### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON

, D

. C

. 20460



### MEMORANDUM

D ATE: 05-NOV-2015 OFFICE OF C H EM I CA L SAFETY AND POLLUT I ON PREV ENT ION



### SU BJECT : Sa flufenacil. Human Health Risk Assessment in Support of Tolerances for Residues in/on Pomegranate.



### PC Code: 118203 

### DP Barcode: D426933 

### D ec i s ion No.: 493885 

### Registration No .: 7969-276 

### Petition No.: 4F8305 

### Regulatory Action: Sec. 3 Registration 

### Risk Assess m e nt Type: Single Chemical / 

### Case No.: NA Aggregate 

### TXR No

. : NA 

### CAS No.: 372 137- 35-4 

### MRID No.: NA 

### 40 CFR : § 180.649**~ ~~?,J**  - 

### F ROM : George F. Kramer

, Ph.D.

, Senior**Chem ~**  Monique 

### M. Perron

, Sc.D., To x icologi st

### ~ -f'.bVVJos hua G. Godshall

, Bi o l ogist 

# J'**~** Risk Assessment Branch l (RAB 1 ) Health Effects Division (HED, 7509P)



### TO: Kathryn Montague / Bethany Benbow

, PM Team 23 R eg istration Di vision 

### ( RD ; 7505P)

Th e HED of the Office of Pesticide Pr ograms ( OPP) i s charged with estimating the risk to human health from exposure to pesticides. The RD of OPP ha s requested th at HED evaluate hazard and
exposure data and conduct dietary

, occupationa l

, residential

, and aggregate exposure assessments, as needed

, to estimate the risk to human health that w ill result from the proposed tolerances for residues in/on pomegranate. The pet i t i oner i s BASF.

A s ummary of the findings and an assessment of hwn an health risk resulting from t he proposed/ r eg ister e d us es of sa flufenacil are pro vided in this document. Th e risk assessment , re s idue chem i stry, and dietar y exposure assessment were provided b y George Kramer 

### (RAB I)

, the occupationa l / residential exposure assessment by Jos h ua Godsha ll (RAB 1 ), and the drinking

water assessment by Mohammed Ruhman of the E n vironmenta l Fate and Effects Division (EFE D )

.

Page I of32Satlufenacil Hum an Health Risk Assessment DP # 426933



### Table of Contents 1.0 Execu ti ve Summary

................................................... . ........................................................ 4 2.0 HED Re commendations

................................... . ........ .. .......... .. ...... . ......... . ........................... 6 2. 1 Data Deficiencies

.................................................................................................... 6 2.2 To l era n ce Co n s id e ration s

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

............................................................................. 7 2.2.2 R ecommended Tole r ances

......... .. .................. ..... .................................................... 7 2.2.3 Revisions to Petitioned-For To l erances

.................................................................. 7 2.2.4 Int ernat i onal Harmonization

..................................... .. .. . ...... . .................................. 7 2.3 Label Recommendations

................................... . ..................... . ............... . ............... 7 3.0 Intr oduction

...................... . .................................................................................................. 8 3.1 C h em i ca l I dentity

... ...... ..... ......... . ........ ... ....... .. ...... ..... ...... ..... ............... . ........ . .. ... .... 8 3.2 Physical / Chemical Characteristics

...... ... ....... ..... ....... . ...... ...... ........ .. ....... .. ....... .. ..... 8 3.3 Pe st icid e Use Pattern

............. . ............. ... ...... ..... ... ....... ...... ....... .. ............... .... . . .... .... 8 3.4 Anticipated Exposure Pathways

. ......... .. ................... .... ..................................... . .... 9 3.5 Cons id e r ation of E n vironmental Ju stice

........ ............. .......................................... 10 4.0 Hazard Characte r ization and Dose-Response Assessme n t..

............................................. l 0 4.1 Toxicology St udi es Avai labl e for Analysis

.. . ....................................................... l 0 4.2 Absorption, Distribution

, Metabolism

, and Excretion (ADME)

.......................... 1 0 4.2.1 Dermal Absorption

................................................................................................ 11 4.3 T oxico l og i cal Effects

...... .. .............................................. ..... ......... . ........ .. ....... .... .. 1 1 4.3.1 Summary of Toxicological Effe cts

..................................................... .................. 11 4.4 Safety Factor for Infants and C hildr en (FQPA SF)

.. .......... . ........ .. ....................... 12 4.4.1 Completeness of the T oxicology Databa se

........................................................... 12 4.4.2 Ev iden ce of Neurotoxicity

.................................................................................... 12 4.4.3 Evidence of Sensitivity / Susceptibility in the Developing or Young Animal

....... 13 4.4.4 Residual U ncert ainty in the Ex po sure D atabase

...... . ............................................ 13 4.5 Toxicity Endpoint and Point of D eparture Se l ect i o n s

.......................................... 13 4.5. 1 Dose-Response Assessment.

