Saflufenacil Human-Health Risk Assessment DP Number: 384602

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

CHEMICAL SAFETY AND

 POLLUTION PREVENTION

MEMORANDUM

DATE: 04-AUG-2011

SUBJECT: Saflufenacil. Human-Health Risk Assessment for Proposed Tolerances for

Residues in/on Imported Coffee, Banana, and Mango. 

PC Code: 118203 DP Barcode: D384602

Decision No.: 442242 Registration No.: NA

Petition No.: 0E7806 Regulatory Action: Tolerances With No U.S. 

Registration

Risk Assessment Type: Single Chemical/ 

Aggregate

Case No.: NA

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

MRID No.: NA 40 CFR: §180.649

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

Chester E. Rodriguez, Ph.D., Toxicologist

Risk Assessment Branch 1 (RAB1)

Health Effects Division (HED, 7509P)

THROUGH: Dana M. Vogel, Branch Chief

RAB 1/HED (7509P)

TO: Kathryn Montague/Susan Stanton, 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 imported coffee, banana, and mango. The petitioner is BASF. 

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

uses of saflufenacil are provided in this document. The risk assessment, residue chemistry data 

review, and dietary exposure assessment were provided by George Kramer (RAB1), the hazard 

characterization by Chester Rodriguez (RAB1), and the drinking water assessment by Greg 

Orrick of the Environmental Fate and Effects Division (EFED).
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Table of Contents

1.0 Executive Summary............................................................................................................... 3

2.0 Ingredient Profile................................................................................................................... 6

2.1 Summary of Registered/Proposed Uses................................................................... 6

2.2 Structure and Nomenclature .................................................................................... 7

2.3 Physical and Chemical Properties............................................................................ 8

3.0 Hazard Characterization/Assessment.................................................................................. 8

3.1 Mode of Action and Toxicological Studies Available for Evaluation ................... 8

3.2 Absorption, Distribution, Metabolism, and Elimination (ADME) ....................... 8

3.3 Hazard Profile ............................................................................................................ 9

3.4 FQPA Considerations.............................................................................................. 10

3.5 Toxicity Endpoint and Point of Departure Selection............................................ 11

3.6 Endocrine Disruption .............................................................................................. 12

4.0 Dietary Exposure/Risk Characterization .......................................................................... 13

4.1 Pesticide Metabolism and Environmental Degradation....................................... 13

4.1.1 Metabolism in Primary Crops................................................................. 13

4.1.2 Analytical Methodology............................................................................ 13

4.1.3 Environmental Degradation .................................................................... 13

4.1.4 Comparative Metabolic Profile ............................................................... 14

4.1.5 Toxicity Profile of Major Metabolites and Degradates......................... 14

4.1.6 Pesticide Metabolites and Degradates of Concern................................. 14

4.1.7 Drinking Water Residue Profile .............................................................. 14

4.1.8 Food Residue Profile................................................................................. 15

4.1.9 International Residue Limits................................................................... 15

4.2 Dietary Exposure and Risk ..................................................................................... 15

4.2.1 Acute Dietary Exposure/Risk................................................................... 15

4.2.2 Chronic Dietary Exposure/Risk............................................................... 16

4.2.3 Cancer Dietary Risk ................................................................................. 16

4.3 Anticipated Residue and %CT Information......................................................... 16

5.0 Residential (Non-Occupational) Exposure/Risk Characterization ................................. 17

6.0 Aggregate Risk Assessments and Risk Characterization................................................. 17

7.0 Cumulative Risk Characterization/Assessment................................................................ 17

8.0 Data Needs and Label Recommendations ......................................................................... 17

8.1 Toxicology................................................................................................................. 17

8.2 Residue Chemistry................................................................................................... 17

Appendix A: Toxicology Assessment ....................................................................................... 18

A.1 Toxicology Data Requirements for Saflufenacil .................................................. 18

A.2 Toxicity Profiles....................................................................................................... 19

Appendix B: Tolerance Summary Table ................................................................................. 24
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1.0 Executive Summary

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

IX oxidase, which leads to chlorophyll destruction by photooxidation and causes bleaching of 

emerging foliar tissue. Protoporphyrinogen IX oxidase is one of the key enzymes in the 

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

catalyzes the last common step in the biosynthesis of chlorophyll and heme. When 

protoporphyrinogen IX oxidase is inhibited in mammals, hemoglobin formation is reduced 

resulting in anemia. In addition, inhibition of the enzyme causes accumulation of different 

porphyrins and their precursors in various organs. 

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

legume vegetables (Crop Group 07), cereal grains (Crop Group 15), forage, fodder, and straw of 

cereal grains (Crop Group 16), cotton, and sunflower. BASF has submitted a petition for 

tolerances for residues of saflufenacil in/on imported coffee, banana, and mango.

Toxicity/Hazard: 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 3-fold higher internal levels 

and being in some cases more sensitive to toxicity than females.

