UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

DATE: 05-NOV-2015 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Saflufenacil. Human Health Risk Assessment in Support of Tolerances for 

Residues in/on Pomegranate. 

PC Code: 118203 DP Barcode: D426933 

Decision No.: 493885 Registration No.: 7969-276 

Petition No.: 4F8305 Regulatory Action: Sec. 3 Registration 

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

Aggregate 

TXR No.: NA CAS No.: 372137-35-4 

MRID No.: NA 40 CFR: § 180.649 

~ ~~?,J - FROM: George F. Kramer, Ph.D., Senior Chem ~ 

Monique M. Perron, Sc.D., Toxicologist ~ -f'.bVVJoshua G. Godshall, Biologist J' ~ 

Risk Assessment Branch l (RAB 1) 

Health Effects Division (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 pomegranate. The petitioner is BASF. 

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

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

residue chemistry, and dietary exposure assessment were provided by George Kramer (RAB I), 

the occupational/residential exposure assessment by Joshua Godshall (RAB 1 ), and the drinking 

water assessment by Mohammed Ruhman of the Environmental Fate and Effects Division 

(EFED). 

Page I of32 
Satlufenacil Human Health Risk Assessment DP# 426933 

Table of Contents 

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

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

2.1 Data Deficiencies .................................................................................................... 6 

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

2.2.4 International Harmonization ....................................... ............................................ 7 

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

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

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

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

3.3 Pesticide Use Pattern ............................................................................................... 8 

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

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

4.0 Hazard Characterization and Dose-Response Assessment.. ............................................. l 0 

4.1 Toxicology Studies Available for Analysis .......................................................... l 0 

4.2 Absorption, Distribution, Metabolism, and Excretion (ADME) .......................... 10 

4.2.1 Dermal Absorption ................................................................................................ 11 

4.3 Toxicological Effects ............................................................................................ 11 

4.3.1 Summary of Toxicological Effects ....................................................................... 11 

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

4.4.1 Completeness of the Toxicology Database ........................................................... 12 

4.4.2 Evidence of Neurotoxicity .................................................................................... 12 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ....... 13 

4.4.4 Residual Uncertainty in the Exposure Database ................................................... 13 

4.5 Toxicity Endpoint and Point of Departure Selections .......................................... 13 

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

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment.. .... 14 

4.5.3 Cancer Classification and Risk Assessment Recommendation ............................ 14 

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

Assessment. ....................................................................................................................... 15 

5.0 Dietary Exposure and Risk Assessment ........................................................................... 16 

5.1 Residues of Concern Summary and Rationale ...................................................... 16 

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

5.3 Water Residue Profile ........................................................................................... 17 

5.4 Dietary Risk Assessment ...................................................................................... 18 

5 .4. I Description of Residue Data Used in Dietary Assessment.. ................................. 18 

5.4.2 Percent Crop Treated Used in Dietary Assessment .............................................. 18 

5.4.3 Acute Dietary Risk Assessment.. .......................................................................... 18 

5.4.4 Chronic Dietary Risk Assessment ........................................................................ 18 

5.4.5 Cancer Dietary Risk Assessment.. ........................................................................ 18 

6.0 Residential (Non-Occupational) Exposure/Risk ............................................................... 19 

6.1 Residential Exposure/Risk Characterization ......................................................... 19 

6.2 Residential Bystander Post-Application Inhalation Exposure .............................. 19 

6.3 Spray Drift ............................................................................................................ 19 

7.0 Aggregate Exposure/Risk Characterization ...................................................................... 20 

7.1 Acute Aggregate Risk ........................................................................................... 20 

Page 2 of32 
Saflufenacil Human Health Risk Assessment DP# 426933

_____________________________________________________________________________________________

Page 3 of 32

7.2 Chronic Aggregate Risk........................................................................................ 20

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

9.0 Occupational Exposure/Risk Characterization ................................................................. 21

9.1 Short- and Intermediate-Term Handler Risk ........................................................ 21

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

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

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

9.3 Restricted-Entry Interval....................................................................................... 24

10.0 References......................................................................................................................... 25

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

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

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

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

Appendix C. Review of Human Research ................................................................................... 32
Saflufenacil Human Health Risk Assessment DP# 426933

_____________________________________________________________________________________________

Page 4 of 32

1.0 Executive Summary

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

herbicide mode-of-action Group 14 (cell membrane disruptors). Saflufenacil acts through the 

inhibition of protoporphyrinogen oxidase (PPO), resulting in cell membrane damage and 

subsequent plant death. BASF has proposed a new use of Treevix® Powered by Kixor®

Herbicide (EPA Reg. No. 7969-276; 30%; water-dispersible granule (WG)) to the base of 

pomegranate trees.

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

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

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

male rats. The 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 

(Toxicity Category III or IV). It was slightly irritating to the eye (Toxicity Category III), but was 

not a dermal irritant or a dermal sensitizer.

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

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

involving PPO inhibition and subsequent disruption of heme biosynthesis, decreased 

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

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

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

(LOAELs) of 13-39 mg/kg/day] across 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 

pups, decreased viability and lactation indices, decreased pre-weaning body weight, and changes 

in hematological parameters occurred at the same dose level as maternal decrements in food 

intake, body weight, and changes in hematological parameters and organ weights indicative of 

anemia. 

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

_____________________________________________________________________________________________

Page 5 of 32

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 

population-adjusted dose (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% dermalabsorption factor (DAF) and a 100% inhalation-absorption factor were used in route-to-route 

extrapolations. 