................................................................................. 13 4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessme nt..

. ... 1 4 4.5.3 Cancer Classification a nd Risk Assessme nt Recommendation

.... . ....................... 14 4.5.4 Summary of Points of Departure and Toxicity E ndpoin ts Used in Human Risk Assessment.

.......................................... .. .............................. .. ........................................... 15 5.0 Dietary Ex po s ur e and Risk Assessment

.. ... ................................ ...... ..... ........ .... . .............. 16 5.1 Re s idu es of Concern Summary and Rationale

.. .................................................... 16 5.2 Food R esidue Pr ofi l e

..................................................................... . ....................... 17 5.3 Water Re s idue Profile

........................................................................................... 17 5.4 Di et ary Risk Assessme nt

...................................................................................... 18 5 .4. I D escr ipti on of Residue Data Used in Dietary Assessment..

........ .. ....................... 18 5.4

. 2 Percent Crop Treated Use d in Di etary Assessment

. .. ........................................... 18 5.4.3 Acute Di etary Risk A ssess ment.. .......................................................................... 18 5.4.4 Chronic Dietary Risk Assess ment

........................................................................ 18 5.4.5 Cancer Di etary Risk Assessment..

.................................. ......... . ......... . . . ..... .. ......... 1 8 6.0 Re side ntial (Non-Occupational) Exposure / Risk

............................................................... 19 6.1 Re s idential Exposure/Risk Characterizat i o n

......................................................... 19 6.2 Re s idential B ys tander Post-Application Inhalation Exposure

.............................. 1 9 6.3 Spray Drift

.... . .......................................................... .. ........ .. ...... ........ ..... . ............. 19 7 .0 Aggr eg ate Exposure/Risk Characterizat i on

................................... .. .............................. ... 20 7

. 1 Acute Aggregate Risk

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

Page 2 of32Saflufenacil Human Health Risk Assessment DP# 426933

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Page 3 of 32 

### 7.2 Chronic Aggregate Risk

................................ ................................ ........................ 20 8.0 Cumulative Risk Characterization/Assessment

................................ ................................ 20 9.0 Occupational Exposure/Risk Characterization

................................ ................................ . 21 9.1 Short

- and Intermediate

- Term Handler Risk

................................ ........................ 21 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 Restricted

- Entry Interval

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

................................ ................................ ................................ ......................... 25 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 Health Risk Assessment DP# 426933

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Page 4 of 32 

### 1.0 Executive Summary

Saflufenacil (BAS 800 H) is a broad

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

- of

- action Group 14 (cell membrane disruptors). Saflufenacil acts through the inhibition of protoporphyrinogen oxidase (PPO), resulting in cell membrane damage and subsequent plant death. BASF has propos ed a new use of Treevix ® 

### Powered by Kixor ® 

### Herbicide (EPA Reg. No. 7969

- 276; 30%; water

- dispersible granule ( WG ) ) to the base of pomegranate trees.

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 feces in male rats. The s ex

- 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 routes of exposure (Toxic ity Category III or IV). It was slightly irritating to the eye (Toxicity Category III), but was not a dermal irritant or a 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 extramedullary 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 s usceptibility was observed in the developmental toxicity studies 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 liv er porphyrins in rabbits) occurred at doses that were not maternally 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, indicating evidence for increased qualitative susceptibility. A n increased number of stillborn pups, decreased viability and lactation indices, decreased pre

- weaning body weight, and changes in hema tological parameters occurred at the same dose level as maternal decrements in food intake, body weight, and changes in hematological parameters and organ weights indicative of anemia.

Saflufenacil was weakly clastogenic in the in vitro chromosomal aberr ation 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.Saflufenacil Human Health Risk Assessment DP# 426933

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Page 5 of 32 

### Carcinogenicity studies in rats and mice sho wed no evidence of 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 an y dermal or systemic 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

asse ssment team for saflufenacil 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, ther e 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 incorpor ated into the acute 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 population

- adjusted dose (cPAD) are equal to the acute and chronic RfDs, respectively, divided by the F QPA SF (1X). Saflufenacil is classified 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 (MOE s), 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 is adequately understood in the subject crops. T here are no residue chemistry issues that would preclude establishing permanent 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 the United States Department of Agriculture (USDA) Nati onal 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

- level or tolerance

level residues adjusted to account for the residues of concern for risk assessment for all foods. Drinking water was incorporated directly into the dietary assessment s using the concentration for surface water generated by Tier I Rice modeling

. The resulting acute dietary (food + drinking water) risk estimates using 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 ch ronic 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 20 % of the cPAD.

