UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

DATE: 

SUBJECT: 

PC Code: 

23-J AN-20 14 

Saflufenacil. Human-Health Risk Assessment in Support of Tolerances for 

Residues in/on Fish, Crayfish, and Imported Sugarcane. 

118203 DP Barcodes: D405506 & D413071 

Decision Nos.: 467996 & 473447 Registration No.: 7969-278 

Petition Nos.: 2E8065 & 2F8129 Regulatory Actions: Sec. 3 Registration and 

Tolerance With No U.S. Registration 

Risk Assessment Type: Single Chemical/ Case No.: 7277 

Aggregate 

TXRNo.: NA CAS No.: 372 137-35-4 

MRID No.: NA 40 CFR: § 180.649 

FROM: George F. Kramer, Ph.D., Senior Chemis 

Chester E. Rodriguez, Ph.D., Toxicologist ~ _;t ~k-1 r/ 

Ri

Cha

sk 

rl

Assessment 

es W. Smith 

Branch 

III, Senio

1 (RAB 

r Environmental 

1) 

ScientiC ~ 

Health Effects Division (HED, 7509P) 

THROUGH: Dana M. Vogel, Associate Division Director 

Associate Division Director, HED (7509P) 

TO: Kathryn Montague/Bethany Benbow, PM Team 23 

Registration Division (RD; 7505P) 

The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human 

health from exposure to pesticides. The RD of OPP has requested that HED evaluate hazard and 

exposure data and conduct dietary, occupational, residential, and aggregate exposure 

assessments, as needed, to estimate the risk to human health that will result from the proposed 

tolerances for residues in/on crayfish, fish, and imported sugarcane. The petitioner is BASF. 

A summary of the findings and an assessment of human-health risk resulting from the 

proposed/registered uses of saflufenacil are provided in this document. The risk assessment and 

dietary exposure assessment were provided by George Kramer (RAB 1 ), the hazard 

characterization by Chester Rodriguez (RAB 1 ), the residue chemistry data review by George 

Kramer (RAB 1 ), the occupational/residential exposure assessment by Charles Smith (RAB I), 

and the drinking water assessment by Mohammed Ruhman of the Envirorunental Fate and 

Effects Division (EFED). 

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Saflufenacil Human-Health Risk Assessment DP Number 405506 

Table of Contents 

1.0 Executive Summary .......................................................................................................... 4 

2.0 HED Recommendations ................................................................................................... 6 

2.1 Data Deficiencies ................................................................................................... 7 

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

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

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

2.2.3 Revisions to Petitioned-For Tolerances .............................................................. 8 

2.2.4 International Harmonization ................................................................................ 8 

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

3.0 Introduction ....................................................................................................................... 8 

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

3.2 Physical/Chemical Characteristics ...................................................................... 9 

3.3 Pesticide Use Pattern ............................................................................................ 9 

3.4 Anticipated Exposure Pathways ........................................................................ 10 

3.5 Consideration of Environmental Justice .......................................................... 10 

4.0 Hazard Characterization and Dose-Response Assessment. ........................................ 11 

4.1 Toxicology Studies Available for Analysis ........................................................ 11 

4.2 Absorption, Distribution, Metabolism, and Excretion (ADME) .................... 11 

4.2.1 Dermal Absorption ............................................................................................. 12 

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

4.3.1 Summary of Toxicological Effects ..................................................................... 12 

4.4 Safety Factor for Infants and Children (FQPA SF) ........................................ 13 

4.4.1 Completeness of the Toxicology Database ........................................................ 13 

4.4.2 Evidence of Neurotoxicity .................................................................................. 13 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal.. 14 

4.4.4 Residual Uncertainty in the Exposure Database .............................................. 14 

4.5 Toxicity Endpoint and Point of Departure Selections ..................................... 14 

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

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment15 

4.5.3 Cancer Classification and Risk Assessment Recommendation ...................... 15 

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

Risk Assessment .............................................................................................................. 16 

5.0 Dietary Exposure and Risk Assessment ........................................................................ 17 

5.1 Residues of Concern Summary and Rationale ................................................. 17 

5.2 Food Residue Profile ........................................................................................... 19 

5.3 Water Residue Profile ......................................................................................... 20 

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

5.4.1 Description of Residue Data Used in Dietary Assessment .............................. 20 

5.4.2 Percent Crop Treated Used in Dietary Assessment ......................................... 21 

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

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

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

6.0 Residential (Non-Occupational) Exposure/Risk .......................................................... 22 

6.1 Residential Exposure/Risk Characterization ............................................................... 22 

6.2 Residential Bystander Post-Application Inhalation Exposure ................................... 22 

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

7.0 Aggregate Exposure/Risk Characterization ................................................................. 22 

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7.1 Acute Aggregate Risk ......................................................................................... 23

7.2 Chronic Aggregate Risk ..................................................................................... 23

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

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

9.1 Short- and Intermediate-Term Handler Risk .................................................. 23

9.2 Short- and Intermediate-Term Post-Application Risk.................................... 24

9.2.1 Dermal Post-Application Risk ........................................................................... 24

9.2.2 Inhalation Post-Application Risk ...................................................................... 24

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

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

Appendix A. Toxicology Assessment........................................................................................ 26

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

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

Appendix B. Physical/Chemical Properties............................................................................. 31

Appendix C. Review of Human Research................................................................................ 32
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1.0 Executive Summary

Saflufenacil is a pre- and post-emergence herbicide that acts by inhibiting protoporphyrinogen 

IX oxidase (PPO), which leads to chlorophyll destruction by photooxidation and causes 

bleaching of emerging foliar tissue. PPO is one of the key enzymes in the porphyrin 

biosynthesis for the production of chlorophyll in plants and heme in mammals. 

Saflufenacil is currently registered for use on legume vegetables (Crop Group 06), the foliage of 

legume vegetables (Crop Group 07), cereal grains (Crop Group 15, pre-plant/pre-emergence

application only), the forage, fodder, and straw of cereal grains (Crop Group 16, pre-plant/preemergence application only), cotton, and sunflower. BASF has submitted a tolerance petition for 

residues in/on imported sugarcane (PP#2E8065). In addition, BASF has submitted a proposal to

allow post-emergence application of saflufenacil to rice in the U.S. and to permit crayfish and 

fish to be grown in the treated rice fields (PP#2F8129). There are no residential uses proposed or 

currently registered for saflufenacil.

Hazard Assessment: Saflufenacil was well absorbed and rapidly excreted via the oral route in 

rat metabolism studies. Maximum blood concentrations were reached within one hour and 

declined rapidly thereafter. Elimination was primarily urinary in female rats and via the feces in 

male rats. The sex-dependent excretion resulted in male rats having up to 3X 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 

(Category III or IV). It was slightly irritating to the eye (Category III), but neither a dermal 

irritant nor dermal sensitizer.

Subchronic and chronic toxicity studies in rats, mice, and dogs identified the hematopoietic 

system as the primary target of saflufenacil. Consistent with its proposed mode of toxicity 

involving PPO inhibition and subsequent disruption of heme biosynthesis, decreased 

hematological parameters [red blood cells (RBC), hematocrit (Ht), mean corpuscular volume 

(MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration 

(MCHC)] were seen at about the same dose level [lowest-observed adverse-effect levels 

(LOAELs) of 13-39 mg/kg/day] across species, 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 were 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 susceptibility 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 liver porphyrins in 

rabbits) occurred at doses that were not maternally toxic in the developmental studies, 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. An increased number of stillborn 
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pups, decreased viability and lactation indices, decreased pre-weaning body weight and/or bodyweight gain, and changes in hematological parameters occurred at the same dose level as 

maternal decrements in food intake, body weight, body-weight gain, and changes in 

hematological parameters and organ weights indicative of anemia. 

Saflufenacil was weakly clastogenic in the in vitro chromosomal aberration assay in 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.”