Food Residue Profile: The nature of the residue is adequately understood in the subject crops. 

There are no residue chemistry issues that would preclude establishing permanent tolerances for 

residues of saflufenacil, as outlined in Table 2.2.2.

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

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

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

Department of Agriculture (USDA) 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 tolerancelevel residues adjusted to account for the residues of concern for risk assessment for all foods. 

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

surface water generated by Tier I Rice modeling. The resulting acute dietary (food + drinking 

water) risk estimates using the DEEM-FCID model at the 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 20% 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 
Saflufenacil Human Health Risk Assessment DP# 426933

_____________________________________________________________________________________________

Page 6 of 32

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.

The occupational handler exposure and risk estimates indicate that the short- and intermediateterm dermal and inhalation combined margins of exposure (MOEs) are not of concern to HED 

(i.e., MOE > 100). At the baseline level of personal protection (i.e., no gloves and no respirator), 

all scenarios result in combined MOEs (dermal + inhalation) ranging from 4,400 to 40,000 ≥ 

level of concern (LOC; MOEs ≥ 100).

A quantitative post-application exposure assessment has not been conducted for the proposed use 

on pomegranate since the use directions indicate that the product is to be applied to the base of 

the tree trunk and is not to contact the foliage. Currently, HED has no transfer coefficients or 

other data to assess post-application dermal exposures to soil by occupational workers. In 

general, such exposures are considered to be negligible. Therefore, for the soil-directed uses, 

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

Since a quantitative post-application assessment has not been conducted, the restricted-entry 

interval (REI) is based on the acute toxicity of saflufenacil technical material. Saflufenacil is 

classified as Toxicity Category III for acute oral, acute dermal toxicity, and acute eye irritation. 

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

It is not a dermal sensitizer. Therefore, the acute toxicity categories for this chemical require a 

12-hour REI under 40 CFR 156.208 (c) (2) (iii). The 12-hour REI, which currently appears on 

the labels, is adequate for the proposed uses.

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

inhalation exposure assessment was not performed for saflufenacil at this time. If new policies 

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

post-application inhalation exposure assessment for saflufenacil.

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

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

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

2.0 HED Recommendations

There are no residue chemistry, occupational, or toxicology data deficiencies that would preclude 

the establishment of permanent tolerances for residues of saflufenacil and it metabolites and 

degradates as outlined in Table 2.2.2. 

2.1 Data Deficiencies

 None
Saflufenacil Human Health Risk Assessment DP# 426933

_____________________________________________________________________________________________

Page 7 of 32

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

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

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

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

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. A revised 

version (Method D0603/04) of the current enforcement method was used for the crop field trials. 

The method was adequate for data collection based on acceptable method validation and 

concurrent recovery data.

HED has determined that Method D0603/02 is a suitable enforcement method for the plant 

commodities, as defined in SOP No. ACB-019 (9/15/08). 

2.2.2 Recommended Tolerances

The proposed uses and the submitted data support the following permanent tolerance for residues 

of saflufenacil and its metabolites in or on the commodity summarized in Table 2.2.2. 

Table 2.2.2. Tolerance Summary for Saflufenacil.

Commodity

Proposed 

Tolerance (ppm)

HED-Recommended 

Tolerance (ppm)

Correct Commodity 

Definition/Comments

Pomegranate 0.03 0.03

2.2.3 Revisions to Petitioned-For Tolerances

HED is not recommending for revisions to the petitioned-for tolerance.

2.2.4 International Harmonization

No Codex, Canadian, or Mexican maximum residue limits (MRLs) have been established for 

saflufenacil on pomegranate. Therefore, harmonization of MRLs and U.S. tolerances is not an 

issue at this time.

2.3 Label Recommendations

None
Saflufenacil Human Health Risk Assessment DP# 426933

_____________________________________________________________________________________________

Page 8 of 32

3.0 Introduction

3.1 Chemical Identity

TABLE 3.1. Saflufenacil Nomenclature.

Chemical Structure

Common name Saflufenacil

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

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

BASF has submitted a draft label for Treevix® Powered by Kixor® Herbicide (EPA Reg. No. 

7969-278). A summary of the proposed use pattern is detailed in Table 3.3.1. F Cl

N

N

O

O

CH3

F

F

F

O

N

H

S

N

O

O

CH3

CH3

CH3

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
Saflufenacil Human Health Risk Assessment DP# 426933

_____________________________________________________________________________________________

Page 9 of 32

Saflufenacil is currently registered for use on legume vegetables, citrus fruit, pome fruit, stone 

fruit, tree nuts, cereal grains, cotton, sunflowers, grapes, pasture and rangeland grass, grass 

grown for seed, olives, and soybean. BASF Corporation is requesting one new use for 

pomegranate.

Based on the proposed new use, it has been determined that the potential exposure scenarios that 

will need to be assessed include short- and intermediate-term occupational exposures (handler 

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

Table 3.1.1 below. 

Table 3.1.1. Proposed and Amended Use Directions for Saflufenacil.

Applic. Timing, Type, and Equip.

Formulation 

[EPA Reg. 

No.]

Application 

Rate

Max No. 