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

Since t here are no residential exposures expected from the proposed or registered saflufenacilSaflufenacil Human Health Risk Assessment DP# 426933

_________ _____________________________________________________________________________ _______

Page 6 of 32 

### uses , the aggregate exposure assessment takes into consideration dietary foo d + drinking water exposure only. The acute and chronic dietary estimates represent acute and chronic aggregate risk, respectively.

The occupational handler exposure and risk estimates indicate that the short

- and intermediate

term dermal and inhalation combined margins of exposure (MOEs) are not of concern to HED (i.e., MOE > 100). At the baseline level of personal protection (i.e., no gloves and no respirator), all scenarios result in combined MOEs (dermal + inhalation) ranging from 4,400 to 40,000 ≥ level of concern (LOC; MOEs ≥ 100).

A quantitative post

- application exposure assessment has not been conducted for the proposed use on pomegranate since the use directions indicate that the product is to be applied to the base of the tree trunk and is not to contact the foliage. Currently, HED has no transfer coefficients or other data to assess post

- application dermal exposures to soil by occupational workers. In general, such exposures are considered to be negligible. Therefore, for the soil

- directed uses, post

- application exposures and risks to occupational workers were not assessed.

Since a quantitative post

- application assessment has not been conducted, the restricted

- entry interval (REI) is based on the acute toxicity of saflufenacil technical material. Saflufenacil is classified a s T oxicity C ategory III for acute oral, 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. Therefore, the acute toxicity cat egories for this chemical require a 12

- hour REI under 40 CFR 156.208 (c) (2) (iii). The 12

- hour REI, which currently appears on the labels, is adequate for the proposed uses.

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

- cancer occupational post

- application inhalation exposure assessment was not performed for saflufenacil at this time. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post

- application inhalation exposure assess ment for saflufenacil

. 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 ri sk assessment.

2.0 HED Recommendations

T here are no 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 outlin ed in Table 2.2.2.

2.1 Data Deficiencies

 NoneSaflufenacil Human Health Risk Assessment DP# 426933

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Page 7 of 32 

### 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. A r evised version (Method D0603/04) of the current enforcement method was used for the crop field trials. The method was adequate for data collection based on acceptable method validation and concurrent recovery data.

HED has determined that Method D0603/02 is a suitable enforcement method for the plant commodities , 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 tolerance for residues of saflufenacil and its m etabolites in or on the commodit y summarized in Table 2.2.2.

Table 2.2.2. Tolerance Summary for Saflufenacil.

Commodity Proposed Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Correct Commodity

Definition/Comments Pomegranate 0.03 0.03



### 2.2.3 Revisions to Petitioned

- For Tolerances

HED is not recommending for revisions to the petitioned

- for tolerance

.

2.2.4 International Harmonization

No Codex, Canadian, or Mexican maximum residue limits (MRLs ) have been established for saflufenacil on pomegranate. Therefore, harmonization of MRLs and U.S. tolerances is not an issue at this time.

2.3 Label Recommendations

NoneSaflufenacil Human Health Risk Assessment DP# 426933

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Page 8 of 32 

### 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)
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 a i/L SC formulation)
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 is a broad

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

- of

- action Group 14 (cell membrane 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 alkaline 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 mor e

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

3.3 Pesticide Use Pattern

BASF has submitted a draft label for Treevix ® 

### Powered by Kixor ® 

### Herbicide (EPA Reg. No. 7969

- 278). A summary of the proposed use pattern is detailed in Table 3.3.1.Saflufenacil Human Health Risk Assessment DP# 426933

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Page 9 of 32 

### Saflufenacil is currently registered for use on legume vegetables, citrus fruit, pome fruit, stone fruit, tree nuts, cereal grains, cotton, sunflowers, grapes, pasture and rangeland grass , grass grown for seed, olives, and soybean. BASF Corporation is requesting one new use for pomegranate.

Based on the proposed new use, it has been determined that the potential exposure scenarios that will need to be assessed include short

- and intermediate

- term occupational exposure s (handler and post

- application). A summary of the proposed and amended use directions are included in Table 3.1.1 below.

Table 3.1.1

. Proposed and Amended Use Directions for Saflufenacil.

Applic. Timing, Type, and Equip. Formulation [EPA Reg. No.] Application

Rate Max No.

Applications per Season Max Seasonal

Application Rate Use Directions

and Limitations

Pomegranate

Apply as broadcast, banded, or spot application directed at the base of the tree trunk

Groundboom, Backpack Treevix ® Powered by Kixor ® Herbicide WG (7969

- 276) 1 oz/A =

0.044 lb ai/A

0.01 oz/gal = 0.00044 lb ai/gal Max of 4

apps only if
one or two occur during the period of postharvest to the beginning of bloom; m ax of 3 apps while trees are in fruiting stage until crop harvest

. 0.131 lb

ai/A/crop season or 0.175 lb ai/A/crop season when

one or more applied during postharvest period.