Saflufenacil exhibited low acute toxicity via the oral, dermal, and inhalation routes of exposure 

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

irritant nor 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 action 

involving protoporphyrinogen oxidase 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 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 2-generation reproduction study in the rat. Developmental effects such as 

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, indicating increased 

quantitative susceptibility. In rabbits, developmental effects such as increased liver porphyrins 

were observed at doses (200 mg/kg/day) that were not maternally toxic, indicating increased 
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quantitative susceptibility. In the 2-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. For instance, an increased number of stillborn 

pups, decreased viability and lactation indices, decreased pre-weaning body weight and/or bodyweight gain, and changes in hematological parameters occurred at the same dose level as 

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

hematological parameters and organ weights indicative of anemia. 

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

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

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

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

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

Saflufenacil was negative in neurotoxicity testing (acute and subchronic studies), 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 saflufenacil risk 

assessment team recommends that the 10X FQPA Safety Factor (SF) for the protection of infants 

and children be reduced to 1X for the following reasons:

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

since (1) clear no-observed adverse-effect levels (NOAELs) were established for the 

developmental effects seen in rats and rabbits as well as for the offspring effects seen in 

the two-generation reproductive toxicity study; (2) the dose-response relationship for the 

effects of concern are also well-characterized and being used for assessing dermal and 

inhalation risks; (3) none of the effects in the developmental or reproduction studies were 

attributable to a single exposure and, therefore, are not of concern for acute risk 

assessment; and (4) the dose used to evaluate chronic dietary risks is lower than the 

NOAELs for fetal/offspring effects in the developmental and reproduction studies and is, 

therefore, protective of the developmental and offspring effects observed in these studies. 

 An immunotoxicity study as part of the revised 40 CFR Part 158 toxicology data 

requirements has been submitted and reviewed by the Agency. The results of the study

indicate that saflufenacil does not directly target the immune system at the dose levels 

being used for risk assessment.

 There was no evidence of neurotoxicity or neuropathology in any study in the database 

including the acute and subchronic neurotoxicity studies. 

 There are also no additional residual uncertainties with respect to exposure data. The 

dietary food exposure assessment utilizes recommended tolerance-level residues and 

assumed 100% crop treated (CT) 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 model and associated modeling 

parameters that are designed to provide conservative, health-protective, high-end 

estimates of water concentrations. There is no potential for residential exposure. 

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

variation) was incorporated into the acute reference dose (aRfD, 5.0 mg/kg) and chronic RfD 

(cRfD, 0.046 mg/kg/day). The acute population-adjusted dose (aPAD) and the chronic PAD
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(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. Since an oral study was used, a 

dermal absorption factor of 3% was used for the dermal risk assessment. Inhalation toxicity is 

assumed to be equivalent to oral toxicity. The toxicological doses relevant to this human-health 

risk assessment are summarized below.

acute dietary (general population, 

including infants and children) NOAEL = 500 mg/kg/day acute RfD and aPAD = 5.0 mg/kg/day

chronic dietary NOAEL = 4.6 mg/kg/day chronic RfD and cPAD = 0.046 mg/kg/day

short-, intermediate-, and long-term dermal

and inhalation oral NOAEL = 5.0 mg/kg/day LOC for MOEs <100 (occupational)

Dietary Risk Estimates (Food + Drinking Water): Acute and chronic dietary risk assessments 

were conducted using the Dietary Exposure Evaluation Model software with the Food 

Commodity Intake Database (DEEM-FCIDTM, Version 2.03), which uses food consumption data 

from the U.S. Department of Agriculture's (USDA’s) Continuing Surveys of Food Intakes by

Individuals (CSFII) from 1994-1996 and 1998. The acute and chronic analyses assumed 100% 

CT, DEEMTM 7.81 default processing factors, and tolerance-level or higher residues for all foods. 

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

ground water generated by the Tier II Pesticide Root Zone Model Ground Water (PRZM GW). 

The resulting acute dietary (food + drinking water) risk estimates using the DEEM-FCIDTM

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). For the 

U.S. population, the exposure for food and water utilized 9.2% of the cPAD. The chronic dietary 

risk estimate for the highest exposed population subgroup, all infants (<1 year old), is 31% of the 

cPAD. 

Residential Exposure: There are no residential uses proposed or currently registered for 

saflufenacil. Therefore, a residential risk assessment was not conducted.

Aggregate Risk: There are no uses of saflufenacil that are expected to result in residential 

exposures. Therefore, 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.

Environmental Justice Considerations: 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.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf).

As a part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP policy, HED estimates 

risks to 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 
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pesticide use in a residential setting. Extensive data on food consumption patterns are compiled 

by the USDA under CSFII 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.