Applications 

per Season

Max Seasonal 

Application 

Rate

Use Directions 

and Limitations

Pomegranate

Apply as broadcast, banded, or spot 

application directed at the base of the 

tree trunk

Groundboom, Backpack

Treevix®

Powered by 

Kixor®

Herbicide WG 

(7969-276)

1 oz/A = 

0.044 lb 

ai/A

0.01 oz/gal 

= 0.00044 lb 

ai/gal

Max of 4 

apps only if 

one or two 

occur during 

the period of 

postharvest 

to the 

beginning of 

bloom; max 

of 3 apps 

while trees 

are in 

fruiting stage 

until crop

harvest.

0.131 lb 

ai/A/crop 

season or 0.175 

lb ai/A/crop 

season when 

one or more 

applied during 

postharvest 

period.

0.175 lb 

ai/A/year

Do not apply via 

aerial or 

chemigation 

equipment.

Do not use in 

tree nurseries.

REI = 12 hours.

Retreatment 

interval (RTI) = 

21 days.

Preharvest 

interval (PHI) = 

0 days.

1. PPE (personal-protective equipment) = long-sleeved shirt and long pants, shoes plus socks, chemical-resistant gloves, protective eyewear such 

as face shield, goggles, or safety glasses.

Conclusions: The proposed use pattern is adequate to allow evaluation of the residue data 

submitted in support of this petition. 

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 petition for residues in/on pomegranates. 

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 use of saflufenacil and considers the existing registered uses as well for the dietary 

and residential exposure assessments. 
Saflufenacil Human Health Risk Assessment DP# 426933

_____________________________________________________________________________________________

Page 10 of 32

3.5 Consideration of Environmental Justice

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

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

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

(http://www.archives.gov/federal-register/executive-orders/pdf/12898.pdf). As a part of every 

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

well-established procedures. In line with OPP policy, HED estimates 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 USDA under 

NHANES/WWEIA; 2003-2008 and are used in pesticide risk assessments for all registered food 

uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season 

of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary 

exposure to smaller, specialized subgroups and exposure assessments are performed when 

conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on 

home use of pesticide products and associated risks for adult applicators and for toddlers, youths, 

and adults entering or playing on treated areas postapplication are evaluated. Further 

considerations are currently in development as OPP has committed resources and expertise to the 

development of specialized software and models that consider exposure to bystanders and farm 

workers as 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 complete and adequate for hazard characterization, 

toxicity endpoint selection, and FQPA SF evaluation. In previous risk assessments (Kramer et 

al., DP# 384602; 04-AUG-2011) and in the current 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 (A. Dunbar, 02-AUG-2013; TXR #0056720).

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

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

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

maximum blood concentrations (Cmax) were reached within 1 hour of dosing and declined 

rapidly thereafter. Excretion of saflufenacil was essentially complete within 96 hours, with the 

majority eliminated within the first 24-48 hours. The blood and plasma data demonstrated that 

the majority of the saflufenacil residues were detected in the plasma and were not bound to 

cellular elements of the blood such as red blood cells. Following single or repeated low- and 
Saflufenacil Human Health Risk Assessment DP# 426933

_____________________________________________________________________________________________

Page 11 of 32

high-dose administration, the main route of elimination in male rats was via the feces, whereas 

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

biliary excretion of saflufenacil residues in males than in females. This sex-dependent difference 

in 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-hour 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. With skin-bound 

residues included, a DAF of 6% should be applied for converting oral doses to dermal equivalent 

doses to assess the potential risk associated with dermal exposures to saflufenacil.

4.3 Toxicological Effects

4.3.1 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 
Saflufenacil Human Health Risk Assessment DP# 426933

_____________________________________________________________________________________________

Page 12 of 32

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

decrements in food intake, body weight, body-weight gain, and changes in organ weights and 

hematological parameters indicative of anemia. 

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

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

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

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

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

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

evidence of neurotoxicity or neuropathology in either the acute or 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 

(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 complete and adequate for FQPA SF consideration. 

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 neurotoxic 

effects were seen in the SCN study. 
Saflufenacil Human Health Risk Assessment DP# 426933

_____________________________________________________________________________________________

Page 13 of 32

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 (see Section 4.4). 

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

Acute Dietary Endpoint (Females 13-49 years old): An acute dietary endpoint, 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 (see Section 4.4). Thus, the cPAD is estimated at 

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

effects. 
Saflufenacil Human Health Risk Assessment DP# 426933

_____________________________________________________________________________________________

Page 14 of 32

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 for 

MOEs less than 100 based on a combined UF of 100 applied to account for interspecies (10X) 

and intraspecies (10X) extrapolation.

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

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

inhalation route. The HASPOC decided, based on a weight-of-evidence approach, that a 28-day 

inhalation toxicity study is not required at this time (TXR #0056720). The effects in the rat 

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

variations at the LOAEL of 20 mg/kg/day (NOAEL of 5 mg/kg/day). The LOC is for MOEs less 

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

intraspecies (10X) extrapolation. 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

Dermal and inhalation exposures should be combined since the dermal and inhalation endpoints 

are based on the same study.

4.5.3 Cancer Classification and Risk Assessment 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.
Saflufenacil Human Health Risk Assessment DP# 426933

_____________________________________________________________________________________________

Page 15 of 32

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

Assessment

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

Risk Assessments.

Exposure

Scenario

Point of 

Departure

UFs/

FQPA SF

RfD, PAD, 

LOC for Risk 

Assessment

Study and Toxicological Effects

Acute Dietary 

(General 

Population, 

including 

Infants and 

Children)

NOAEL = 500 

mg/kg bw

UFA = 10X

UFH = 10X

FQPA SF = 1X

aRfD = 5.0 

mg/kg

aPAD = 5.0 

mg/kg

Acute Neurotoxicity Study (rat)

NOAEL = 500 mg/kg bw.