0.175 lb ai/A/year Do not apply via

aerial or chemigation equipment.

Do not use in tree nurseries.

REI = 12 hours.

R etreatment interval (RTI) = 21 days.

P reharvest interval (PHI) = 0 days

. 1. PPE (personal

- protective equipment) = long

- sleeved shirt and long pants, shoes plus socks, chemical

- resistant gloves, protective eyewear such as face shield, goggles, or safety glasses.



### Conclusions: The proposed use pattern i s adequate to allow evaluation of the residue data submitted in support of th i s petition.

3.4 Anticipated Exposure Pathways

RD has requested that HED evaluate hazard and exposure data and conduct dietary, occupat ional, residential, and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from the tolerance petition for residues in/on pomegranate s

. Humans may be exposed to saflufenacil in food and drinking water, since s aflufenacil 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 sett ings is not likely. In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application. 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 use of saflufenacil and considers the existing registered uses as well for the dietary and residential exposure assessments

.Saflufenacil Human Health Risk Assessment DP# 426933

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Page 10 of 32 

### 3.5 Consideration of Envi ronmental Justice

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

- Income Populations,” ( http://www.archives.gov/federal

- register/executive

- orders/pdf/12898.pdf ). As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates ri sks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumptio n, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under 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, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

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

4.0 Hazard Characterization 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 in porphyrin biosynthesis for the produc tion 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 organs.

4.1 Toxicology Studies Availab le for Analysis

The toxicology database for saflufenacil is complete and 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 a ssessment , 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 ( A. Dunbar, 0 2

- AUG

- 2013; TXR #0056720 ).

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 egardless of the dose administered, maximum blood concentrations (Cmax) were reached within 1 hour of dosing and declined rapidly thereafter . Excretion 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 were detected in the plasma and were not bound to cellular elements of the blood such as red blood cells. Following single or repeated low

- andSaflufenacil Human Health Risk Assessment DP# 426933

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Page 11 of 32 

### 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. Thi s sex

- dependent difference in excretion was more pronounced at the low

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

time curve (AUC). Increasing the administ ered 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 residues 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 our 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 f or dermal absorption. With skin

- bound residues included, a DAF of 6% should be applied for converting oral doses to dermal equivalent doses to assess the potential risk associated with dermal exposures to saflufenacil.

4.3 Toxicological Effects

4.3.1 Su mmary of Toxicological Effects

The effects observed following repeated oral exposures to saflufenacil are consistent with the proposed mode of toxicity involving inhibition of PPO in mammals, resulting in disruption of heme biosynthesis. Toxicological ef fects 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 achieve a greater systemic exposure than females, males were the most sensitive sex in mice and rats, with LOAELs approximately 3

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

- through long

- term exposures without increasing in severity. Toxic effects were also seen in the liver (i ncreased organ weight, centrilobular fatty change, lymphoid infiltrate) in mice, the spleen (increased organ weight and extramedullary 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 toxi city 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 fetuses 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 base d on an increased number of stillborn pups, decreased pup viability and lactation indices, decreased pre

- weaning body weight and/or body

- weight gain, and changesSaflufenacil Human Health Risk Assessment DP# 426933

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Page 12 of 32 

### 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 and 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 sub chronic neurotoxicity study.

In a 28

- day dermal toxicity study 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 ( Toxicity Category III or IV) via the oral, dermal, 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 toxici ty 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 recomme nds 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 th ere is no uncertainty in the exposure database

.

4.4.1 Completeness of the Toxicology Database

The toxicology database for saflufenacil is complete and adequate for FQPA SF consideration.

4.4.2 Evidence of Neurotoxicity

There was no evidence of neurot oxicity or neuropathology 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 toxicity and not a substance

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

.Saflufenacil Human Health Risk Assessment DP# 426933

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Page 13 of 32 

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

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

- observed adverse

- effect levels (NOAELs) /LOAELs were established for the developmental effects 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 unde restimated. The dietary drinking water assessment 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 res idential uses of saflufenacil; therefore, residential 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 inte rspecies (10X) and intraspecies (10X) extrapolation. The FQPA SF was reduced to 1X for this exposure scenario (see Section 4.4)

. Thus, the aPAD is estimated at 5.0 mg/kg bw.

Acute Dietary Endpoint (Females 13

- 49 years old): An acute dietary endpoint , s eparate 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 ossi fication, 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 begins with cartilage deposition followed by calcification and does not occur during a si ngle 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 a ppropriate for this endpoint.