Saflufenacil displayed no evidence of neurotoxicity in acute and subchronic neurotoxicity 

studies, did not produce any 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 

assessment 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, there is no evidence of 

neurotoxicity, there is low concern for offspring susceptibility, and there is no uncertainty in the 

exposure database.

A 100X uncertainty factor (UF) (10X for interspecies extrapolation and 10X for intraspecies 

variation) was incorporated 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 PAD 

(cPAD) are equal to the acute and chronic RfDs, respectively, divided by the FQPA 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 (MOEs), the level of concern (LOC) is for 

MOEs <100 for the dermal and inhalation risk assessments. A 6% dermal-absorption factor 

(DAF) and a 100% inhalation-absorption factor were used in route-to-route extrapolations. 

Food Residue Profile: The nature of the residue in plants is adequately understood in the 

subject crops. Organization for Economic Co-operation and Development (OECD) tolerancecalculation procedures and the submitted residue data sets were used to calculate the HEDrecommended tolerances. Provided that issues related to storage stability in crayfish are 

resolved, the submitted magnitude of the residue data are adequate and there are no residue 

chemistry issues that would preclude establishing unconditional tolerances for residues of 

saflufenacil, as outlined in Table 2.2.2.

Exposure/Risk Assessment Characterization: Acute and chronic dietary risk assessments were 

conducted using the Dietary Exposure Evaluation Model - Food Consumption Intake Database 

(DEEM-FCID, ver. 3.16) which incorporates consumption data from United States Department 

of Agriculture (USDA) National Health and Nutrition Examination Survey, What We Eat in 

America, (NHANES/WWEIA; 2003-2008). The acute and chronic analyses assumed 100% crop 

treated (CT), DEEM 7.81 default processing factors, and tolerance-level or higher residues for all 

foods. Drinking water was incorporated directly into the dietary assessments using the 
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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 95th percentile [<1%

aPAD for all infants (<1 year old), the most highly exposed population subgroup] are not of 

concern (<100% aPAD). The chronic dietary risk assessment shows that the chronic dietary risk 

estimates are not of concern (i.e., <100% cPAD). The chronic dietary risk estimate for the 

highest exposed population subgroup, all infants (<1 year old), is 18% of the cPAD. 

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

residential risk assessment was not conducted.

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

uses, the aggregate exposure assessment takes into consideration dietary food + drinking water 

exposure only. The acute and chronic dietary estimates represent acute and chronic aggregate 

risk, respectively.

There is potential for occupational handler short- and intermediate-term exposure resulting from 

the proposed use of saflufenacil on rice. Potential occupational handler exposure scenarios 

include mixing/loading liquids for aerial and ground applications, applications via aerial and 

ground equipment, and flagging. The proposed label has proposed maximum rates of 0.089 and 

0.044 lbs ai/A for pre-plant/pre-emergent and post-emergent applications, respectively. The 

2009 saflufenacil risk assessment (L. Austin, et al., 22-JUL-2009; D367317) assessed 

application rates up to 0.35 lbs ai/A with applications made via aerial and ground equipment. 

This assessment showed that all risks for occupational handlers are above the target MOE of 100 

with the use of gloves, and do not exceed the LOC. Since the proposed label includes 

applications made using similar application equipment and lower maximum application rates 

than those previously assessed for saflufenacil; no new occupational handler assessment has been 

performed at this time.

Occupational post-application exposures associated with the proposed use on rice are expected to 

be negligible as the proposed label allows applications to be made prior to planting, prior to crop 

emergence, or from the two-leaf stage up to internode elongation. Saflufenacil is classified as 

Toxicity Category III for acute oral toxicity, acute dermal toxicity, and acute eye irritation. It is 

classified as toxicity Category IV for acute inhalation toxicity and acute dermal irritation. It is 

not a dermal sensitizer. The restricted-entry interval (REI) of 12 hours on the Sharpen®label 

complies with the Worker Protection Standard (WPS). 

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. Please refer to Appendix C for a 

discussion of the human study data used in this risk assessment. 

2.0 HED Recommendations

Provided that issues related to storage stability in crayfish are resolved, and pending submission 

of revised Section Fs, there are no other residue chemistry, occupational, or toxicology data 

deficiencies that would preclude the establishment of permanent tolerances for residues of 

saflufenacil and it metabolites and degradates as outlined in Table 2.2.2. 
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2.1 Data Deficiencies

860.1380 Storage Stability (PP# 2F8129)

Actual analysis dates of the samples from the submitted magnitude of residue study in 

freshwater crayfish were not provided. No supporting storage stability data were 

submitted. Sample analysis dates are required to determine the duration of storage. 

Ruminant storage stability data are available which show that saflufenacil is stable for up 

to 35 days in ruminant matrices (47128015.der.doc). These data can be translated to 

crayfish. However, if crayfish samples were stored for more than 35 days, then storage 

stability data may be required for saflufenacil in crayfish.

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

The petitioner is requested to submit revised Section Fs specifying revised tolerances, as 

presented in Table 2.2.2.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

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

(LC-MS/MS) analytical methods for the determination of residues of the parent and its 

metabolites in/on plant and livestock commodities. BASF Method D0603/02 was developed for 

determination 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. BASF analytical 

Method No. L0073/01 was developed for determination of saflufenacil in livestock matrices 

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

data-collection methods in the analysis of samples for residues of concern from the various 

studies associated with the current petitions. Each method has been adequately validated by the 

petitioner as well as by independent laboratories and were adequately radiovalidated using 

weathered samples obtained from metabolism studies.

HED has determined that Methods D0603/02 and L0073/01 are suitable enforcement methods 

for the plant and livestock commodities associated with this petition, respectively, as defined in 

SOP No. ACB-019 (9/15/08). 

2.2.2 Recommended Tolerances

The proposed uses and the submitted data support the following permanent tolerances for 

residues of saflufenacil in or on the commodities summarized in Table 2.2.2. 

Table 2.2.2. Tolerance Summary for Saflufenacil.

Commodity

Proposed 

Tolerance (ppm)

HED-Recommended 

Tolerance (ppm)

Comments; Correct Commodity 

Definition

40 CFR §180.649(a)(1)

Sugarcane, cane 0.03 ppm 0.051-

Sugarcane, molasses 0.075 ppm 0.081-
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Table 2.2.2. Tolerance Summary for Saflufenacil.

Commodity

Proposed 

Tolerance (ppm)

HED-Recommended 

Tolerance (ppm)

Comments; Correct Commodity 

Definition

Sugarcane, refined sugar 0.045 ppm - -

Grain, cereal, forage, fodder 

and straw group 16 (except 

rice straw)

0.1 - -

Rice, straw 0.30 - -

40 CFR §180.649(a)(2)

Fish-freshwater finfish 0.01 0.01 -

Fish-shellfish, crustacean 0.01 0.01 -

1

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

2.2.3 Revisions to Petitioned-For Tolerances

The residue data for sugarcane were analyzed using the OECD tolerance calculation procedures, 

resulting in a value for sugarcane, cane (0.05 ppm) higher than that proposed (0.03 ppm). 

Multiplication of the sugarcane highest-average field trial (HAFT) residue (0.04 ppm) by the 

observed molasses processing factor of 2.0X yields a value (0.08 ppm) which is significantly 

greater than the recommended raw agricultural commodity (RAC) tolerance (0.05 ppm); 

therefore, a separate tolerance of 0.08 ppm is required for residues in/on sugarcane, molasses. 

Residues did not concentrate in refined sugar, so the tolerance proposed for this commodity 

should be withdrawn. In addition, the proposed tolerances for rice straw and grain, cereal, 

forage, fodder and straw group 16 (except rice straw) should be withdrawn since rice straw is not 

a regulated commodity. 