LOAEL = 2000 mg/kg bw based on decreased 

motor activity representing mild and transient 

systemic toxicity in males. 

Chronic 

Dietary (All 

Populations)

NOAEL = 4.6 

mg/kg/day

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). 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

Dermalabsorption 

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 = 

Assumed to 

be equivalent 

with oral 

absorption

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. 

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. 
Saflufenacil Human Health Risk Assessment DP# 426933

_____________________________________________________________________________________________

Page 16 of 32

5.0 Dietary Exposure and Risk Assessment 

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

the 22-JUL-2009 human health risk assessment (L. Austin, et al., 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 HED Residues of Concern Knowledgebase Subcommittee 

(ROCKS) determined that residues of concern for the tolerance expression and risk assessment 

consist of saflufenacil, M800H11, and M800H35 (Memo, B. Daiss, 06-JAN-2009; D359645). 

This conclusion was translated to perennial crops (i.e., tree fruits and tree nuts) where 

saflufenacil application is directed to the weeds on the orchard floor (Memo, G. Kramer, 22-

JUL-2009; D349938). As the proposed use on pomegranate is also directed to weeds at the base 

of the plants, HED concludes that the residues of concern for the tolerance expression and risk 

assessment also consist of saflufenacil, M800H11, and M800H35 for this crop.

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

metabolism studies conducted on lactating goats and laying hens. There are no livestock 

feedstuffs associated with the proposed use; therefore, no changes in the existing tolerances for 

livestock commodities are needed.

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

on soil (half-lives of 83 and 87 days) at 22 °C. In addition, the compound is relatively stable to 

hydrolysis at pH 5, almost stable at pH 7 (half-life of 248 days), and readily hydrolyzed at 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).
Saflufenacil Human Health Risk Assessment DP# 426933

_____________________________________________________________________________________________

Page 17 of 32

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

Matrix Residues Included in Risk 

Assessment

Residues Included in 

Tolerance Expression

Plants

Primary Crops (preplant

application)*

Saflufenacil + M800H11, 

M800H35

Saflufenacil + M800H11, 

M800H35

Primary Crops (foliar 

application)

Saflufenacil + M800H11, 

M800H02, M800H35

Rotational Crops Saflufenacil + M800H11, 

M800H35

Livestock

Ruminants

Saflufenacil Saflufenacil

Poultry

Drinking Water

Saflufenacil + M800H01, 

M800H02, M800H07, M800H08, 

M800H15, M800H22, Product 8

Not Applicable

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

5.2 Food Residue Profile

The submitted crop field trial data are adequate to fulfill data requirements. The available data 

will support the proposed use patterns. Quantifiable residues were not found in any pomegranate

sample. There are no regulated processed commodities associated with pomegranate. There are 

no livestock feedstuffs associated with the proposed use; therefore, no changes in the existing 

tolerances for livestock commodities are needed. No Codex, Canadian, or Mexican MRLs have 

been established for saflufenacil on pomegranate. Therefore, harmonization of MRLs and U.S. 

tolerances is not an issue at this time.

5.3 Water Residue Profile

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

assessment were provided by EFED in a memorandum dated 12-MAR-2014 (Memo, M. 

Ruhman; DP# 414485). 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 5.3) of saflufenacil were generated by Tier I Rice modeling for 

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

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

1

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

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

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

drinking water (Table 5.1). 

Table 5.3. Tiered EDWCs for Proposed Saflufenacil Uses.

Source (Tier: Model) 1-in-10-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
Saflufenacil Human Health Risk Assessment DP# 426933

_____________________________________________________________________________________________

Page 18 of 32

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

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

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

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

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

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

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

surface water generated by Tier I Rice modeling. 

5.4.2 Percent Crop Treated Used in Dietary Assessment

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

5.4.3 Acute Dietary Risk Assessment

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

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

year old), is <1% of the aPAD at the 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 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 9.2% of the cPAD for the U.S. 

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

(<1-year old), is 20% of the cPAD. A summary table of chronic dietary exposure and risk for 

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

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

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.
Saflufenacil Human Health Risk Assessment DP# 426933

_____________________________________________________________________________________________

Page 19 of 32

5.4.6 Summary Table

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

Population Subgroup

Acute Dietary

(95th Percentile) Chronic Dietary

Dietary Exposure 

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

General U.S. Population 0.010106 <1 0.004223 9.2

All Infants (<1-year old) 0.026582 <1 0.009099 20

Children 1-2 years old 0.017044 <1 0.008368 18

Children 3-5 years old 0.013965 <1 0.006993 15

Children 6-12 years old 0.010852 <1 0.004872 11

Youth 13-19 years old 0.008383 <1 0.003409 7.4

Adults 20-49 years old 0.009095 <1 0.003946 8.6

Adults 50-99 years old 0.007781 <1 0.003679 8.0

Females 13-49 years old 0.009078 <1 0.003759 8.2

*The values for the highest exposed population for each type of risk assessment are bolded.

6.0 Residential (Non-Occupational) Exposure/Risk

6.1 Residential Exposure/Risk Characterization

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

6.2 Residential Bystander Post-Application Inhalation Exposure

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

individuals nearby pesticide applications. The agency sought expert advice and input on issues 

related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

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

on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The 

agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). During Registration 

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

inhalation toxicological studies) or further analysis is required for saflufenacil.