Chronic Dietary Endpoint: This endpoint was based on decreases in red blood cells, hemoglobin, and hematocrit as well as porphyria observed 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 (10X) extrapolation. The FQPA SF was reduced to 1X for this exposure scenario (see Secti on 4.4)

. Thus, the cPAD is estimated at 0.046 mg/kg bw/day. This point of departure is protective of the developmental and offspring effects.Saflufenacil Human Health Risk Assessment DP# 426933

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Page 14 of 32 

### 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 fetal weights and increased skeletal variations were observed in the rat oral prenatal developmental toxicity s tudy 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 from 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 study can be estimated at 83.3 mg/kg/day. The LOC is for MOEs less than 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 as sumed via the inhalation route

. The HASPOC decided, based on a weight

- of

- evidence approach, that a 28

- day inhalation toxicity study is not required at this time (TXR #0056720)

. The effects in the rat prenatal developmental toxicity study consisted of dec reased fetal weights and increased skeletal variations at the LOAEL of 20 mg/kg/day (NOAEL of 5 mg/kg/day). The LOC is for MOEs less than 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

Dermal and inhalation exposures should be combined since the dermal and inhalation endpoints are based on the same study.

4.5.3 Cancer Classification and Risk Assessment Recommend ation

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” ; therefore, a cancer risk assessment is not required.Saflufenacil Human Health Risk Assessment DP# 426933

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Page 15 of 32 

### 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, PAD,

LOC for Risk Assessment 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 (rat)

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). LOC = level of concern. FQPA SF = FQPA Safety Factor . PAD = population

- adjusted 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

Assessment 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 = Assumed to be equivalent with oral absorption 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 increas ed 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.

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. LO C = level of concern.Saflufenacil Human Health Risk Assessment DP# 426933

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Page 16 of 32 

### 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 Summary 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 HED Resid ues of Concern Knowledgebase Subcommittee (ROCKS) determined that residues of concern for the tolerance expression and risk assessment consist of saflufenacil, M800H11, and M800H35 (Memo, B. Daiss, 06

- JAN

- 2009; D 359645 ). This conclusion was translated to perennial crops (i.e., tree fruits and tree nuts) where saflufenacil application is directed to the weeds on the orchard floor (Memo, G. Kramer, 22

- JUL

- 2009; D 349938 ). As the proposed use on pomegranate is also directed to weeds at the base of the plants, HED concludes that the residues of concern for the tolerance expression and risk assessment also consist of saflufenacil, M800H11, and M800H35 for this crop.

Livestock: The nature of the residue in livestock is adequately understood based on acceptable metabolism studies conducted on lactating goats and laying hens. There are no livestock feedstuffs associated with the proposed use; therefore, no changes in the existing tolerances for livestock commodities are needed.

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 22 °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 p H 9 (half

- life of 4.9 days). Therefore, alkaline hydrolysis is a major degradation route for saflufenacil 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 en vironments of pH 5.6 to 6.4 (half

- lives of 50 and 107 days). Therefore, aerobic soil metabolism is another 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 da ys in terrestrial field dissipation studies conducted in the continental U.S., which is consistent with the 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 photolysis product number 8. Major cleavage products of saflufenacil include M26, trifluoroacetic acid, M31, M33, and TFP. Anoth er major aqueous photolysis product was isolated as well (unknown 3/4/7/6), but not identified. Major degradates that did not decline 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 Health Risk Assessment DP# 426933

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Page 17 of 32 Table 5.1. Summary of Metabolites and Degradates to be Included in the Risk Assessment.

Matrix Residues Included in Risk Assessment Residues Included in Tolerance Expression

Plants Primary Crops (preplant

application)* Saflufenacil + M800H11, M800H35 Saflufenacil + M800H11, M800H35 Primary Crops (foliar 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

* Plus post

- emergence foliar application to cereal grains and grasses and to weeds in fruit/nut orchards/groves.



### 5.2 Food Residue Profile

The submitted crop field trial data are adequate to fulfill data requirements. The available data will support the proposed use patterns. Quantifiable residues were not found in any pomegranate sample. There are no regulated processed commoditi es associated with pomegranate. There are no livestock feedstuffs associated with the proposed use; therefore, no changes in the existing tolerances for livestock commodities are needed. No Codex, Canadian, or Mexican MRLs have been established for saflu fenacil on pomegranate. Therefore, harmonization of MRLs and U.S. tolerances is not an issue at this time.

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

- M A R

- 201 4 (Memo, M. Ruhman; DP# 414485 ) . 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. 3 ) 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 accordi ng to current guidance (USEPA, 2002). EDWCs reflect exposure to saflufenacil and all degradates of concern in drinking water ( Table 5.1 ).

Table 5.3. Tiered EDWCs for Proposed Saflufenacil Uses.

Source (Tier: Model) 1

- in

- 10

- Y ear Peak Exposure (ppb) 1

- in

- 10

- Y ear 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 51.5Saflufenacil Human Health Risk Assessment DP# 426933

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Page 18 of 32 

### 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 incorpora ted directly into the dietary assessment using the concentration for surface water generated by Tier I Rice modeling

.