Recommendation for Tolerances

Pending submission of a revised Section F (see requirements under Proposed Tolerances), there 

are no residue chemistry or toxicology issues that would preclude granting the following 

permanent tolerances: “Tolerances are established for residues of saflufenacil, including its 

metabolites and degradates, in or on the commodities in the table below. Compliance with the 

tolerance levels specified below is to be determined by measuring only the sum of saflufenacil 

(2-chloro-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-4-fluoroN-[[methyl(1-methylethyl)amino]sulfonyl]benzamide) and its metabolites N-[2-chloro-5-(2,6-

dioxo-4-(trifluoromethyl)-3,6-dihydro-1(2H)-pyrimidinyl)-4-fluorobenzoyl]-N'-

isopropylsulfamide and N-[4-chloro-2-fluoro-5-

({[(isopropylamino)sulfonyl]amino}carbonyl)phenyl]urea, calculated as the stoichiometric 

equivalent of saflufenacil, in or on the following commodities.”

Coffee, green bean 0.03 ppm

Banana 0.03 ppm

Mango 0.03 ppm

Note to RD: These tolerances should include a footnote stating “No U.S. registrations as of 

[date of FR notice].”

Data Gaps

See Section 8.0 for data needs.

2.0 Ingredient Profile

2.1 Summary of Registered/Proposed Uses

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

legume vegetables (Crop Group 07), cereal grains (Crop Group 15), forage, fodder, and straw of 

cereal grains (Crop Group 16), cotton, and sunflower. BASF has submitted a petition for 

tolerances for saflufenacil residues in/on coffee, banana, and mango imported from Central and 

South America. BASF has submitted a draft Brazilian label for the 70% water-dispersible 
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granule (WDG) formulation (Heat®), which is representative of the Central and South American 

labels. A summary of the proposed use patterns is detailed in Table 2.1.2. 

Table 2.1.2. Summary of Directions for Use of Saflufenacil.

Applic. Timing, 

Type, and Equip. Formulation

App. rate

(lb ai/acre)

Max. No. 

App. per 

Season

Max. Seasonal 

App. Rate

(lb ai/acre)

PHI

(days)

Use Directions and 

Limitations

Coffee, Banana, and Mango

Ground directed 

to weeds Heat®

0.022-0.044 3 0.131

7 (coffee)

15 (mango) 

30 (banana) 

Applications are to be 

made in 16-43 gal/acre

Note: A non-ionic adjuvant system is required for optimum activity.

Conclusions: The submitted use directions for Heat®are adequate to allow evaluation of the 

residue data relative to the proposed uses. 

2.2 Structure and Nomenclature

Table 2.2. Saflufenacil and Metabolite 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) SharpenTM Powered by Kixor Herbicide (EPA Reg. No. 7969-278) (2.85 lb ai/gal 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

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
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2.3 Physical and Chemical Properties

Table 2.3. 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.

3.0 Hazard Characterization/Assessment

3.1 Mode of Action and Toxicological Studies Available for Evaluation

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

IX oxidase which leads to chlorophyll destruction by photooxidation and causes bleaching of 

emerging foliar tissue. Protoporphyrinogen IX oxidase is one of the key enzymes in the 

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

catalyzes the last common step in the biosynthesis of chlorophyll and heme. When 

protoporphyrinogen IX oxidase is inhibited in mammals, hemoglobin biosynthesis is reduced, 

resulting in anemia and accumulation of different porphyrins and their precursors in various 

organs. 

Saflufenacil has been evaluated extensively for its toxicity and mode of action. Its toxicity

database is adequate to support registration. In the last risk assessment (Austin, et al., 7/22/09; 

D367317), the only database deficiency noted was the lack of a guideline immunotoxicity study

as part of the revised toxicity data requirements in the 40 CFR Part 158 for conventional 

pesticide registration. Since then, an immunotoxicity study has been submitted and reviewed by 

the Agency. The evaluation of the immunotoxicity study is included in this hazard assessment. 

3.2 Absorption, Distribution, Metabolism, and Elimination (ADME)

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

rapidly excreted. Regardless of the dose administered, maximum blood concentrations were 

reached within 1 hour of dosing and declined rapidly. Excretion of saflufenacil was essentially

complete within 96 hours, with the majority eliminated within the first 24 to 48 hours. The 

blood and plasma data demonstrated that the majority of the saflufenacil residues occurred in the 
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plasma and were not bound to cellular elements of the blood. Following single or repeated lowand 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. The sex-dependent 

excretion was more pronounced at the low-dose level and resulted in males having up to threefold higher internal exposures than females and being in some cases more sensitive to toxicity

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

than in females. Increasing the dose by a factor of 25 resulted in an increase of the AUC-values 

by a factor of 6.1 in males and 12.4 in females. Saflufenacil residues remained very low in 

tissues at168 hours after dosing, occurring mainly in carcass, liver, skin, and gut contents. 

Exhalation was not a relevant excretion pathway.

3.3 Hazard Profile

Saflufenacil exhibited low acute toxicity via the oral, dermal, and inhalation routes of exposure 

(Category III or IV). It was slightly irritating to the eye (Category III), but not a dermal irritant 

nor a 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 action 

involving protoporphyrinogen oxidase inhibition and subsequent disruption of heme 

biosynthesis, decreased hematological parameters [RBC, Ht, MCV, MCH, MCHC] were seen at 

about the same dose level (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, and lymphoid infiltrate) in mice, the spleen (increased spleen weight 

and extramedullary hematopoiesis) in rats, and in both 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. 

