                 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).

                               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
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 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 body-weight 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 (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-FCID[(TM)], 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, DEEM[(TM)] 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-FCID[(TM)] model at the 95[th] percentile [<1% aPAD for all infants (<1 year old), the most highly exposed population subgroup], are not of concern (<100% aPAD).  The chronic dietary risk assessment shows that the chronic dietary risk estimates are not of concern (i.e., <100% cPAD).  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 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-fluoro-N-[[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 granule (WDG) formulation (Heat[(R)]), 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[(R)]
                                  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[(R)] 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)
Sharpen[(TM)] 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

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 plasma and were not bound to cellular elements of the blood.  Following single or repeated low- and high-dose administration, the main route of elimination in male rats was via the feces, whereas urinary excretion was the major route of elimination in females.  The sex-dependent excretion was more pronounced at the low-dose level and resulted in males having up to three-fold 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 pups, decreased viability and lactation indices, decreased pre-weaning body weight and/or body-weight 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 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 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.
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/.

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.
 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 (N-dealkylation) 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 directly into the DEEM-FCID[(TM)] 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, DEEM[(TM)] 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 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, DEEM[(TM)] 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
                              (95[th] 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.

5.0  Residential (Non-Occupational) Exposure/Risk Characterization

Saflufenacil has no registered or proposed residential uses; therefore, a quantitative non-occupational 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
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)	
                                       -
                                       -
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 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 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 = 36.7mg/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.
870.3100
90-Day Oral Toxicity feeding-rat
47128109 (2007)
Acceptable/guideline
0, 50, 150, 450 (males), 1350, or 4050 (females) ppm. 
M = 0, 3.5, 10.5, 32.3, 94.7.
F = 0, 4.3, 12.6, 110.5, 344.7 mg/kg bw/day.
LOAEL = 32.3 mg/kg bw/day (M) and 110.5 mg/kg bw/day (F) based on multiple hematological effects and increased spleen weight and extramedullary hematopoiesis. 
NOAEL = 10.5 (M), 12.6 mg/kg bw/day (F).
870.3150
28-Day Oral Toxicity feeding-dog
47128112 (2005)
Acceptable/non-guideline
0, 30, 100, or 300 mg/kg bw/day.
LOAEL = 100 mg/kg bw/day based decreased mean corpuscular volume, MCH, and MCHC, bone marrow hyperplasia, increased iron storage in the liver and extramedullary hematopoiesis in the spleen. 
NOAEL = 30 mg/kg bw/day.
870.3150
90-Day Oral Toxicity feeding-dog
47128113 (2006)
Acceptable/guideline
0, 10, 50, or 150 mg/kg bw/day.
LOAEL = 50 mg/kg bw/day based on lower MCV and MCH values in both sexes.
NOAEL = 10 mg/kg bw/day.
870.3200
21/28-Day dermal toxicity (rat)
47128114 (2006)
Acceptable/guideline
0, 100, 300, or 1000 mg/kg.
LOAEL was not established.
NOAEL = 1000 mg/kg bw/day.
870.3700a
Prenatal developmental in (rat)
47128115 (2007)
Acceptable/guideline
0, 5, 20, or 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.
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 assay- V79 cells
47128124 (2005)
Acceptable/guideline
0, 5, 10, and 20 ug/ml without S9 activation. 
0, 10, 20, and 40 ug/ml with S9 activation.
Saflufenacil was considered clastogenic in vitro in V79 cells in the presence of S9 metabolic activation.  Saflufenacil was not clastogenic in the absence of metabolic activation.
Cytogenetics-other
870.5395 In Vivo Mammalian Cytogenetics - Erythrocyte Micronucleus assay in mice
47128125 (2005)
Acceptable/guideline
0, 500, 1000, or 2000 mg/kg bw.
There was no increase in the frequency of micronucleated immature erythrocytes in mouse bone marrow.
870.5550 Other Genotoxicity-In vivo unscheduled DNA synthesis (rat)
47128126 (2005)
Acceptable/guideline
single oral dose of 1000 or 2000 mg/kg bw. 
Negative

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

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

There was no evidence of neurotoxicity.
870.6200b
Subchronic neurotoxicity (rat)
47128128 (2007)
Acceptable/Guideline
0, 50, 250, 1000 (males), or 1350 (females) ppm.
M = 0, 3.3, 16.6, 66.2.
F = 0, 3.9, 19.4, 101.0 mg/kg bw/d.  
Systemic NOAEL = 16.6 (males), 19.4 (females) mg/kg bw/day. 
Systemic LOAEL = 66.2 (males) and 101 (females) mg/kg bw/day based on decreased 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 sex-dependent difference in the excretion of orally administered saflufenacil.  Following single low- and high-dose administration or a repeat high-dose administration, the main route of elimination in male rats was via the feces, while urinary excretion was the major route of elimination in females.  There was 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 differences in 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 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.


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]."