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 empirical processi ng 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 9.2 % of the cPAD for the U.S. population. The chronic dietary risk for the highest exposed population subgroup, all infants ( <1

- year old ), is 20 % 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 asse ssments could be refined using average field trial values, us ing 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.” Ther efore, cancer risk is not a concern for this chemical.Saflufenacil Human Health Risk Assessment DP# 426933

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Page 19 of 32 

### 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 0.010106 <1 0.004223 9.2 All Infants (<1

- year old) 0.026582 <1 0.009099 20 Children 1

- 2 years old 0.017044 <1 0.008368 18 Children 3

- 5 years old 0.013965 <1 0.006993 15 Children 6

- 12 years old 0.010852 <1 0.004872 11 Youth 13

- 19 years old 0.008383 <1 0.003409 7.4 Adults 20

- 49 years old 0.009095 <1 0.003946 8.6 Adults 50

- 99 years old 0.007781 <1 0.003679 8.0 Females 13

- 49 years old 0.009078 <1 0.003759 8.2 *The values for the highest exposed population for each type of risk assessment are bolded.



### 6.0 Residential (Non

- Occupational) Exposure/Risk

6.1 Residential Exposure/Risk Characterization

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

occupational exposure assessment was not performed.

6.2 Residential Bystander Post

- Application Inhalation Exposure

Volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fu ngicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219). During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis is required for saflufenacil

.

6.3 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularly the case with aer ial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed for saflufenacil. The Agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call

- In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see t he Agency ’s Spray Drift website for more information). 1 

### The Agency has also developed a policy on how to appropriately consider spray drift as a potential source of exposure in risk assessments for

1 Available: http://www2.epa.gov/red ucing

- pesticide

- driftSaflufenacil Human Health Risk Assessment DP# 426933

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Page 20 of 32 

### pesticides. The potential for spray drift will be quanti tatively evaluated for each pesticide during the Registration Review process , which ensures that all uses for that pesticide will be considered concurrently. The approach is outlined in the revised ( 2012) Standard Operating Procedures For Residential Risk Assessment (SOPs)

- Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification of indirect non

- occupational exposure to 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 compared 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 duration of exposure.

For saflufenaci l , aggregate exposure 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

- , a nd long

- term aggregate

- 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

no t 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

Unli ke 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 produ ce 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 determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to haveSaflufenacil Human Health Risk Assessment DP# 426933

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Page 21 of 32 

### 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

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

Based on the anticipated use patterns, and the current labeling regarding types of equipment and techniques that can be used, occupational handler exposure is expected. The quantitative exposure/risk assessment developed for occupational handlers is bas ed on the following scenarios:

1) Mixing/loading WG s /DF s (dry flowables) for groundboom applications; 2) applying sprays via groundboom equipment; 3) mixing /loading/applying WGs/DFs via backpack.

Occupational Handler Exposure Data and Assumptions

A series of a ssumptions and exposure factors served as the basis for completing the occupational handler risk assessments. Each assumption and factor is detailed below on an individual basis.

Application Rate : The application rates used in this assessment are provid ed in Table 3.1. 1.

Unit Exposures: It is the policy of HED to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical

- specific data, include Pesticide Handlers Exposure Database (PHED) 1.1, the Agricultural Handler Exposure Task Force (AHETF) database, the Outdoor Residential Exposure Task Force (ORETF) database, or other registrant

- submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. The stand ard values recommended for use in predicting handler exposure that are used in this assessment, known as “unit exposures

, ” are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table 2



### , ” which, along with additional informati on on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website 3



### .

 80 acres for groundboom application to typical acreage crops;

 40 gallons for backpack applications.

Exposure Duration: HED classifies exposures from 1 to 30 days as short

- term and exposures 30 days to six months as intermediate

- term. Exposure duration is determined by many things,

2 Available: http://www2.epa.gov/sites/production/files/2015

- 09/documents/handler

- exposure

- table

- 2015.pdf

3 Available: http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risks/occupational

- pesticide

- handler

exposure

- dataSaflufenacil Human Health Risk Assessment DP# 426933

_________ _____________________________________________________________________________ _______

Page 22 of 32 

### including the exposed population, the use site, the pest pressure triggering the use of the pesticide, and the cultural practices surrounding that use site. For most agricultural uses, it is reasonable to believe that occupational handlers will not apply the same chemical every day for more than a one

- month time frame; however, there may be a la rge agribusiness and/or commercial applicators who may apply a product over a period of weeks.

