- and high

dose administration or a repeat high

- dose administration, the main route of elimination in male rats was via the feces, while urinary excretion was the major route of elimination in females. There was signific antly higher biliary excretion of saflufenacil residues in males than in females. Exhalation was not a relevant excretion pathway of saflufenacil. At 168 h after dosing, saflufenacil residues remaining in tissues were very low, and occurred mainly in car cass, liver, skin, and gut contents. Saflufenacil was metabolized by three major transformation steps: demethylation of the uracil ring system,Saflufenacil Human

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Guideline No./Study Type MRID No. (year)/Classification/Doses Results
degradation of the N

- methyl

- N

- isopropyl group to NH 2 , and cleavage of the uracil ring, forming a sulfonylamide group. The predominant metabolites were M800H01, M800H03, M800H07 and the parent compound. Other minor metabolites were M800H05, M800H16, M800H17, M800H18, M800M19, and M800M20. There were no significant sex differences in metabolic profiles. 870.7600 Dermal penetration (rat) 47128214 (2007) Acceptable/guideline 1.1723 mg/cm 2 , 0,1172 mg/cm 2 and 0.0117 mg/cm 2

11.723, 1.172 and 0.117 mg/rat Dermal absorption is 6%.

870.7800 Immunotoxicity (mice) 48233701 (2010) Acceptable/guideline

0, 50, 125, and 250 ppm (0, 10, 27, and 52 mg/kg/day) LOAEL for systemic toxicity was 125 ppm (or 27 mg/kg bw/day) based on significant changes in pathological and clinical pathology parameters. The NOAEL for systemic toxicity was 50 ppm (10 mg/kg bw/day)

. The LOAEL for immunotoxicity was not identified.

The NOAEL for immunotoxicity is the highest dose tested of 250 ppm (52 mg/kg bw/day)

. Comparative Bioavailability/Toxicity Study (rat) 47128133 (2005) Acceptable/non

- guideline

0 or 1350 ppm The bioavailability and toxicity potential of the hydrated and anhydrated forms of saflufenacil were similar.

Mechanistic study

– total porphyrin analysis in rat 47128132 (2006) Acceptable/non

- guideline
0, 10, 50, or 1000 ppm (♂ = 0, 0.8, 4.1, 80.6; ♀ = 0, 0.9, 4.6, 89.5 mg/kg bw/day, respectively) Total porphyrins in feces and liver provided the most reliable and sensitive data. Statistically significant effects on porphyrin metabolism could be detected at exposure concentrations well below those associated with adverse hematological effects. NOAEL= 4.1 mg/kg/day. LOAEL = 80.6 mg/kg/day based on decreased Hb , Ht, MCV, MCH, and MCHC. Mechanistic study

- porphyrin analysis supplementary (rat) 47128131 (2005) Acceptable/non

- guideline
0, 1, 5, or 25 ppm (♂ = 0, 0.1, 0.4, 2.0; ♀ = 0, 0.1, 0.5, 2.3 mg/kg bw/day Dietary administration of saflufenacil at 25 ppm caused an increase in por phyrin in feces of male (237%) and female (61%) rats, while saflufenacil at 5 ppm caused an increase in fecal porphyrin only in males. There were no effects on hematology parameters.Saflufenacil Human

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### Appendix B. Physical/Chemical Properties

Table B.1. Physicochemical Properties of Technical Grade Saflufenacil.
Parameter Value Melting point Average = 189.9 ° C, peak max = 193.4 ° C pH 4.43 of 1% solution at 25 ° C Bulk Density (ambient temp.) 0.661 kg/L (free fall), 0.736 kg/L (packed)
Water solubility (20 °C) in g/100 mL: 0.0025 in water (pH = 5); 0.0014 in pH 4 buffer; 0.21 in pH 7 buffer; not determined due to degradation in pH 9 buffer Solvent solubility (20 °C) in g/100 mL: 19.4 acetonitrile; 24.4 dichloromethane; 55.4 N,N

- dimethylformamide; 27.5 acetone; 6.55 ethyl acetate; 36.2 tetrahydrofuran; 35.0 butyrolactone; 2.98 methanol; 0.25 isopropyl alcohol; 0.23 toluene; <0.01 1

- octanol; <0.005 n

- heptane Vapor pressure at 20/25 °C 20 °C = 4.5 x 10 - 15 Pa 25 °C = 2.0 x 10 - 15 Pa Dissociation constant (pK a ) 4.41 Octanol/water partition coefficient Mean Log P ow = 2.6 (P ow = 368.3)
UV/visible absorption spectrum wavelength maximum: λ max = 271.6 nm extinction coefficient: ε = 9709 L/mol

- cm Reference : BASF Registration Document Number (DocID) 2005/1026464.Saflufenacil Human

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### Appendix C. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from the PHED 1.1, the AHETF database, and the ARTF database are (1) subj ect to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 2



### .

2 http://www.epa.gov/pesticides/science/handler

- exposure

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

- app

- exposure

- data.html