6.3 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is 

particularly the case with aerial application, but, to a lesser extent, spray drift can also be a 

potential source of exposure from the ground application methods (e.g., groundboom and 

airblast) employed for saflufenacil. The Agency has been working with the Spray Drift Task 

Force (a task force composed of various registrants which was developed as a result of a Data 

Call-In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation 

and other parties to develop the best spray drift management practices (see the Agency’s Spray 

Drift website for more information).1 The Agency has also developed a policy on how to 

appropriately consider spray drift as a potential source of exposure in risk assessments for 

 

1 Available: http://www2.epa.gov/reducing-pesticide-drift 
Saflufenacil Human Health Risk Assessment DP# 426933

_____________________________________________________________________________________________

Page 20 of 32

pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during 

the Registration Review process, which ensures that all uses for that pesticide will be considered 

concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures 

For Residential Risk Assessment (SOPs) - Residential Exposure Assessment Standard Operating 

Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification 

of indirect non-occupational exposure to drift. 

7.0 Aggregate Exposure/Risk Characterization

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

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

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure.

For 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 
Saflufenacil Human Health Risk Assessment DP# 426933

_____________________________________________________________________________________________

Page 21 of 32

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

9.0 Occupational Exposure/Risk Characterization

9.1 Short- and Intermediate-Term Handler Risk

HED uses the term handlers to describe those individuals who are involved in the pesticide 

application process. HED believes that there are distinct job functions or tasks related to 

applications and exposures can vary depending on the specifics of each task. Job requirements 

(amount of chemical used in each application), the kinds of equipment used, the target being 

treated, and the level of protection used by a handler can cause exposure levels to differ in a 

manner specific to each application event. 

Based on the anticipated use patterns, and the current labeling regarding types of equipment and 

techniques that can be used, occupational handler exposure is expected. The quantitative 

exposure/risk assessment developed for occupational handlers is based on the following 

scenarios: 

1) Mixing/loading WGs/DFs (dry flowables) for groundboom applications;

2) applying sprays via groundboom equipment; 

3) mixing/loading/applying WGs/DFs via backpack.

Occupational Handler Exposure Data and Assumptions

A series of assumptions and exposure factors served as the basis for completing the occupational 

handler risk assessments. Each assumption and factor is detailed below on an individual basis.

Application Rate: The application rates used in this assessment are provided in Table 3.1.1. 

Unit Exposures: It is the policy of HED to use the best available data to assess handler exposure. 

Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, 

include Pesticide Handlers Exposure Database (PHED) 1.1, the Agricultural Handler Exposure 

Task Force (AHETF) database, the Outdoor Residential Exposure Task Force (ORETF) 

database, or other registrant-submitted occupational exposure studies. Some of these data are 

proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. The 

standard values recommended for use in predicting handler exposure that are used in this 

assessment, known as “unit exposures,” are outlined in the “Occupational Pesticide Handler Unit 

Exposure Surrogate Reference Table2,” which, along with additional information on HED policy 

on use of surrogate data, including descriptions of the various sources, can be found at the 

Agency website3. 

 80 acres for groundboom application to typical acreage crops;

 40 gallons for backpack applications.

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

days to six months as intermediate-term. Exposure duration is determined by many things, 

 

2 Available: http://www2.epa.gov/sites/production/files/2015-09/documents/handler-exposure-table-2015.pdf

3 Available: http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/occupational-pesticide-handlerexposure-data
Saflufenacil Human Health Risk Assessment DP# 426933

_____________________________________________________________________________________________

Page 22 of 32

including the exposed population, the use site, the pest pressure triggering the use of the 

pesticide, and the cultural practices surrounding that use site. For most agricultural uses, it is 

reasonable to believe that occupational handlers will not apply the same chemical every day for 

more than a one-month time frame; however, there may be a large agribusiness and/or 

commercial applicators who may apply a product over a period of weeks. 

For saflufenacil, based on the proposed use patterns, short- and intermediate-term exposures are 

anticipated for the following reasons: (1) up to three in-season and one dormant season foliar 

applications can be made per crop season 21 days apart; and (2) commercial applicators may 

apply this product at various locations within a region over a period of weeks. In addition, the 

short- and intermediate-term PODs are the same; therefore, short-term risk estimates are 

protective of longer-term exposures.

Mitigation/Personal Protective Equipment: Estimates of dermal and inhalation exposure were 

calculated for various levels of personal-protective equipment (PPE). Results are presented for 

“baseline,” defined as a single layer of clothing consisting of a long-sleeved shirt, long pants, 

shoes plus socks, no protective gloves, and no respirator. The saflufenacil product labels direct 

mixers, loaders, applicators and other handlers to wear long-sleeved shirt and long pants, shoes 

plus socks, chemical-resistant gloves, and protective eyewear such as a face shield, goggles, or 

safety glasses.

Combining Exposures/Risk Estimates

Dermal and inhalation risk estimates were combined in this assessment, since the toxicological 

effects for these exposure routes were similar. Dermal and inhalation risk estimates were 

combined using the following formula:

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

Summary of Occupational Handler Non-Cancer Exposure and Risk Estimates

The occupational handler exposure and risk estimates indicate that the short- and intermediateterm dermal and inhalation combined MOEs are not of concern to HED (i.e., MOE > 100). At 

the baseline level of PPE (i.e., no gloves and no respirator), all scenarios result in combined 

MOEs (dermal + inhalation) ≥ LOC (MOEs ≥ 100).
Saflufenacil Human Health Risk Assessment DP# 426933

_____________________________________________________________________________________________

Page 23 of 32

Table 9.1.1. Occupational Handler Non-Cancer Exposure and Risk Estimates for Saflufenacil. 