2.2.4 International Harmonization

There are no Canadian or Codex maximum residue limits (MRLs) established for residues of 

saflufenacil and its metabolites in sugarcane commodities, fish-freshwater finfish, or fishshellfish, crustacean. Harmonization is thus not an issue at this time.

2.3 Label Recommendations

None

3.0 Introduction

3.1 Chemical Identity

TABLE 3.1. Saflufenacil Nomenclature.

Chemical Structure

Common name Saflufenacil

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

F Cl

N

N

O

O

CH3

F

F

F

O

N

H

S

N

O

O

CH3

CH3

CH3
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TABLE 3.1. Saflufenacil Nomenclature.

IUPAC name N'-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydro-1(2H)-

pyrimidinyl)benzoyl]-N-isopropyl-N-methylsulfamide

CAS name 2-chloro-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-4-

fluoro-N-[[methyl(1-methylethyl)amino]sulfonyl]benzamide

CAS registry number 372137-35-4

End-use product (EP) BAS 800 04 H (342 g ai/L SC formulation)

Chemical Structure

Common name M800H11

Chemical name N-[2-chloro-5-(2,6-dioxo-4-(trifluoromethyl)-3,6-dihydro-1(2H)-pyrimidinyl)-4-

fluorobenzoyl]-N'-isopropylsulfamide

Chemical Structure

Common name M800H35

Chemical name N-[4-chloro-2-fluoro-5-({[(isopropylamino)sulfonyl]amino}carbonyl)phenyl]urea

3.2 Physical/Chemical Characteristics

Saflufenacil (BAS 800 H) is a broad-spectrum herbicide developed by BASF. It belongs to the 

herbicide mode-of-action Group 14 (cell 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 more-volatile herbicides. A summary of the physicochemical 

properties can be found in Appendix B. 

3.3 Pesticide Use Pattern

Sharpen®Powered by Kixor Herbicide (EPA Reg. No. 7969-278), a 2.85 lb ai/gal suspensionconcentrate (SC) formulation, is currently registered for use on legume vegetables (Crop Group 

06), the foliage of legume vegetables (Crop Group 07), cereal grains (Crop Group 15, preplant/pre-emergence application only), the forage, fodder, and straw of cereal grains (Crop 

Group 16, pre-plant/pre-emergence application only), cotton, and sunflower. BASF has 

submitted a tolerance petition for residues in/on imported sugarcane (PP#2E8065). In addition, 

BASF has submitted a proposal to allow post-emergence application of saflufenacil to rice in the 

U.S. and to permit crayfish and fish to be grown in the treated rice fields (PP#2F8129). Example 

labels were provided and the proposed use directions are summarized in Table 3.3.1. 

F Cl

N

N

H

O

O

F

F

F

O

N

H

S

N

H

O

O

CH3

CH3

F Cl

N

H

O

O

N

H

S

N

H

O

O

CH3

CH3 H2N
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Table 3.3.1. Summary of Directions for Use of Saflufenacil.

Applic. Timing, 

Type, and Equip. Formulation

App. rate

(lb ai/acre)

Max. No. 

App. per 

Season

Max. Seasonal 

App. Rate

(lb ai/acre)

PHI

(days) Use Directions and Limitations

Rice

Ground, Air

Sharpen®

Powered by 

Kixor Herbicide

0.045-0.090 2 0.135 -

- A maximum of 0.045 lb 

ai/A applied post-emergence 

between the two-leaf stage 

and internode elongation.

- Minimum retreatment 

interval (RTI) = 14 days.

- May be applied to fields 

used for crayfish and fish

production.

- May not be applied to fields 

used for mollusc production.

- Flood water from treated 

fields must be held at least 7 

days prior to release.

- A crop-oil concentrate is 

required for optimum activity.

Sugarcane

Ground, Air Heat®0.022-0.075 1 0.075 7

Applications are to be made 

in 16-43 gal/acre (ground) or 

4.3-5.3 gal/acre (air)

Conclusions: The proposed use patterns are adequate to allow evaluation of the residue data 

submitted in support of these petitions. 

3.4 Anticipated Exposure Pathways

RD has requested that HED evaluate hazard and exposure data and conduct dietary, 

occupational, residential, and aggregate exposure assessments, as needed, to estimate the risk to 

human health that will result from the tolerance petitions for residues in/on fish, crayfish, and 

sugarcane. Humans may be exposed to saflufenacil in food and drinking water, since 

saflufenacil may be applied directly to growing crops and application may result in saflufenacil 

reaching surface and ground water sources of drinking water. There are no residential uses of 

saflufenacil, so exposure in residential or non-occupational settings is not likely. In an 

occupational setting, applicators may be exposed while handling the pesticide prior to 

application, as well as during 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 uses of saflufenacil, but also considers the existing registered uses as well. 

3.5 Consideration of Environmental Justice

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

human health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations,” 

(http://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf). As a part of every 
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pesticide risk assessment, OPP considers a large variety of consumer subgroups according to 

well-established procedures. In line with OPP policy, HED estimates risks to population 

subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water 

consumption, and activities in and around the home that involve pesticide use in a residential 

setting. Extensive data on food consumption patterns are compiled by the U.S. Department of 

Agriculture (USDA) under the National Health and Nutrition Examination Survey, What We Eat 

in America, (NHANES/WWEIA; 2003-2008) and are used in pesticide risk assessments for all 

registered food uses of a pesticide. These data are analyzed and categorized by subgroups based 

on age, 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 well 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 production of chlorophyll in 

plants and heme in mammals. When PPO is inhibited in mammals, hemoglobin biosynthesis is 

reduced, resulting in anemia and accumulation of different porphyrins and their precursors in 

various organs. 

4.1 Toxicology Studies Available for Analysis

The toxicology database for saflufenacil is adequate for hazard characterization, toxicity 

endpoint selection, and FQPA SF evaluation. In previous risk assessments (Kramer et al., DP# 

384602; 04-AUG-2011) and in the current assessment, an oral toxicity study is used for the 

inhalation endpoint. The HED Hazard and Science Policy Council (HASPOC) concluded, based 

on a weight-of-evidence approach, that a 28-day inhalation toxicity study is not required at this 

time (TXR #056720).

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

In rat metabolism/pharmacokinetic studies via the oral route, radiolabeled saflufenacil was well 

absorbed and rapidly excreted. Following a single dose and regardless of the dose administered, 

maximum blood concentrations 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 occurred in the plasma and were not bound to cellular 

elements of the blood such as red blood cells. Following single or repeated low- and high-dose 

administration, the main route of elimination in male rats was via the feces, whereas urinary 

excretion was the major route of elimination in females. There was significantly higher biliary 

excretion of saflufenacil residues in males than in females. This sex-dependent difference in 
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excretion was more pronounced at the low-dose level and resulted in males having up to 3X

higher internal exposures than females as measured by the plasma area under the concentrationtime curve (AUC). Increasing the administered dose by a factor of 25 resulted in less than 

proportional increases in plasma AUC values at 6.1 in males and 12.4 in females. Saflufenacil 

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 exposure, the 

estimated DAF was 3.4%. However, about 50% of the radioactivity remaining at the end of 

exposure penetrated through the skin during a 120-hour (5-day) observational period, indicating 

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

residues were included, a DAF of 6% will assess the potential risk associated with dermal 

exposures to saflufenacil from the proposed uses.

4.3 Toxicological Effects

4.3.1 Summary of Toxicological Effects

The effects observed following repeated oral exposures to saflufenacil are consistent with the 

proposed mode of toxicity involving inhibition of PPO in mammals, resulting in disruption of 

heme biosynthesis. Toxicological effects from subchronic and chronic toxicity studies in rats, 

mice and dogs consisted of decreased hematological parameters (RBC, Ht, MCV, MCH, and 

MCHC) at approximately the same dose level (13-39 mg/kg/day), except in the case of the dog, 

where the effects were seen at a slightly higher dose (50-100 mg/kg/day). In line with the 

ADME findings suggesting that male rats achieve a greater systemic exposure than females, 

males were the most sensitive sex in mice and rats, with LOAELs approximately 3-4X lower 

than 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 (increased 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 

toxicity studies in the rat and rabbit and in the two-generation reproduction study in the rat. 