In an acute neurotoxicity study, a decrease in motor activity was observed on the day of dosing at 

the limit dose (2000 mg/kg) in males only. 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

study, systemic toxicity (anemia) was seen at 1000 (66.2 mg/kg/day) and 1350 (101 mg/kg/day) 

ppm in males and females, respectively. There was no evidence of neurotoxicity or 

neuropathology in either the acute or subchronic neurotoxicity study.

Increased fetal susceptibility was observed in the developmental toxicity studies in the rat and 

rabbit and in the 2-generation reproduction study in the rat. Developmental effects such as 

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, indicating increased 

quantitative susceptibility. In rabbits, developmental effects such as increased liver porphyrins 

were observed at doses (200 mg/kg/day) that were not maternally toxic, indicating increased 

quantitative susceptibility. In the 2-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. For instance, an increased number of stillborn 
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pups, decreased viability and lactation indices, decreased pre-weaning body weight and/or bodyweight gain, and changes in hematological parameters occurred at the same dose level as 

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

hematological parameters and organ weights indicative of anemia.

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. 

In a recently submitted 28-day immunotoxicity study, saflufenacil failed to induce toxicity

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

saflufenacil does not directly target the immune system at the dose levels being used for risk 

assessment.

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.”

3.4 FQPA Considerations

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

following acceptable studies are available:

 Developmental toxicity study in rats and rabbits (2);

 Two-generation reproduction study in rats (1);

 Acute and subchronic neurotoxicity studies (2); and

 Immunotoxicity study (1).

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

following reasons:

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

since (1) clear NOAELs were established for the developmental effects seen in rats and 

rabbits as well as for the offspring effects seen in the two-generation reproductive 

toxicity study; (2) the dose-response relationship for the effects of concern are also wellcharacterized and being used for assessing dermal and inhalation risks; (3) none of the 

effects in the developmental or reproduction studies were attributable to a single exposure 

and, therefore, are not of concern for acute risk assessment; and (4) the dose used to 

evaluate chronic dietary risks is lower than the NOAELs for fetal/offspring effects in the 

developmental and reproduction studies and is, therefore, protective of the developmental 

and offspring effects observed in these studies.. 

 An immunotoxicity study as part of the revised 40 CFR Part 158 toxicology data 

requirements has been submitted and reviewed by the Agency. The results of the study

indicate that saflufenacil does not directly target the immune system at the dose levels 

being used for risk assessment.

 There was no evidence of neurotoxicity or neuropathology in any study in the database 

including the acute and subchronic neurotoxicity studies. 

 There are also no additional residual uncertainties with respect to exposure data. The 

dietary food exposure assessment utilizes recommended tolerance-level residues and 
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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 model and associated modeling parameters that

are designed to provide conservative, health-protective, high-end estimates of water 

concentrations. Additionally, there is no potential for residential exposure. 

3.5 Toxicity Endpoint and Point of Departure Selection

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 acute neurotoxicity study. The NOAEL was 

500 mg/kg bw. A combined UF of 100 was applied to account for interspecies extrapolation 

(10X) and intraspecies variation (10X). Thus, the aPAD is calculated to be 5.0 mg/kg bw 

(NOAEL of 500 mg/kg bw divided by 100).

Acute Dietary Endpoint (Females 13-49 years old): An acute dietary endpoint was considered 

but not established for this subpopulation group because developmental effects resulting from a 

single dose of saflufenacil could not be identified in the database. 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 establishing 

an aRfD for females of 13-49 years old.

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. This study provides the 

lowest NOAEL in the toxicity database for saflufenacil. A combined UF of 100 was applied to 

account for interspecies extrapolation (10X) and intraspecies variation. Thus, the cPAD is 0.046 

mg/kg bw/day (NOAEL of 4.6 divided by 100) (Table 3.5).

Table 3.5. Summary of Toxicological Doses and Endpoints for Saflufenacil for Use in Dietary Human-Health 

Risk Assessments.

Exposure

Scenario

Point of 

Departure

Uncertainty/

FQPA SFs RfD and PAD Study and Toxicological Effects

Acute Dietary 

(General 

Population, 

including 

Infants and 

Children)

NOAEL = 500 

mg/kg bw

UFA = 10X

UFH = 10X

FQPA SF = 1X

aRfD = 5.0 

mg/kg

aPAD = 5.0 

mg/kg

Acute Neurotoxicity Study.

NOAEL = 500 (M) and 2000 (F) mg/kg bw.

LOAEL was 2000 mg/kg bw (males) based on 

the decreased motor activity representing mild 

and transient systemic toxicity. 

LOAEL was not established for females.
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Table 3.5. Summary of Toxicological Doses and Endpoints for Saflufenacil for Use in Dietary Human-Health 

Risk Assessments.

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, and Ht 

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.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

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

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

sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = 

population-adjusted dose (a = acute, c = chronic). RfD = reference dose. 