Exposure Scenario Crop or Target

Dermal Unit 

Exposure 

(μg/lb ai)1

Inhalation Unit 

Exposure 

(μg/lb ai)1

Maximum 

Application 

Rate (lb 

ai/A)2

Area 

Treated 

(acres)3

Dermal

(LOC = 100)

Inhalation

(LOC = 100)

Total

(LOC = 

100)

Mitigation Level

Mitigation 

Level

Dose 

(mg/kg/day)4 MOE5

Dose 

(mg/kg/day)6 MOE7 MOE8

Mixer/Loader

Mixing/loading WGs

Groundboom application Pomegranate 227(baseline)

8.96

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

Applicator

Groundboom spray 

application Pomegranate 78.6(baseline)

0.34

(baseline) 0.044 80 0.000241 21,000 0.0000174 290,000 20,000

Mixer/Loader/Applicator

Mixing/loading/applying 

WGs via backpack 

applications

Pomegranate 8260

(baseline)

2.58

(baseline)

0.00044 lb 

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

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

3 Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre) × Area Treated (A/day) × DAF (6 %) ÷ BW (69 kg).

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

6 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre) × Area Treated (A/day) ÷ BW (69 kg).

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

8 Total MOE = NOAEL (5 mg/kg/day) ÷ (Dermal Dose + Inhalation Dose).
Saflufenacil Human Health Risk Assessment DP# 426933

___________________________________________________________________________________________

Page 24 of 32

9.2 Short- and Intermediate-Term Post-Application Risk

HED uses the term post-application to describe exposures that occur when individuals are 

present in an environment that has been previously treated with a pesticide (also referred to as reentry exposure). Such exposures may occur when workers enter previously treated areas to 

perform job functions, including activities related to crop production, such as scouting for pests 

or harvesting. Post-application exposure levels vary over time and depend on such things as the 

type of activity, the nature of the crop or target that was treated, the type of pesticide application, 

and the chemical’s degradation properties. In addition, the timing of pesticide applications, 

relative to harvest activities, can greatly reduce the potential for post-application exposure.

9.2.1 Dermal Post-Application Risk

A dermal post-application exposure assessment has not been conducted for the proposed use on 

pomegranate since the use directions indicate that the product is to be applied to the base of the 

tree trunk and is not to contact the foliage. Currently, HED has no transfer coefficients or other 

data to assess post-application dermal exposures to soil by occupational workers. In general, 

such exposures are considered to be negligible. Therefore, for the soil-directed uses, postapplication exposures and risks to occupational workers were not assessed. 

9.2.2 Inhalation Post-Application Risk

There are multiple potential sources of post-application inhalation exposure to individuals 

performing post-application activities in previously treated fields. These potential sources 

include volatilization of pesticides and resuspension of dusts and/or particulates that contain 

pesticides. The Agency sought expert advice and input on issues related to volatilization of 

pesticides from its FIFRA SAP in December 2009, and received the SAP’s final report on March 

2, 2010 (http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2009-0687-0037). 

The Agency has evaluated the SAP report and has developed a Volatilization Screening Tool and 

a subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). During Registration 

Review, the Agency will utilize this analysis to determine if data (i.e., flux studies, route-specific 

inhalation toxicological studies) or further analysis is required for saflufenacil

In addition, the Agency is continuing to evaluate the available post-application inhalation 

exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the 

Agency will continue to identify the need for and, subsequently, the way to incorporate 

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

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in 

higher exposure than post-application exposure. Therefore, it is expected that these handler 

inhalation exposure estimates would be protective of most occupational post-application 

inhalation exposure scenarios.

9.3 Restricted-Entry Interval

The 12-hour REI specified on the proposed label is based on the acute toxicity of saflufenacil. 
Saflufenacil Human Health Risk Assessment DP# 426933

_____________________________________________________________________________________________

Page 25 of 32

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

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

dermal irritation. It is not a dermal sensitizer. Short- and intermediate-term post-application risk 

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

activities. Under 40 CFR 156.208 (c) (2) (iii), ai’s classified as Acute III or IV for acute dermal, 

eye irritation, and primary skin irrigation are assigned a 12-hour REI. Therefore, the [156 

subpart K] Worker Protection Statement interim REI of 12 hours is adequate to protect

agricultural workers from post-application exposures to saflufenacil.

10.0 References

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

APR-2011; D380636. G. Kramer, et al.; 23-JAN-2014; D405506. G. Kramer, et al.; 24-

JUN-2014; D418587

HASPOC Memo: A. Dunbar, 02-AUG-2013; TXR #0056720

Chemistry Memo: G. Kramer, 05-NOV-2015; D422467

Drinking Water Memo: M. Ruhman, 12-MAR-2014; D414485

Dietary Memo: G. Kramer, 05-NOV-2015; D426932

Occupational and Residential Exposure Assessment Memo: J. Godshall, 14-MAY-2015; 

D426980

List of Appendices:

Appendix A. Toxicology Profile

Appendix B. Physical/Chemical Properties

Appendix C. Review of Human Research

cc: G. Kramer (RAB1)

RDI: RAB1 (5/20/15)

G.F. Kramer:S10957:PY-S:(703)305-5079:7509P:RAB1
Saflufenacil Human Health Risk Assessment DP# 426933

_____________________________________________________________________________________________

Page 26 of 32

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 Neurotox. Screening Battery (rat) ....................