Decreased fetal body weights and increased skeletal variations occurred at doses (20 mg/kg/day) 

that were not maternally toxic in the developmental study in rats. Similarly, in rabbits, increased 

liver porphyrins in 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 based on an increased number of stillborn pups, decreased pup viability 

and lactation indices, decreased pre-weaning body weight and/or body-weight gain, and changes 

in hematological parameters at the same dose level as less severe maternal effects consisting of 

decrements in food intake, body weight, body-weight gain, and changes in organ weights and 
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hematological parameters indicative of anemia. 

In an acute neurotoxicity (ACN) study in rats, a decrease in motor activity was observed on the 

day of dosing at the limit dose (2000 mg/kg/day) in males only. However, the finding was not 

accompanied by any neuropathological changes and was considered a reflection of a mild and 

transient general systemic toxicity and not a substance-specific neurotoxic effect. In the 

subchronic neurotoxicity (SCN) study, systemic toxicity (anemia) was seen at 1000 ppm (66.2 

mg/kg/day) and 1350 ppm (101 mg/kg/day) in males and females, respectively. There was no 

evidence of neurotoxicity or neuropathology in either the acute or subchronic neurotoxicity 

study.

In a 28-day dermal toxicity 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 

(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 toxicity specific to the 

immune system at the highest dose tested (i.e., 52 mg/kg bw/day). 

Saflufenacil was weakly clastogenic in the in vitro chromosomal aberration assay in V79 cells in 

the presence of S9 activation; however, the response was not evident in the absence of S9 

activation. It was neither mutagenic in bacterial cells nor clastogenic in rodents in vivo. 

Carcinogenicity studies in rats and mice showed no evidence of increased incidence of tumors at 

the tested doses. Saflufenacil is classified as “not likely carcinogenic to humans.”

4.4 Safety Factor for Infants and Children (FQPA SF)

The saflufenacil risk assessment team recommends that the FQPA SF be reduced to 1X for all 

exposure scenarios based on the following rationale: the toxicological database is adequate for 

FQPA assessment, there is no evidence of neurotoxicity, there is low concern for offspring 

susceptibility, and there is no uncertainty in the exposure database.

4.4.1 Completeness of the Toxicology Database

The toxicology database for saflufenacil is adequate for FQPA SF consideration. The following 

acceptable studies are available for evaluation: developmental toxicity study in rats and rabbits, 

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

4.4.2 Evidence of Neurotoxicity

There was no evidence of neurotoxicity or 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 

neurotoxicity effects were seen in the SCN study. The systemic toxicity (anemia) observed is in 

line with the mode of toxicity proposed for saflufenacil as a PPO inhibitor.
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4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

The concern for increased susceptibility following prenatal or postnatal exposure is low because 

clear no-observed adverse-effect levels (NOAELs)/LOAELs were established for the 

developmental effects seen in rats and rabbits as well as for the offspring effects seen in the twogeneration reproductive toxicity study. Further, the dose-response relationship for the effects of 

concern are also well characterized and being used for assessing risks. The point of departure for 

risk assessments would be protective of the developmental and offspring effects. 

4.4.4 Residual Uncertainty in the Exposure Database

There are no additional residual uncertainties with respect to exposure data. The dietary food

exposure assessment utilizes recommended tolerance-level residues and 100% CT information 

for all commodities. By using these screening-level assessments, acute and chronic 

exposures/risks will not be underestimated. The dietary drinking water assessment utilizes 

values generated by models and associated modeling parameters that are designed to provide 

conservative, health-protective, high-end estimates of water concentrations. There are no 

registered residential uses of saflufenacil; therefore, 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 interspecies (10X) and intraspecies (10X) 

extrapolation. The FQPA SF was reduced to 1X for this exposure scenario since the toxicology 

database is complete and there were no residual uncertainties for pre-and or postnatal 

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

Acute Dietary Endpoint (Females 13-49 years old): An acute dietary endpoint, separate from 

that defined above, was not established for this population group. The developmental effects 

following saflufenacil exposure are unlikely to be the result of a single dose event. The skeletal 

variations (e.g., misshapen bones, delays in ossification, and wavy ribs) observed in the prenatal 

developmental study in the rat are not considered to be the result of a single dose. The process of 

bone deposition begins with cartilage deposition followed by calcification and does not occur 

during a single day. Unlike supernumerary ribs or missing bones, which may be caused by the 

activation or inactivation of genes and could be the outcome of a single exposure, the process of 

bone deposition occurs over several days and, therefore, is not considered appropriate for this 

endpoint.

Chronic Dietary Endpoint: This endpoint was based on decreases in red blood cells, 

hemoglobin, and hematocrit as well as porphyria 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 since the toxicology database is complete and there 
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were no residual uncertainties for pre-and or postnatal susceptibility. Thus, the cPAD is 

estimated at 0.046 mg/kg bw/day. This point of departure is protective of the developmental and 

offspring effects. 

Incidental Oral (Short- and Intermediate-Term): Selection of this endpoint is not warranted 

since there are no registered or proposed uses of saflufenacil.

Dermal (Short- and Intermediate-Term): Although a 28-day dermal toxicity study with nonpregnant 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 study 

at the LOAEL of 20 mg/kg/day (NOAEL of 5 mg/kg/day). The concern for developmental 

toxicity is also supported by findings at higher doses 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 100 

based on a combined UF of 100 applied to account for interspecies (10X) and intraspecies (10X) 

extrapolation.

Inhalation (Short- and Intermediate-Term): The inhalation risk for saflufenacil is being assessed 

using the rat prenatal developmental toxicity study with 100% absorption assumed via the 

inhalation route. The HASPOC (TXR #056720) decided, based on a weight-of-evidence 

approach, that a 28-day inhalation toxicity study is not required at this time. The effects in the 

rat prenatal developmental toxicity study consisted of decreased fetal weights and increased 

skeletal variations at the LOAEL of 20 mg/kg/day (NOAEL of 5 mg/kg/day). The LOC is 100 

based on a combined UF of 100 applied to account for interspecies (10X) and intraspecies (10X) 

extrapolation. 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

For occupational risk, dermal and inhalation exposures are of concern and should be combined 

since the dermal and inhalation endpoints are the same. Currently, there are no registered 

residential uses of saflufenacil.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Carcinogenicity studies in rats and mice showed no evidence of increased incidence of tumors at 

the tested doses. Saflufenacil is classified as “not likely carcinogenic to humans”; therefore, a 

cancer risk assessment is not required.
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4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

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

Risk Assessments.

Exposure

Scenario

Point of 

Departure

UFs/

FQPA SF RfD and PAD Study and Toxicological Effects

Acute Dietary 

(General 

Population, 

including 

Infants and 

Children)

NOAEL = 500 

mg/kg bw

UFA = 10X

UFH = 10X

FQPA SF = 1X

aRfD = 5.0 

mg/kg

aPAD = 5.0 

mg/kg

Acute Neurotoxicity Study - rats

NOAEL = 500 mg/kg bw.

LOAEL = 2000 mg/kg bw based on decreased 

motor activity representing mild and transient 

systemic toxicity in males. 

Chronic 

Dietary (All 

Populations)

NOAEL = 4.6 

mg/kg/day

UFA = 10X

UFH = 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. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among 

members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. FQPA SF 

= FQPA Safety Factor. PAD = population-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 Shortand 

IntermediateTerm (1-30 

days and 1-6 

months, 

respectively)

NOAEL = 5 

mg/kg/day

Dermal 

absorption 

factor = 6%

UFA = 10X

UFH = 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 

IntermediateTerm (1-30 

days and 1-6 

months, 

respectively)

NOAEL = 5 

mg/kg/day

Inhalationabsorption = 

100%

UFA = 10X

UFH = 10X

FQPA SF = 

1X

Occupational LOC 

for MOE = 100

Developmental study -Rat

NOAEL = 5 mg/kg bw/day.