3.6 Endocrine Disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor 

Screening Program (EDSP) to determine whether certain substances (including pesticide active 

and other ingredients) may have an effect in humans or wildlife similar to an effect produced by

a “naturally occurring estrogen, or other such endocrine effects as the Administrator may

designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first 

group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. 

This list of chemicals was selected based on the potential for human exposure through pathways 

such as food and water, residential activity, and certain post-application agricultural scenarios. 

This list should not be construed as a list of known or likely endocrine disruptors.

Saflufenacil is not among the group of 58 pesticide active ingredients on the initial list to be 

screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide 

chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all 

pesticide active ingredients. 

For further information on the status of the EDSP, the policies and procedures, the list of 67 

chemicals, the test guidelines and the Tier 1 screening battery, please visit our website: 

http://www.epa.gov/endo/.
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4.0 Dietary Exposure/Risk Characterization

The following references apply to this section: 

Residue Chemistry Summary - D390922, G. Kramer, 04-AUG-2011

Dietary Exposure - D390923, G. Kramer, 04-AUG-2011

Drinking Water Degradates Identification - D356619, G. Orrick, 01-DEC-2008

Estimated Drinking Water Concentrations (EDWCs) - D349860, G. Orrick, 15-APR-2009

4.1 Pesticide Metabolism and Environmental Degradation

4.1.1 Metabolism in Primary Crops

The previously-submitted metabolism data for corn, soybean, and tomato were adequate to 

elucidate the nature of the residue in plants resulting from pre-plant/pre-emergence application. 

The main reactions involved in the metabolic pathway of saflufenacil were N-demethylation at 

the uracil ring, stepwise degradation (N-dealkylation) of the N-methyl-N-isopropyl group, 

hydrolytic cleavage of the uracil ring generating a urea side chain, and hydroxylation of the 

phenyl ring. 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, 1/6/09; 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, 7/22/09; D349938). As the 

proposed use on coffee, banana, and mango 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 these crops.

4.1.2 Analytical Methodology

BASF Method D0603/02 is the current enforcement method for determination of residues of 

saflufenacil and its metabolites M800H11 and M800H35 in different plant matrices. Residues of 

saflufenacil and its metabolites M800H11 and M800H35 were extracted with methanol:water 

(70:30; v:v). The methanol extract was evaporated and reconstituted in methanol:water (50:50; 

v:v) for liquid chromatography/mass spectroscopy/mass spectroscopy (LC-MS/MS) analysis. 

Two transitions per analyte were monitored for the quantitation and confirmation of saflufenacil, 

M800H11 and M800H35. The residues of each analyte were expressed as parent equivalents 

using a molecular weight conversion factor (1.0 for saflufenacil, 1.06 for M800H11, and 1.42 for 

M800H35). The limit of quantitation (LOQ) was 0.01 ppm for each analyte. The limit of 

detection (LOD) was reported to be 3X the standard deviation (SD) at the LOQ for each analyte 

(0.002-0.003 ppm). Recovery samples, prepared at levels of LOQ and 10X LOQ in each matrix, 

were generally within the acceptable range of 70-120%.

4.1.3 Environmental Degradation

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.
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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 Austin, et al., 7/22/09; D367317).

4.1.4 Comparative Metabolic Profile

The primary routes of metabolism in animals and plants and degradation in the environment 

were basically the same: N-demethylation at the uracil ring, stepwise degradation (Ndealkylation) of the N-methyl-N-isopropyl group, and hydrolytic cleavage of the uracil ring. 

Unique environmental pathways included the addition of hydrogen to the double bond in the 

uracil ring and the formation of trifluoroacetic acid.

4.1.5 Toxicity Profile of Major Metabolites and Degradates

Toxicity data were not submitted for the metabolites of saflufenacil.

4.1.6 Pesticide Metabolites and Degradates of Concern

Table 4.1.8. 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 Seed Crops 

(post-emergence)

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

4.1.7 Drinking Water Residue Profile

The EDWCs used in the dietary exposure risk assessment were provided by EFED in a 

memorandum dated 4/15/09 (Memo, G. Orrick; DP# 349860). Water residues were incorporated 
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directly into the DEEM-FCIDTM in the food categories “water, direct, all sources” and “water, 

indirect, all sources.”

Screening EDWCs (Table 4.1.9) of saflufenacil were generated with FQPA Index Reservoir 

Screening Tool (FIRST) for surface water and with PRZM GW for ground water. Modeled 

application rates represent the maximum use patterns of five proposed end-use labels with 

selected uses on row crops, orchard trees, vineyards, tree plantations, and non-agricultural areas. 

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 

4.1.8). 

Table 4.1.9. 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: FIRST) 37.3 23.8

Ground water (Tier II: PRZM GW) 180

(used in acute analysis)

173

(used in chronic analysis)

4.1.8 Food Residue Profile

The submitted magnitude of the residue data for coffee, banana, and mango are adequate. There 

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

collected from the field trials. Quantifiable residues were not found in coffee RAC samples 

(green beans) even after application of saflufenacil at exaggerated rates (~3X); therefore, 

analysis of coffee processed fractions (roasted beans, instant coffee) was not necessary and 

separate tolerances for processed fractions are not required.