For saflufenacil, based on the proposed use patterns, short

- and intermediate

- term exposures are anticipated for the following reasons: (1) up to three in

- se ason and one dormant season foliar applications can be made per crop season 21 days apart; and (2) commercial applicators may apply this product at various locations within a region over a period of weeks. In addition, the short

- and intermediate

- term POD s are the same; therefore, short

- term risk estimates are protective of longer

- term exposures.

Mitigation/Personal Protective Equipment: Estimates of dermal and inhalation exposure were calculated for various levels of personal

- protective equipment (PPE). Results are presented for “baseline,” defined as a single layer of clothing consisting of a long

- sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator. The saflufenacil product labels direct mixers, loaders, applicators an d other handlers to wear long

- sleeved shirt and long pants, shoes plus socks, chemical

- resistant gloves, and protective eyewear such as a face shield, goggles, or safety glasses.

Combining Exposures/Risk Estimates Dermal and inhalation risk estimates were combined in this assessment, since the toxicological effects for these exposure routes were similar. Dermal and inhalation risk estimates were combined using the following formula:

Total MOE = Point of Departure (mg/kg/day) ÷ Combined dermal + inhalation dose (mg/kg/day)



### Summary of Occupational Handler Non

- Cancer Exposure and Risk Estimates The occupational handler exposure and risk estimates indicate that the short

- and intermediate

term dermal and inhalation combined MOEs ar e not of concern to HED (i.e., MOE > 100). At the baseline level of PPE (i.e., no gloves and no respirator), all scenarios result in combined MOEs (dermal + inhalation) ≥ LOC (MOEs ≥ 100).Saflufenacil Human Health Risk Assessment DP# 426933

_________ _____________________________________________________________________________ _______

Page 23 of 32 Table 9.1.1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Saflufenacil.

Exposure Scenario Crop or Target Dermal Unit Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application Rate (lb ai/A) 2 Area

Treated (acres) 3 Dermal

(LOC = 100) Inhalation (LOC = 100) Total

(LOC = 100)

Mitigation Level Mitigation

Level Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8
Mixer/Loader Mixing/loading WG s Groundboom application Pomegranate 227 (baseline) 8.96

(baseline) 0.044 80 0.000695 7,200 0.000457 11,000 4,400

Applicator Groundboom spray application Pomegranate 78.6 (baseline) 0.34

(baseline) 0.044 80 0.000241 21,000 0.0000174 290,000 20,000
Mixer/Loader/Applicator Mixing/loading/applying WG s via backpack applications Pomegranate 8260 (baseline) 2.58

(baseline) 0.00044 lb

ai/gallon 40 gallons 0.000126 40,000 0.000000658 7,600,000 40,000

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2013); Level of mitigation: Baseline

. 3 Exposure Science Advisory Council Policy #9.1. 4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre) × Area Treate d (A/day) × DAF (6 %) ÷ BW (69 kg). 5 Dermal MOE = Dermal NOAEL (5 mg/kg/day) ÷ Dermal Dose (mg/kg/day). 6 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre) × Are a Treated (A/day) ÷ BW (69 kg). 7 Inhalation MOE = Inhalation NOAEL (5 mg/kg/day) ÷ Inhalation Dose (mg/kg/day). 8 Total MOE = NOAE L (5 mg/kg/day) ÷ (Dermal Dose + Inhalation Dose).Saflufenacil Human Health Risk Assessment DP # 426933

______________________________________________________________________________________ _____

Page 24 of 32 

### 9.2 Short

- and Intermediate

- Term Post

- Application Risk

HED uses the term post

- application to describe exposures that occur when individuals are present in an environment that has been previ ously treated with a pesticide (also referred to as re

entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvestin g. Post

- application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post

- application exposure.

9.2.1 Dermal Post

- Application Risk

A dermal post

- application exposure assessment has not been conducted for the proposed use on
po megranate since the use directions indicate that the product is to be applied to the base of the tree trunk and is not to contact the foliage. Currently, HED has no transfer coefficients or other data to assess post

- application dermal exposures to soil by occupational workers. In general, such exposures are considered to be negligible. Therefore, for the soil

- directed uses, post

application exposures and risks to occupational workers were not assessed.

9.2.2 Inhalation Post

- Application Risk

There are multiple potential sources of post

- application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA SAP in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPP

- 2009

- 0687

- 0037 ). The Agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Scr eening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219 ). During Registration Review, the Agency will utilize this analysis to determine if dat a (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis is required for saflufenacil

In addition, the Agency is continuing to evaluate the available post

- application inhalation exposure data generated by the Agricultura l Reentry Task Force. Given these two efforts, the Agency will continue to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the Agency 's risk assessments.

Although a quantitative occup ational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in high er exposure than post

- application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post

- application inhalation exposure scenarios.