LOAEL = 20 mg/kg bw/day based on 

decreased fetal bodyweight and increased 

skeletal variations. 

Cancer (oral, 

dermal, 

inhalation)

Classification: Not likely carcinogenic to humans based on the lack of tumors in the mouse and rat 

carcinogenicity studies and lack of mutagenicity. 

No long term uses are expected for saflufenacil

NOAEL = no-observed adverse-effect level. LOAEL = lowest-observed adverse-effect level. UF = uncertainty 

factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among 

members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. 
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5.0 Dietary Exposure and Risk Assessment 

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

the 22-JUL-2009 human-health risk assessment (L. Austin, et al., D367317).

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

were N-demethylation at the uracil ring, stepwise degradation (N-dealkylation) of the N-methylN-isopropyl group, hydrolytic cleavage of the uracil ring generating a urea side chain, and 

hydroxylation of the phenyl ring. The HED ROCKS determined that residues of concern for the 

tolerance expression and risk assessment consist of saflufenacil, M800H11, and M800H35 

(Memo, B. Daiss, 1/6/09; D359645). The metabolic pathway of radiolabeled saflufenacil in 

soybean following a late-season post-emergence treatment follows the same initial pathways, but 

is not as extensive. No new metabolites were observed following post-emergence treatment; 

however, an additional major metabolite (M800H02), that is not included in the tolerance 

expression, was observed in soybean seed. As the structure of M800H02 is closely related to the 

parent compound and it is the precursor of the regulated metabolite M800H11, HED concluded

that M800H02 is a residue of concern for risk-assessment purposes in seed crops following lateseason post-emergence treatment.

BASF Corporation has submitted a study investigating the metabolism of uniformly phenyl ringlabeled [phenyl-U14C]saflufenacil (PH label) and pyrimidine ring-labeled [uracil-4-

14C]saflufenacil (UR label) following early post-emergence foliar application to rice. The 

radiolabeled test substances were applied to rice plants (BBCH growth stages 22-24) grown in 

growth chambers as a single broadcast foliar spray at a nominal rate of 0.089 lb ai/A (2X the 

proposed post-emergence use rate). 

Metabolism of saflufenacil in rice is consistent with the other crops studied. The combined 

residues of saflufenacil, M800H11, and M800H35 (the current residues of concern for the 

tolerance expression and risk assessment) in rice forage were 71-89% of the total radioactive 

residue (TRR). The only other major metabolite was M800H02, which accounted for 4-16% of 

the TRR in forage. In rice grain, the combined residues of saflufenacil and all metabolites was 

<10% of the TRR (≤0.01 ppm). HED thus concludes that current tolerance expression 

adequately accounts for the residues of concern following post-emergence foliar application to 

rice and sugarcane. Additional metabolism data may be required to support foliar application to 

non-grass crops.

Plants (Rotational Crops): The metabolism of saflufenacil in rotational crops appears to be 

consistent with the pathway observed in the plant metabolism studies. The previously submitted 

confined and field rotational crop data are adequate to satisfy data requirements for application 

rates up to 0.137 lb ai/A (1X). The available data indicate that residues of saflufenacil and its 

metabolites M800H11 and M800H35 were each <LOQ in/on all rotational crop matrices at a 

120-day plantback interval (PBI). These data support the labeled rotational crop restriction of 4 

months for all non-labeled crops. Unless the petitioner requests PBIs shorter than 120 days, no 

additional data are required, and tolerances for inadvertent residues in/on rotational crops need 
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not be established in conjunction with the currently proposed uses. 

Livestock: The nature of the residue in livestock is adequately understood based on acceptable 

metabolism studies conducted on lactating goats and laying hens. Saflufenacil was metabolized 

by several dealkylation steps occurring at two different sites in the molecule (N-isopropyl-Nmethylsulfamide side chain and at the uracil ring) and via hydrolytic opening of the uracil ring 

(goat only). In the ruminant metabolism study, saflufenacil was a major residue in all matrices. 

M800H04, a ring opening product, was the only significant metabolite (>10% total radioactive 

residue, TRR) found (liver). In the poultry metabolism study, saflufenacil was a major residue in 

all matrices and no significant metabolites were found. The HED ROCKS determined that 

saflufenacil per se is the only residue of concern for the tolerance expression and risk assessment 

(Memo, B. Daiss, 1/6/09; D359645). 

The HED ChemSAC waived the data requirement for metabolism studies in fish (Memo G. 

Kramer, 4/5/12; D396260) based on the results of a bioaccumulation study in bluegill sunfish 

(conducted for EFED) in which the concentration of saflufenacil in the edible tissue of the fish 

was only 0.35 ppb at the 10-ug/L dose level (~2X).

Drinking Water: Saflufenacil is slowly photolyzed in water (half-life of 57 days at pH 5) and 

on soil (half-lives of 83 and 87 days) at 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 pH 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 environments 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 days 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. Another 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).
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Table 5.1. Summary of Metabolites and Degradates to be Included in the Tolerance Expression and Risk 

Assessment.

Matrix Residues Included in Risk 

Assessment

Residues Included in 

Tolerance Expression

Plants

Primary Crops (pre-plant

application)

Saflufenacil + M800H11, 

M800H35

Saflufenacil + M800H11, 

M800H35

Primary Crops (lateseason preharvest 

application)*

Saflufenacil + M800H11, 

M800H02, M800H35

Rotational Crops Saflufenacil + M800H11, 

M800H35

Livestock

Ruminants

Saflufenacil Saflufenacil

Poultry

Drinking Water

Saflufenacil + M800H01, 

M800H02, M800H07, M800H08, 

M800H15, M800H22, Product 8

Not Applicable

* Excluding rice and sugarcane.

5.2 Food Residue Profile

The submitted rice field trial data are adequate to fulfill data requirements. Following two 

broadcast applications of the 342 g ai/L SC formulation of saflufenacil at 0.131-0.139 lb ai/A, 

combined residues (and per-trial averages) of saflufenacil, M800H11, and M800H35 in/on rice 

grain harvested at a 54- to 103-day PHI were all <LOQ (<0.03 ppm). The available data will 

thus support the proposed use pattern. Since the existing tolerance of 0.03 ppm for residues 

in/on rice grain (as a member of cereal grains Crop Group 15) is supported by the residue data 

reflecting the post-emergent use pattern, no changes in the existing tolerances for Crop Group 15 

are needed. However, a tolerance is not required for rice straw since it is not a regulated 

commodity. 

The submitted magnitude of the residue data for sugarcane are also adequate. There are also 

adequate storage stability data to validate the storage conditions and intervals of samples 

collected from the field trials. Using the OECD tolerance-calculation procedures for the residue 

data sets indicate that the requested tolerance levels are too low. 

The actual analysis dates of the samples from the submitted magnitude of residue study in 

freshwater crayfish were not provided. Based on the sample collection dates and the final report 

date, the estimated storage duration for frozen samples is <125 days. No supporting storage 

stability data were submitted. Sample analysis dates are required to determine the duration of 

storage. Ruminant storage stability data are available which show that saflufenacil is stable for 

up to 35 days in ruminant matrices (47128015.der.doc). These data can be translated to crayfish. 

However, if crayfish samples were stored for more than 35 days, then storage stability data may 

be required for saflufenacil in crayfish. Provided issues related to storage stability are resolved, 

the submitted magnitude of saflufenacil residue study in freshwater crayfish will support the 

proposed tolerance for residues in/on fish-shellfish, crustacean. In addition, the crayfish 

magnitude of saflufenacil residue data can be translated to support the proposed tolerance for 

residues in/on fish-freshwater finfish.