Analytical standards of saflufenacil (expiration date: 2/1/13), M800H11 (expiration date: 

7/1/14), and M800H35 (expiration date: 7/1/14) are currently available in the National Pesticide 

Standards Repository [source: personal communication with T. Cole of Analytical Chemistry 

Laboratory (ACL)/Biological and Economics Analysis Division (BEAD), 6/20/11]. 

A summary of the recommended tolerances for the current petition are listed in Appendix C: 

Tolerance Reassessment Summary. The petitioner should submit a revised Section F reflecting 

the recommended tolerances and commodity definitions presented in Appendix C.

4.1.9 International Residue Limits

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

saflufenacil and its metabolites in coffee, banana, and mango commodities. Harmonization is 

thus not an issue for this petition.

4.2 Dietary Exposure and Risk

4.2.1 Acute Dietary Exposure/Risk

The unrefined acute analysis assumed 100% CT, DEEMTM 7.81 default concentration factors, and 

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

ground water generated by the Tier II PRZM GW model. The acute dietary exposure and risk 

estimates (food + water) are 0.010415 mg/kg/day for the general U.S. population (<1% of the 

aPAD) and 0.038388 mg/kg/day (<1% of the aPAD) for the most highly exposed population 

subgroup [all infants (<1 year old)] and are, thus, below HED’s LOC (<100% aPAD; Table 4.2).

4.2.2 Chronic Dietary Exposure/Risk

The unrefined chronic analysis assumed 100% CT, DEEMTM 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 ground water generated by PRZM GW (173 ppb). The chronic dietary

exposure and risk estimates (food + water) are 0.004232 mg/kg/day for the general U.S. 

population (9.2% of the cPAD) and 0.014043 mg/kg/day (31% of the cPAD) for the most highly

exposed population subgroup [all infants (<1 year old)] and are, thus, below HED’s LOC

(<100% cPAD; Table 4.2).

Table 4.2. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Saflufenacil.1

Population Subgroup

Acute Dietary

(95th Percentile) Chronic Dietary

Dietary Exposure 

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

General U.S. Population 0.010415 <1 0.004232 9.2

All Infants (<1 year old) 0.038388 <1 0.014043 31

Children 1-2 years old 0.017262 <1 0.007290 16

Children 3-5 years old 0.015438 <1 0.006535 14

Children 6-12 years old 0.010471 <1 0.004383 10

Youth 13-19 years old 0.008451 <1 0.003164 6.9

Adults 20-49 years old 0.009266 <1 0.003821 8.3

Adults 50+ years old 0.008388 <1 0.003959 8.6

Females 13-49 years old 0.009336 <1 0.003802 8.3

1 The population subgroup with the greatest exposure is in bold.

4.2.3 Cancer Dietary Risk

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

concern for this chemical (a cancer dietary risk assessment was not conducted).

4.3 Anticipated Residue and %CT Information

The acute and chronic dietary exposure analyses were based on tolerance-level or higher residues 

and the assumption of 100% CT. Anticipated residues and percent CT estimates were not 

incorporated into the assessments.
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5.0 Residential (Non-Occupational) Exposure/Risk Characterization

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

6.0 Aggregate Risk Assessments and Risk Characterization

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.

7.0 Cumulative Risk Characterization/Assessment

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

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

to saflufenacil and any other substances and saflufenacil does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, 

EPA has not assumed that saflufenacil has a common mechanism of toxicity with other 

substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

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

8.0 Data Needs and Label Recommendations

8.1 Toxicology

 none

8.2 Residue Chemistry

860.1550 Proposed Tolerances

The petitioner is requested to submit a revised Section F specifying the following: 

 Revised tolerance levels and commodity definitions, as presented in Appendix B: 

Tolerance Summary Table.

cc: G. Kramer (RAB1)

RDI: RAB1 (8/3/11)

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

A.1 Toxicology Data Requirements for Saflufenacil

Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

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

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

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

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

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

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)...............................................

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

870.3200 21-Day Dermal ..............................................................

870.3250 90-Day Dermal ..............................................................

870.3465 90-Day Inhalation..........................................................

yes

yes

yes

no

no

yes

yes

yes

-

-

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 Neurotoxicity (hen)...............................

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

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

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

870.6300 Developmental Neurotoxicity........................................

no

no

yes

yes

no

-

-

yes

yes

no

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

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

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

yes

yes

yes

yes

yes

yes

Special Studies for Ocular Effects

Acute Oral (rat)...........................................................

Subchronic Oral (rat) ..................................................

Six-month Oral (dog)..................................................

- -
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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 was >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%

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

Guideline No./ Study Type MRID (yr.)/Classification/Doses Results

870.3100

28-Day Oral Toxicity feedingmice

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 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 feedingmice

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 = 36.7mg/kg bw/day (males) 

based on multiple hematological changes, 

liver-weight increases with centrilobular 

fatty change and lymphoid infiltrate in 

males.