9. 3 Restricted

- Entry Interval

The 12

- hour REI specified on the proposed label is based on the acute toxicity of saflufenacil.Saflufenacil Human Health Risk Assessment DP# 426933

_________ _____________________________________________________________________________ _______

Page 25 of 32 

### Saflufenacil is classified as Toxicity Category III for acute oral, acute dermal toxicity, and acute eye irritation

. It is classified as Toxicity Category IV for acu te inhalation toxicity and acute dermal irritation. It is not a dermal sensitizer. Short

- and intermediate

- term post

- application risk estimates were not a concern on day 0 (12 hours following application) for all post

- application activities. Under 40 CF R 156.208 (c) (2) (iii), ai’s classified as Acute III or IV for acute dermal, eye irritation

, and primary skin irrigation are assigned a 12

- hour REI. Therefore, the [156 subpart K] Worker Protection Statement interim REI of 12 hours is adequate to protect agricultural workers from post

- application exposures to saflufenacil.

10.0 References

Previous Risk Assessments: L. Austin, et al.

, 22

- JUL

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

- APR

- 2011 ; D380636 . G. Kramer, et al. ; 23

- JAN

- 2014 ; D405506 . G. Kramer, et al. ; 24

- JUN

- 2014 ; D418587

HASPOC Memo: A. Dunbar, 02

- AUG

- 2013; TXR #0056720

Chemistry Memo: G. Kramer

, 05

- NOV

- 2015 ; D422467

Drinking Water Memo: M. Ruhman, 12

- MAR

- 2014 ; D 414485

Dietary Memo: G. Kramer

, 05

- NOV

- 2015 ; D426932

Occupational and Reside ntial Exposure Assessment Memo: J. Godshall

, 14

- MAY

- 20 15 ; D426980

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

cc: G. Kramer (RAB1) RDI: RAB1 ( 5 / 20 /1 5 ) G.F. Kramer:S10957:PY

- S:(703)305

- 5079:7509P:RAB1Saflufenacil Human Health Risk Assessment DP# 426933

_________ _____________________________________________________________________________ _______

Page 26 of 32 

### 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 tox . Screening Battery (rat)

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

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

no yes yes

no -

- yes yes

- 870.7485 General Metabolism

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

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

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

yes yes
1 Waived by the HASPOC ( A. Dunbar, 02

- AUG

- 2013; TXR #0056720 ).


### 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 Health Risk Assessment DP# 426933

_________ _____________________________________________________________________________ _______

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. NOAEL = 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 weight 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) and 12.6 mg/kg bw/day (F).

870.3150 28

- Day Ora l 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 extramedullary 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 Health Risk Assessment DP# 426933

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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)

A cceptable/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, 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 changes in hematological parameters. 87 0.4300b 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.

There was 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 decreas ed red blood cells, Hb , and Ht and porphyria observed in the satellite group.

There was 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.

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 the absence of metabolic activation.

Cytogenetics

- other 47128125 (2005) There was no increase in the frequency ofSaflufenacil Human Health Risk Assessment DP# 426933

_________ _____________________________________________________________________________ _______

Page 29 of 32 Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile for Saflufenacil.

Guideline No./Study Type MRID No. (year)/Classification/Doses Results 870.5395 In Vivo Mammalian Cytogenetics

- Erythrocyte Micronucleus assay in mice Acceptable/guideline 0, 500, 1000, or 2000 mg/kg bw 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 ne urotoxicity. 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) and 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 residu es occurred in the plasma and w ere 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 administra tion, 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 significantly 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 carcass, liver, skin, and gut contents. Saflufenacil was metabolized by three major transformation s teps: demethylation of the uracil ring system, 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. Oth er minor metabolites were M800H05, M800H16, M800H17, M800H18, M800M19, and M800M20. There were no significant sex

- related differences inSaflufenacil Human Health Risk Assessment DP# 426933

_________ _____________________________________________________________________________ _______

Page 3 0 of 32 Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile for Saflufenacil.

Guideline No./Study Type MRID No. (year)/Classification/Doses Results 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 (M = 0, 0.8, 4.1, 80.6; F = 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 (M = 0, 0.1, 0.4, 2.0; F = 0, 0.1, 0.5, 2.3 mg/kg bw/day Dietary administration of saflufenacil at 25 ppm caused an increase in porphyrin 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 Health Risk Assessment DP# 426933

_________ _____________________________________________________________________________ _______

Page 31 of 32 

### 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 Health Risk Assessment DP# 426933

_________ _____________________________________________________________________________ _______

Page 32 of 32 

### 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) subject to ethics review pursuant to 40 CFR § 26, (2) have received that review, and (3) ar e 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 4



### .

4 http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risks/occupational

- pesticide

- handler

- exposure

- data and http://www2.epa.gov/pesticide

- science

- and

- assessing

- pesticide

- risks/occupational

- pesticide

- post

- application

exposure