The submitted rice processing data are adequate to fulfill data requirements. As the residues in 
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the RAC were <LOQ after treatment at a 5X rate, a separate tolerance for hulls and bran will not 

be required. The submitted sugarcane processing study is also adequate. Concentration 

following processing was observed in molasses, but not in refined sugar. Multiplication of the 

sugarcane HAFT residue (0.04 ppm) by the molasses processing factor of 2.0X yields a value 

(0.08 ppm) which is significantly greater than the recommended RAC tolerance (0.05 ppm); 

therefore, a separate tolerance of 0.08 ppm is required for residues in/on sugarcane, molasses.

The previously submitted confined and field rotational crop data are adequate to satisfy data 

requirements for application rates up to 0.137 lb ai/A (1X). The available data indicate that 

residues of saflufenacil and its metabolites M800H11 and M800H35 were each <LOQ in/on all 

rotational crop matrices at a 120-day PBI. These data support the labeled rotational crop 

restriction of 4 months for all non-labeled crops. 

5.3 Water Residue Profile

The Estimated Drinking Water Concentrations (EDWCs) used in the dietary exposure risk 

assessment were provided by EFED in a memorandum dated 12-AUG-2013 (Memo, M. 

Ruhman; DP# 413592). Water residues were incorporated directly into the DEEM-FCID in the 

food categories “water, direct, all sources” and “water, indirect, all sources.”

Screening EDWCs (Table 5.1.9) of saflufenacil were generated by Tier I Rice modeling for 

surface water and with Pesticide Root Zone Model-Ground Water (PRZM-GW) for ground 

water. Modeled application rates represent the maximum use patterns for dry-seeded rice: the 

1

st application at planting, the second application 14 days after planting and flooding at 45 days 

after planting. Remaining model input parameters were chosen according to current guidance 

(USEPA, 2002). EDWCs reflect exposure to saflufenacil and all degradates of concern in 

drinking water (Table 5.1.8). 

Table 5.3. Tiered EDWCs for Proposed Saflufenacil Uses.

Source (Tier: Model) 1-in-10-year Peak Exposure 

(ppb)

1-in-10-year Annual Mean 

Exposure (ppb)

Surface water (Tier I: Rice Model) 133

(used in acute analysis)

120

(used in chronic analysis)

Ground water (Tier II: PRZM GW) 69.2 51.5

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

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

tolerance-level residues for all commodities [except for cottonseed; sunflower subgroup 20B; 

soybean, seed; vegetable, legume, subgroup 6C, pea and bean (except soybean); and rapeseed 

subgroup 20A for which the recommended tolerance levels were multiplied by a correction 

factor to account for a metabolite of concern which is not included in the tolerance expression]. 

Drinking water was incorporated directly into the dietary assessment using the concentration for 

surface water generated by Tier I Rice modeling. 
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5.4.2 Percent Crop Treated Used in Dietary Assessment

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

5.4.3 Acute Dietary Risk Assessment

The acute dietary risk for food and drinking water utilized <1% of the aPAD for the U.S. 

population. The acute dietary risk for the highest exposed population subgroup, all infants (<1 

year old), is <1% of the aPAD at the 95th percentile. A summary table of acute dietary exposure 

and risk for saflufenacil can be found in Section 5.4.6. Although further refinement to the 

analysis is not required at this time, future assessments could be refined using average field trial 

values, use of empirical processing factors, incorporation of %CT data, or monitoring data. 

5.4.4 Chronic Dietary Risk Assessment

The chronic dietary risk for food and drinking water utilized 6.7% of the cPAD for the U.S. 

population. The chronic dietary risk for the highest exposed population subgroup, all infants (<1 

year old), is 18% of the cPAD. A summary table of chronic dietary exposure and risk for 

saflufenacil can be found in Section 5.4.6. Although further refinement to the analysis is not 

required at this time, future assessments could be refined using average field trial values, use of 

empirical processing factors, incorporation of %CT data, or monitoring data. 

5.4.5 Cancer Dietary Risk Assessment

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

concern for this chemical.

5.4.6 Summary Table

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

Population Subgroup

Acute Dietary

(95th Percentile) Chronic Dietary

Dietary Exposure 

(mg/kg/day) % aPAD Dietary Exposure(mg/kg/day) % cPAD

General U.S. Population 0.008199 <1 0.003105 6.7

All Infants (<1 year old) 0.026256 <1 0.008506 18

Children 1-2 years old 0.014271 <1 0.005786 13

Children 3-5 years old 0.011052 <1 0.004637 10

Children 6-12 years old 0.008171 <1 0.003098 6.7

Youth 13-19 years old 0.006825 <1 0.002347 5.1

Adults 20-49 years old 0.007652 <1 0.002943 6.4

Adults 50-99 years old 0.006909 <1 0.002867 6.2

Females 13-49 years old 0.007849 <1 0.002923 6.4

*The values for the highest exposed population for each type of risk assessment are bolded.
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6.0 Residential (Non-Occupational) Exposure/Risk

6.1 Residential Exposure/Risk Characterization

Saflufenacil has no registered or proposed residential uses; therefore, a quantitative nonoccupational exposure assessment was not performed.

6.2 Residential Bystander Post-Application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for saflufenacil at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV) and the low use rate (0.13 lb ai/A). However, 

volatilization of pesticides may be a source of post-application inhalation exposure to individuals 

nearby pesticide applications. The Agency sought expert advice and input on issues related to 

volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) 

Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on 

March 2, 20101. The Agency is in the process of evaluating the SAP report and may, as 

appropriate, develop policies and procedures to identify the need for and, subsequently, the way 

to incorporate post-application inhalation exposure into the Agency's risk assessments. If new 

policies or procedures are developed, then the Agency may revisit the need for a quantitative 

post-application inhalation exposure assessment for saflufenacil.

6.3 Spray Drift

Spray drift is always a potential source of exposure to residents nearby spraying operations. This 

is particularly the case with aerial application, but, to a lesser extent, could also be a potential 

source of exposure from the ground application method employed for saflufenacil. The Agency 

has been working with the Spray Drift Task Force, EPA Regional Offices, and State Lead 

Agencies for pesticide regulation and other parties to develop the best spray-drift-management 

practices. On a chemical-by-chemical basis, the Agency is now requiring interim mitigation 

measures for aerial applications that must be placed on product labels/labeling. The Agency has 

completed its evaluation of the new database submitted by the Spray Drift Task Force, a 

membership of U.S. pesticide registrants, and is developing a policy on how to appropriately 

apply the data and the AgDRIFT®computer model to its risk assessments for pesticides applied 

by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency 

may impose further refinements in spray-drift-management practices to reduce off-target drift 

with specific products with significant risks associated with drift.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks 

from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and 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 

 

1 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
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duration of exposure.

For saflufenacil, 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-, and 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 

not of concern to HED (<100% cPAD) for the general U.S. population and all population 

subgroups (see Table 5.4.6). 

7.2 Chronic Aggregate Risk

The chronic aggregate risk assessment takes into account average exposure estimates from 

dietary consumption of saflufenacil (food and drinking water). The chronic dietary exposure 

estimates are not of concern to HED (<100% cPAD) for the general U.S. population and all 

population subgroups (see Table 5.4.6). 

8.0 Cumulative Risk Characterization/Assessment

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to saflufenacil and any other substances and saflufenacil does not appear to produce 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 have 

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

9.0 Occupational Exposure/Risk Characterization

9.1 Short- and Intermediate-Term Handler Risk

There is potential for occupational handler short- and intermediate-term exposure resulting from 

the proposed use of saflufenacil on rice. Potential occupational handler exposure scenarios 

include mixing/loading liquids for aerial and ground applications, applications via aerial and 

ground equipment, and flagging. The proposed label has proposed maximum rates of 0.089 and 

0.044 lbs ai/A for pre-plant/pre-emergent and post-emergent applications, respectively. The 

2009 saflufenacil risk assessment (L. Austin, et al., 22-JUL-2009; D367317) assessed 
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application rates up to 0.35 lbs ai/A with applications made via aerial and ground equipment. 