NOAEL = 12.4mg/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.
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Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile for Saflufenacil.

Guideline No./ Study Type MRID (yr.)/Classification/Doses Results

870.3100

90-Day Oral Toxicity feeding-rat

47128109 (2007)

Acceptable/guideline

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

4050 (females) ppm.

M = 0, 3.5, 10.5, 32.3, 94.7.

F = 0, 4.3, 12.6, 110.5, 344.7 

mg/kg bw/day.

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

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

hematological effects and increased spleen 

weight and extramedullary hematopoiesis. 

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

(F).

870.3150

28-Day Oral Toxicity feedingdog

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 feedingdog

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 60mg/kg/day.

Maternal NOAEL = 20 mg/kg/day.

LOAEL = 60 mg/kg/day based on 

decreased hemoglobin and Ht, mean 

corpuscular volume and MCH.

Developmental NOAEL = 5 mg/kg/day. 

LOAEL = 20 mg/kg/day based on 

decreased fetal body weights and increase 

in skeletal variations. 

870.3700b

Prenatal developmental in 

(rabbit)

47128116 (2006)

Acceptable/guideline

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

Maternal NOAEL = 200 mg/kg bw/day.

LOAEL = 600 mg/kg bw/d based on 

mortality and increased necropsy findings.

Developmental NOAEL = 50 mg/kg/day 

LOAEL = 200 mg/kg/day based on 

increased liver porphyrins.

870.3800

Reproduction and fertility effects

(rat)

47128117 (2007)

Acceptable/guideline

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

Parental Systemic NOAEL = 15 

mg/kg/day.

Parental Systemic LOAEL = 50 

mg/kg/day based on decreased food 

intake, body weight, body weight gain and 

changes in hematological parameters and 

organ weights indicative of anemia.

Reproduction NOAEL = M/F 50 

mg/kg/day.

Reproduction LOAEL was not 

established.

Offspring NOAEL = 15 mg/kg/day.

Offspring LOAEL = 50 mg/kg/day based 

on decreased number of live born pups, 

increased number of stillborn pups, 

decreased viability and lactation indices, 

decreased pre-weaning body weight 

and/or body-weight gain and changes in 

hematological parameters.
Saflufenacil Human-Health Risk Assessment DP Number: 384602

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Page 21 of 24

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

Guideline No./ Study Type MRID (yr.)/Classification/Doses Results

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 hemoglobin, Ht, MCV 

and MCH. 

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

LOAEL was not established in males. 

NOAEL = 24.2 mg/kg bw/day.

No evidence of carcinogenicity.

870.4300

Chronic/Carcinogenicity

(mouse)

47128119 (2007)

Acceptable/guideline

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

(females) ppm.

M = 0, 0.2, 0.9, 4.6, 13.8.

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

bw/day.

satellite groups: 

M = 0, 14.2.

F = 0, 39.0 mg/kg bw/d.

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

18.9 mg/kg bw/day (females). 

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

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

on decreased red blood cells, hemoglobin, 

and Ht and porphyria observed in the 

satellite group.

No evidence of carcinogenicity.

Gene Mutation

870.5100 

In vitro Bacterial Gene Mutation

47128121 (2005)

Acceptable/guideline

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

μg/plate (saflufenacil hydrate).

There was no evidence of induced mutant 

colonies over background.

Gene Mutation

870.5100 

In vitro Bacterial Gene Mutation

47128122 (2005)

Acceptable/guideline

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

μg/plate (saflufenacil anhydrate).

There was no evidence of induced mutant 

colonies over background.

Gene Mutation

870.5300 

In vitro Mammalian Cells Gene 

Mutation (Chinese Hamster 

Ovary Cells) 

47128123 (2005)

Acceptable/guideline

0, 312.5, 625, 1250, 2500, or 

5000 μg/mL.

There was no evidence of induced mutant 

colonies over background.

Cytogenetics 

870.5375 

In vitro Mammalian Cytogenetics

chromosomal aberration assayV79 cells

47128124 (2005)

Acceptable/guideline

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

activation.

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

activation.

Saflufenacil was considered clastogenic in 

vitro in V79 cells in the presence of S9 

metabolic activation. Saflufenacil was not 

clastogenic in the absence of metabolic 

activation.

Cytogenetics-other

870.5395 In Vivo Mammalian 

Cytogenetics - Erythrocyte 

Micronucleus assay in mice

47128125 (2005)

Acceptable/guideline

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

There was no increase in the frequency of 

micronucleated immature erythrocytes in 

mouse bone marrow.

870.5550 Other Genotoxicity-In 

vivo unscheduled DNA synthesis 

(rat)

47128126 (2005)

Acceptable/guideline

single oral dose of 1000 or 2000 

mg/kg bw.