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

no

no

yes

yes

no

-

-

yes

yes

-

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

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

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

yes

yes

yes

yes

yes

yes

1 Waived by the HASPOC (A. Dunbar, 02-AUG-2013; TXR #0056720).

A.2 Toxicity Profiles

Table A.2.1. Acute Toxicity Profile – Saflufenacil.

Guideline No. Study Type MRID(s) Results

Toxicity 

Category Purity

870.1100 Acute oral [rat] 47128101 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%
Saflufenacil Human Health Risk Assessment DP# 426933

_____________________________________________________________________________________________

Page 27 of 32

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

Guideline No./Study Type

MRID No. 

(year)/Classification/Doses Results

870.3100

28-Day Oral Toxicity feeding-mice

47128110 (2007)

Acceptable/non-guideline

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

M\F: 0, 12.8/17.9, 36.6/63.4, 

112/153.1, 335/446, 882/1630 mg/kg 

bw/day

LOAEL = 36.6 mg/kg bw/day (males) based 

on increased alanine aminotransferase, 

aspartate aminotransferase, urea and total 

bilirubin, decreased hemoglobin (Hb) and 

Ht, and increased liver weight and 

centrilobular fatty change. 

NOAEL = 12.8 mg/kg bw/day. 

LOAEL = 153.1 mg/kg bw/day (females) 

based on moderate centrilobular fatty change 

in the liver. 

NOAEL = 63.4 mg/kg bw/day.

870.3100

28-Day Oral Toxicity feeding-rat

47128108 (2007)

Acceptable/non-guideline

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

M = 0, 4.5, 13.4, 39.2, 117, 357

F = 0, 5.0, 15.9, 43.6, 130.4, 376 

mg/kg bw/day

LOAEL = 39.2 mg/kg bw/day (males) based 

on decreased Hb, MCV, and MCH. 

NOAEL =13.4 mg/kg bw/day. 

LOAEL = 130.4 mg/kg bw/day (females) 

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

NOAEL = 43.6 mg/kg bw/day.

870.3100

90-Day Oral Toxicity feeding-mice

47128111 (2007)

Acceptable/guideline

0, 15 (males only), 50, 150, 450, and 

1350 (females only) ppm 

M = 0, 3.6, 12.4, 36.7, 109.1

F = 0, 17.6, 51.8, 156.6, 471.2 mg/kg 

bw/day

LOAEL = 36.7 mg/kg bw/day (males) based 

on multiple hematological changes, liverweight increases with centrilobular fatty 

change and lymphoid infiltrate in males.

NOAEL = 12.4 mg/kg bw/day. 

LOAEL = 156.6 mg/kg/day (females) based 

on increased liver weight with centrilobular 

fatty change and lymphoid infiltrate. 

NOAEL = 51.8 mg/kg/day.

870.3100

90-Day Oral Toxicity feeding-rat

47128109 (2007)

Acceptable/guideline

0, 50, 150, 450 (males), 1350, or 

4050 (females) ppm 

M =0, 3.5, 10.5, 32.3, 94.7

F = 0, 4.3, 12.6, 110.5, 344.7 mg/kg 

bw/day

LOAEL = 32.3 mg/kg bw/day (M) and 110.5 

mg/kg bw/day (F) based on multiple 

hematological effects and increased spleen 

weight and extramedullary hematopoiesis. 

NOAEL = 10.5 (M) and 12.6 mg/kg bw/day 

(F).

870.3150

28-Day 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. 
Saflufenacil Human Health Risk Assessment DP# 426933

_____________________________________________________________________________________________

Page 28 of 32

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

Guideline No./Study Type

MRID No. 

(year)/Classification/Doses Results

870.3700b

Prenatal developmental in (rabbit)

47128116 (2006)

Acceptable/guideline

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

Maternal NOAEL = 200 mg/kg bw/day.

LOAEL = 600 mg/kg bw/d based on 

mortality and increased necropsy findings.

Developmental NOAEL = 50 mg/kg/day 

LOAEL = 200 mg/kg/day based on increased 

liver porphyrins.

870.3800

Reproduction and fertility effects

(rat)

47128117 (2007)

Acceptable/guideline

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

Parental Systemic NOAEL = 15 mg/kg/day.

Parental Systemic LOAEL = 50 mg/kg/day 

based on decreased food intake, body weight, 

and changes in hematological parameters and 

organ weights indicative of anemia.

Reproduction NOAEL = M/F 50 

mg/kg/day.

Reproduction LOAEL was not established.

Offspring NOAEL = 15 mg/kg/day.

Offspring LOAEL = 50 mg/kg/day based on 

decreased number of live born pups, 

increased number of stillborn pups, 

decreased viability and lactation indices, 

decreased pre-weaning body weight, and 

changes in hematological parameters.

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.

There was no evidence of carcinogenicity.

870.4300

Chronic/Carcinogenicity

(mouse)

47128119 (2007)

Acceptable/guideline

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

(females) ppm

M = 0, 0.2, 0.9, 4.6, 13.8

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

bw/day

satellite groups: 

M = 0, 14.2

F = 0, 39.0 mg/kg bw/d

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

18.9 mg/kg bw/day (females). 

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

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

decreased red blood cells, Hb, and Ht and 

porphyria observed in the satellite group.

There was no evidence of carcinogenicity.