This assessment showed that all risks for occupational handlers are above the target MOE of 100 

with the use of gloves, and do not exceed the LOC. Since the proposed label includes 

applications made using similar application equipment and lower maximum application rates 

than those previously assessed for saflufenacil; no new occupational handler assessment has been 

performed at this time.

9.2 Short- and Intermediate-Term Post-Application Risk

9.2.1 Dermal Post-Application Risk

Occupational post-application exposures associated with the proposed use on rice are expected to 

be negligible as the proposed label allows applications to be made prior to planting, prior to crop 

emergence, or from the two-leaf stage up to internode elongation.

9.2.2 Inhalation Post-Application Risk

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

exposure assessment was not performed for saflufenacil at this time. However, there are 

multiple potential sources of post-application inhalation exposure to individuals performing postapplication 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. The Agency received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures, to identify the need for and, subsequently, the way to incorporate occupational 

post-application inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for saflufenacil.

9.3 REI

Saflufenacil is classified as Toxicity Category III for acute oral toxicity, acute dermal toxicity, 

and acute eye irritation. It is classified as toxicity Category IV for acute inhalation toxicity and 

acute dermal irritation. It is not a dermal sensitizer. The REI of 12 hours appearing on the 

Sharpen®label complies with the WPS. 

10.0 References

Previous Risk Assessments: L. Austin, et al., 22-JUL-2009; D367317. G. Kramer, et al.; 19-

APR-2011; D380636

HASPOC Memo: 02-AUG-2013; TXR# 056720

Chemistry Memos: G. Kramer, 02-APR-2013; D405746. G. Kramer, 23-JAN-2014; D407976
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Drinking Water Memo: M. Ruhman, 12-AUG-2013; D413592

Dietary Memo: G. Kramer, 23-JAN-2014; D405747

List of Appendices:

Appendix A. Toxicology Profile

Appendix B. Physical/Chemical Properties

Appendix C. Review of Human Research

cc: G. Kramer (RAB1)

RDI: RAB1 (8/7/13)

G.F. Kramer:S10957:PY-S:(703)305-5079:7509P:RAB1
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Appendix A. Toxicology Assessment

A.1 Toxicology Data Requirements for Saflufenacil

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

-

yes1

870.3700a Developmental Toxicity (rodent)...................................

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

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

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent) ..............................................

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

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

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

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

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial.....................

870.5300 Mutagenicity—Gene Mutation - mammalian................

870.5xxx Mutagenicity—Structural Chromosomal Aberrations...

870.5xxx Mutagenicity—Other Genotoxic Effects.......................

yes

yes

yes

yes

yes

yes

yes

yes

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

870.6100b 90-Day Neurotoxicity (hen)...........................................

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

870.6200b 90-Day Neuro. Screening Battery (rat)..........................

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

no

no

yes

yes

no

-

-

yes

yes

no

870.7485 General Metabolism ......................................................

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

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

yes

yes

yes

yes

yes

yes

1 Waived by the HASPOC (TXR #056720).

A.2 Toxicity Profiles

Table A.2.1. Acute Toxicity Profile – Saflufenacil.

Guideline No. Study Type MRID(s) Results

Toxicity 

Category Purity

870.1100 Acute oral [rat] 47128101 LD50 >2000 mg/kg 

bw

III 93.8%

870.1200 Acute dermal [rat] 47128102 LD50 >2000 mg/kg III 93.8%

870.1300 Acute inhalation [rat] 47128103 LC50 >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%
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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), 12.6 mg/kg bw/day (F).

870.3150

28-Day Oral Toxicity feeding-dog

47128112 (2005)

Acceptable/non-guideline

0, 30, 100, or 300 mg/kg bw/day.

LOAEL = 100 mg/kg bw/day based decreased 

mean corpuscular volume, MCH, and MCHC, 

bone marrow hyperplasia, increased iron 

storage in the liver and 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. 
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Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile for Saflufenacil.

Guideline No./Study Type MRID No. 

(year)/Classification/Doses Results

870.3700b

Prenatal developmental in (rabbit)

47128116 (2006)

Acceptable/guideline

0, 50, 200, or 600 mg/kg/day

Maternal NOAEL = 200 mg/kg bw/day

LOAEL = 600 mg/kg bw/d based on mortality 

and increased necropsy findings.

Developmental NOAEL = 50 mg/kg/day 

LOAEL = 200 mg/kg/day based on increased 

liver porphyrins.

870.3800

Reproduction and fertility effects

(rat)

47128117 (2007)

acceptable/guideline

0, 5, 15, or 50 mg/kg bw/day

Parental Systemic NOAEL = 15 mg/kg/day.

Parental Systemic LOAEL = 50 mg/kg/day 

based on decreased food intake, body weight, 

body-weight gain and changes in 

hematological parameters and organ weights 

indicative of anemia.

Reproduction NOAEL = M/F 50 mg/kg/day.

Reproduction LOAEL was not established.

Offspring NOAEL = 15 mg/kg/day.

Offspring LOAEL = 50 mg/kg/day based on 

decreased number of live born pups, increased 

number of stillborn pups, decreased viability 

and lactation indices, decreased pre-weaning 

body weight and/or body-weight gain and 

changes in hematological parameters.

870.4300b

Chronic Toxicity

(dog)

47128118 (2007)

Acceptable/guideline 

0, 5, 20, or 80 mg/kg bw/day

LOAEL = 80 mg/kg bw/day based on 

decreased albumin, MVH, and MCH.

NOAEL = 20 mg/kg bw/day.

870.4300

Chronic/Carcinogenicity

(rat)

47128120 (2007)

Acceptable/guideline

0, 20, 100, 250 (males), 500 or 1000 

(females) ppm 

M = 0, 0.9, 4.8, 12.0, 24.2

F = 0, 1.3, 6.2, 31.4, 63.0 mg/kg 

bw/day.

LOAEL = 31.4 mg/kg bw/day (females) 

based on decreased Hb, Ht, MCV, and MCH. 

NOAEL = 6.2 mg/kg bw/day (females).

LOAEL was not established in males. 

NOAEL = 24.2 mg/kg bw/day.

No evidence of carcinogenicity.

870.4300

Chronic/Carcinogenicity

(mouse)

47128119 (2007)

Acceptable/guideline

0, 1 (males), 5, 25, 75, or 150 

(females) ppm

M = 0, 0.2, 0.9, 4.6, 13.8

F = 0, 1.2, 6.4, 18.9, 38.1 mg/kg 

bw/day.

satellite groups: 

M = 0, 14.2

F = 0, 39.0 mg/kg bw/d

NOAEL = 4.6 mg/kg bw/day (males) and 

18.9 mg/kg bw/day (females). 

LOAELs = 13.8 mg/kg bw/day (males) and 

38.1 mg/kg bw/day (females) based on 

decreased red blood cells, Hb, and Ht and 

porphyria observed in the satellite group.

No evidence of carcinogenicity.

Gene Mutation

870.5100 

In vitro Bacterial Gene Mutation 

47128121 (2005)

Acceptable/guideline

0, 20, 100, 500, 2500, or 5000 

μg/plate (saflufenacil hydrate)

There was no evidence of induced mutant 

colonies over background.

Gene Mutation

870.5100 

In vitro Bacterial Gene Mutation

47128122 (2005)

Acceptable/guideline

0, 20, 100, 500, 2500, or 5000

μg/plate (saflufenacil anhydrate)

There was no evidence of induced mutant 

colonies over background.