Negative

870.6200a

Acute neurotoxicity battery (rat)

47128127 (2007)

Acceptable/Guideline

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

Systemic LOAEL was 2000 mg/kg bw 

(males) based on the decreased motor 

activity representing mild and transient 

systemic toxicity. 

Systemic LOAEL was not established for 

females. 

Systemic NOAEL = 500 (M) and 2000 (F) 
Saflufenacil Human-Health Risk Assessment DP Number: 384602

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Page 22 of 24

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

Guideline No./ Study Type MRID (yr.)/Classification/Doses Results

mg/kg bw.

There was no evidence of neurotoxicity.

870.6200b

Subchronic neurotoxicity (rat)

47128128 (2007)

Acceptable/Guideline

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

(females) ppm.

M = 0, 3.3, 16.6, 66.2.

F = 0, 3.9, 19.4, 101.0 mg/kg 

bw/d. 

Systemic NOAEL = 16.6 (males), 19.4 

(females) mg/kg bw/day. 

Systemic LOAEL = 66.2 (males) and 101 

(females) mg/kg bw/day based on 

decreased hemoglobin, Ht, mean 

corpuscular volume, and MCH.

There was no evidence of neurotoxicity. 

870.7485

Metabolism and 

pharmacokinetics

(rat)

47128130, 47128129 (2007)

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

oral dose).

5 or 100 mg/kg bw (single dose)

100 mg/kg for 14 days.

Saflufenacil was rapidly absorbed, 

distributed, and excreted. Regardless of 

the dose administered, maximum 

concentration of saflufenacil in blood and 

plasma was reached within 1 h of dosing 

and declined rapidly after 24 h. Excretion 

of orally dosed saflufenacil was essentially 

complete within 96 h; the majority was

eliminated within the first 24 to 48 h. 

Demonstrating that the majority of the 

saflufenacil residues occurred in the 

plasma and was not bound to cellular 

elements of the blood. There was a 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-Nisopropyl group to NH2, and cleavage of 

the uracil ring, forming a sulfonylamide 

group. The predominant metabolites were 

M800H01, M800H03, M800H07 and the 

parent compound. Other minor 

metabolites were M800H05, M800H16, 

M800H17, M800H18, M800M19, and 

M800M20. There were no significant sex 

differences in metabolic profiles.
Saflufenacil Human-Health Risk Assessment DP Number: 384602

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

Guideline No./ Study Type MRID (yr.)/Classification/Doses Results

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 3%.

870.7800

Immunotoxicity

(mice)

48233701 (2010)

Acceptable/guideline

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

27, and 52 mg/kg/day).

LOAEL for systemic toxicity was 125 

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

significant changes in pathological and 

clinical pathology parameters. The 

NOAEL for systemic toxicity was 50 ppm

(10 mg/kg bw/day).

The LOAEL for immunotoxicity was not 

identified.

The NOAEL for immunotoxicity is the 

highest dose tested of 250 ppm (52 mg/kg 

bw/day).

Comparative 

Bioavailability/Toxicity Study 

(rat)

47128133 (2005)

Acceptable/non-guideline

0 or 1350 ppm.

The bioavailability and toxicity potential 

of the hydrated and anhydrated forms of 

saflufenacil were similar.

Mechanistic study – total 

porphyrin analysis in rat

47128132 (2006)

Acceptable/non-guideline

0, 10, 50, or 1000 ppm (♂ = 0, 

0.8, 4.1, 80.6; ♀ = 0, 0.9, 4.6, 

89.5 mg/kg bw/day, respectively).

Total porphyrins in feces and liver 

provided the most reliable and sensitive 

data. Statistically significant effects on 

porphyrin metabolism could be detected at 

exposure concentrations well below those 

associated with adverse hematological 

effects.

NOAEL= 4.1 mg/kg/day.

LOAEL = 80.6 mg/kg/day based on 

decreased hemoglobin, Ht, MCV, MCH, 

and MCHC.

Mechanistic study-porphyrin 

analysis supplementary (rat)

47128131 (2005)

Acceptable/non-guideline

0, 1, 5, or 25 ppm (♂ = 0, 0.1, 

0.4, 2.0; ♀ = 0, 0.1, 0.5, 2.3 

mg/kg bw/day).

Dietary administration of saflufenacil at 

25 ppm caused an increase in porphyrin in 

feces of male (237%) and female (61%) 

rats, while saflufenacil at 5 ppm caused an 

increase in fecal porphyrin only in males. 

There were no effects on hematology 

parameters.
Saflufenacil Human-Health Risk Assessment DP Number: 384602

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Page 24 of 24

Appendix B: Tolerance Summary Table

Table B.1. Tolerance Summary for Saflufenacil.

Commodity

Proposed 

Tolerance (ppm)

HED-Recommended 

Tolerance (ppm)

Correct Commodity 

Definition/Comments

Coffee, green bean 0.03 0.03

Banana, whole fruit 0.03 0.03 Banana

Mango, fruit 0.03 0.03 Mango

Note to RD: These tolerances should include a footnote stating “No U.S. registrations as of 

[date of FR notice].”