Gene Mutation

870.5100 

In vitro Bacterial Gene Mutation 

47128121 (2005)

Acceptable/guideline

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

μg/plate (saflufenacil hydrate)

There was no evidence of induced mutant 

colonies over background.

Gene Mutation

870.5100 

In vitro Bacterial Gene Mutation

47128122 (2005)

Acceptable/guideline

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

μg/plate (saflufenacil anhydrate)

There was no evidence of induced mutant 

colonies over background.

Gene Mutation

870.5300 

In vitro Mammalian Cells Gene 

Mutation (Chinese Hamster Ovary 

Cells) 

47128123 (2005)

Acceptable/guideline

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

μg/mL

There was no evidence of induced mutant 

colonies over background.

Cytogenetics 

870.5375 

In vitro Mammalian Cytogenetics

chromosomal aberration assay- V79 

cells

47128124 (2005)

Acceptable/guideline

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

activation 

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

activation

Saflufenacil was considered clastogenic in 

vitro in V79 cells in the presence of S9 

metabolic activation. Saflufenacil was not 

clastogenic in the absence of metabolic

activation.

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

_____________________________________________________________________________________________

Page 29 of 32

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

Guideline No./Study Type

MRID No. 

(year)/Classification/Doses Results

870.5395 In Vivo Mammalian 

Cytogenetics - Erythrocyte 

Micronucleus assay in mice

Acceptable/guideline

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

micronucleated immature erythrocytes in 

mouse bone marrow.

870.5550 Other Genotoxicity-In vivo

unscheduled DNA synthesis (rat)

47128126 (2005)

Acceptable/guideline

single oral dose of 1000 or 2000 

mg/kg bw 

Negative.

870.6200a

Acute neurotoxicity battery (rat)

47128127 (2007)

Acceptable/Guideline

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

Systemic LOAEL was 2000 mg/kg bw 

(males) based on the decreased motor 

activity representing mild and transient 

systemic toxicity. 

Systemic LOAEL was not established for 

females. 

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

mg/kg bw.

There was no evidence of 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) and 19.4 

(females) mg/kg bw/day. 

Systemic LOAEL = 66.2 (males) and 101 

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

Hb, Ht, MCV, and MCH.

There was no evidence of neurotoxicity. 

870.7485

Metabolism and pharmacokinetics

(rat)

47128130, 47128129 (2007)

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

dose)

5 or 100 mg/kg bw (single dose)

100 mg/kg for 14 days

Saflufenacil was rapidly absorbed, 

distributed, and excreted. Regardless of the 

dose administered, maximum concentration 

of saflufenacil in blood and plasma was 

reached within 1 h of dosing and declined 

rapidly after 24 h. Excretion of orally dosed 

saflufenacil was essentially complete within 

96 h; the majority was eliminated within the 

first 24 to 48 h. Demonstrating that the 

majority of the saflufenacil residues occurred 

in the plasma and were not bound to cellular 

elements of the blood. There was a sexdependent difference in the excretion of 

orally administered saflufenacil. Following 

single low- and high-dose administration or a 

repeat high-dose administration, the main 

route of elimination in male rats was via the 

feces, while urinary excretion was the major 

route of elimination in females. There was 

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, 

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-related differences in 
Saflufenacil Human Health Risk Assessment DP# 426933

_____________________________________________________________________________________________

Page 30 of 32

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

Guideline No./Study Type

MRID No. 

(year)/Classification/Doses Results

metabolic profiles.

870.7600

Dermal penetration

(rat)

47128214 (2007)

Acceptable/guideline

1.1723 mg/cm2, 0,1172 mg/cm2, and 

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 (M = 0, 0.8, 

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

bw/day, respectively)

Total porphyrins in feces and liver provided 

the most reliable and sensitive data. 

Statistically significant effects on porphyrin 

metabolism could be detected at exposure 

concentrations well below those associated 

with adverse hematological effects.

NOAEL= 4.1 mg/kg/day.

LOAEL = 80.6 mg/kg/day based on 

decreased Hb, Ht, MCV, MCH, and MCHC.

Mechanistic study-porphyrin 

analysis supplementary (rat)

47128131 (2005)

Acceptable/non-guideline

0, 1, 5, or 25 ppm (M = 0, 0.1, 0.4, 

2.0; F = 0, 0.1, 0.5, 2.3 mg/kg 

bw/day

Dietary administration of saflufenacil at 25 

ppm caused an increase in porphyrin in feces 

of male (237%) and female (61%) rats, while 

saflufenacil at 5 ppm caused an increase in 

fecal porphyrin only in males. There were 

no effects on hematology parameters.
Saflufenacil Human Health Risk Assessment DP# 426933

_____________________________________________________________________________________________

Page 31 of 32

Appendix B. Physical/Chemical Properties

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

Parameter Value

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

pH 4.43 of 1% solution at 25 °C

Bulk Density (ambient 

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

Water solubility (20 °C) in g/100 mL:

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

degradation in pH 9 buffer

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

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

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

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

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

25 °C = 2.0 x 10-15 Pa

Dissociation constant (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.
Saflufenacil Human Health Risk Assessment DP# 426933

_____________________________________________________________________________________________

Page 32 of 32

Appendix C. Review of Human Research

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

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

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

pursuant to 40 CFR §26, (2) have received that review, and (3) 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 website4. 

 

4 http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/occupational-pesticide-handler-exposure-data

and http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/occupational-pesticide-post-applicationexposure