Gene Mutation

870.5300 

In vitro Mammalian Cells Gene 

Mutation (Chinese Hamster Ovary 

Cells) 

47128123 (2005)

Acceptable/guideline

0, 312.5, 625, 1250, 2500, or 5000 

μg/mL

There was no evidence of induced mutant 

colonies over background.
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Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile for Saflufenacil.

Guideline No./Study Type MRID No. 

(year)/Classification/Doses Results

Cytogenetics 

870.5375 

In vitro Mammalian Cytogenetics

chromosomal aberration assay- V79 

cells

47128124 (2005)

Acceptable/guideline

0, 5, 10, and 20 ug/ml without S9 

activation 

0, 10, 20, and 40 ug/ml with S9 

activation

Saflufenacil was considered clastogenic in 

vitro in V79 cells in the presence of S9 

metabolic activation. Saflufenacil was not 

clastogenic in the absence of metabolic 

activation.

Cytogenetics-other

870.5395 In Vivo Mammalian 

Cytogenetics - Erythrocyte 

Micronucleus assay in mice

47128125 (2005)

Acceptable/guideline

0, 500, 1000, or 2000 mg/kg bw.

There was no increase in the frequency of 

micronucleated immature erythrocytes in 

mouse bone marrow.

870.5550 Other Genotoxicity-In vivo

unscheduled DNA synthesis (rat)

47128126 (2005)

Acceptable/guideline

single oral dose of 1000, or 2000 

mg/kg bw 

Negative

870.6200a

Acute neurotoxicity battery (rat)

47128127 (2007)

Acceptable/Guideline

0, 125, 500, or 2000 mg/kg bw

Systemic LOAEL was 2000 mg/kg bw 

(males) based on the decreased motor activity 

representing mild and transient systemic 

toxicity. 

Systemic LOAEL was not established for 

females. 

Systemic NOAEL = 500 (M) and 2000 (F) 

mg/kg bw.

There was no evidence of neurotoxicity.

870.6200b

Subchronic neurotoxicity (rat)

47128128 (2007)

Acceptable/Guideline

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

(females) ppm

M = 0, 3.3, 16.6, 66.2

F = 0, 3.9, 19.4, 101.0 mg/kg bw/d. 

Systemic NOAEL = 16.6 (males), 19.4 

(females) mg/kg bw/day. 

Systemic LOAEL = 66.2 (males) and 101 

(females) mg/kg bw/day based on decreased 

Hb, Ht, MCV, and MCH.

There was no evidence of neurotoxicity. 

870.7485

Metabolism and pharmacokinetics

(rat)

47128130, 47128129 (2007)

4, 20, or 100 mg/kg bw (single oral 

dose)

5 or 100 mg/kg bw (single dose)

100 mg/kg for 14 days

Saflufenacil was rapidly absorbed, 

distributed, and excreted. Regardless of the 

dose administered, maximum concentration of 

saflufenacil in blood and plasma was reached 

within 1 h of dosing and declined rapidly after 

24 h. Excretion of orally dosed saflufenacil 

was essentially complete within 96 h; the 

majority was eliminated within the first 24 to 

48 h. Demonstrating that the majority of the 

saflufenacil residues occurred in the plasma 

and was not bound to cellular elements of the 

blood. There was a sex-dependent difference 

in the excretion of orally administered 

saflufenacil. Following single low- and highdose administration or a repeat high-dose 

administration, the main route of elimination 

in male rats was via the feces, while urinary 

excretion was the major route of elimination 

in females. There was 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 steps: 

demethylation of the uracil ring system, 
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Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile for Saflufenacil.

Guideline No./Study Type MRID No. 

(year)/Classification/Doses Results

degradation of the N-methyl-N-isopropyl 

group to NH2, and cleavage of the uracil ring, 

forming a sulfonylamide group. The 

predominant metabolites were M800H01, 

M800H03, M800H07 and the parent 

compound. Other minor metabolites were 

M800H05, M800H16, M800H17, M800H18, 

M800M19, and M800M20. There were no 

significant sex differences in metabolic 

profiles.

870.7600

Dermal penetration

(rat)

47128214 (2007)

Acceptable/guideline

1.1723 mg/cm2, 0,1172 mg/cm2and 

0.0117 mg/cm2

11.723, 1.172 and 0.117 mg/rat

Dermal absorption is 6%.

870.7800 

Immunotoxicity

(mice)

48233701 (2010)

Acceptable/guideline

0, 50, 125, and 250 ppm (0, 10, 27, 

and 52 mg/kg/day)

LOAEL for systemic toxicity was 125 ppm 

(or 27 mg/kg bw/day) based on significant 

changes in pathological and clinical pathology 

parameters. The NOAEL for systemic 

toxicity was 50 ppm (10 mg/kg bw/day).

The LOAEL for immunotoxicity was not 

identified.

The NOAEL for immunotoxicity is the 

highest dose tested of 250 ppm (52 mg/kg 

bw/day).

Comparative Bioavailability/Toxicity 

Study (rat)

47128133 (2005)

Acceptable/non-guideline

0 or 1350 ppm

The bioavailability and toxicity potential of 

the hydrated and anhydrated forms of 

saflufenacil were similar.

Mechanistic study – total porphyrin 

analysis in rat

47128132 (2006)

Acceptable/non-guideline

0, 10, 50, or 1000 ppm (♂ = 0, 0.8, 

4.1, 80.6; ♀ = 0, 0.9, 4.6, 89.5 mg/kg 

bw/day, respectively)

Total porphyrins in feces and liver provided 

the most reliable and sensitive data. 

Statistically significant effects on porphyrin 

metabolism could be detected at exposure 

concentrations well below those associated 

with adverse hematological effects.

NOAEL= 4.1 mg/kg/day.

LOAEL = 80.6 mg/kg/day based on decreased 

Hb, Ht, MCV, MCH, and MCHC.

Mechanistic study-porphyrin analysis 

supplementary (rat)

47128131 (2005)

Acceptable/non-guideline

0, 1, 5, or 25 ppm (♂ = 0, 0.1, 0.4, 

2.0; ♀ = 0, 0.1, 0.5, 2.3 mg/kg 

bw/day

Dietary administration of saflufenacil at 25 

ppm caused an increase in 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.
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Appendix B. Physical/Chemical Properties

Table B.1. Physicochemical Properties of Technical Grade Saflufenacil.

Parameter Value

Melting point Average = 189.9 °C, peak max = 193.4 °C

pH 4.43 of 1% solution at 25 °C

Bulk Density (ambient 

temp.) 0.661 kg/L (free fall), 0.736 kg/L (packed)

Water solubility (20 °C) in g/100 mL:

0.0025 in water (pH = 5); 0.0014 in pH 4 buffer; 0.21 in pH 7 buffer; not determined due to 

degradation in pH 9 buffer

Solvent solubility (20 °C) in g/100 mL: 

19.4 acetonitrile; 24.4 dichloromethane; 55.4 N,N-dimethylformamide; 27.5 acetone; 6.55 ethyl 

acetate; 36.2 tetrahydrofuran; 35.0 butyrolactone; 2.98 methanol; 0.25 isopropyl alcohol;

0.23 toluene; <0.01 1-octanol; <0.005 n-heptane

Vapor pressure at 20/25 °C 20 °C = 4.5 x 10-15 Pa

25 °C = 2.0 x 10-15 Pa

Dissociation constant (pKa) 4.41

Octanol/water partition 

coefficient Mean Log Pow = 2.6 (Pow = 368.3)

UV/visible absorption 

spectrum

wavelength maximum: λmax = 271.6 nm

extinction coefficient: ε = 9709 L/mol-cm

Reference: BASF Registration Document Number (DocID) 2005/1026464.
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Appendix C. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These data, which include studies from 

the PHED 1.1, the AHETF database, and the ARTF database are (1) subject to ethics review 

pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable 

ethics requirements. For certain studies, the ethics review may have included review by the 

Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, 

can be found at the Agency website2. 

 

2

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

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