                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460

                                                                               
OFFICE OF                                                            CHEMICAL SAFETY AND
	                                                                                                POLLUTION PREVENTION

MEMORANDUM

DATE:	19-APR-2011

SUBJECT:	Saflufenacil.  Human-Health Risk Assessment for Proposed Uses in/on Vegetable, Legume, Subgroup 6C, pea and bean (except soybean); Soybean; Rapeseed Subgroup 20A; Sunflower Subgroup 20B; and Cottonseed Subgroup 20C.  
 
PC Code:  118203
DP Barcodes:  D380636, D381292
Decision Nos.:  436793, 437943
Registration No.:  7969-278
Petition Nos.:  0F7744, 0F7766
Regulatory Action:  Sec. 3 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
		Sarah J. Levy, Chemist
	Chester E. Rodriguez, Ph.D., Toxicologist
	Allison Nowotarski, Biologist
	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 uses of saflufenacil in/on vegetable, legume, subgroup 6C, pea and bean (except soybean); soybean; rapeseed subgroup 20A; sunflower subgroup 20B; and cottonseed subgroup 20C.  The petitioner is BASF.  This is a shared joint review with the Pest Management Regulatory Agency (PMRA) of Canada.  The residue definition and recommended tolerances are harmonized with Canada.

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 and dietary exposure assessment were provided by George Kramer (RAB1), the hazard characterization by Chester Rodriguez (RAB1), the residue chemistry data review by George Kramer and Sarah Levy (RAB1), the occupational/residential exposure assessment by Allison Nowotarski (RAB1), and the drinking water assessment by Greg Orrick of the Environmental Fate and Effects Division (EFED).

                               Table of Contents
1.0  Executive Summary	4
2.1  Summary of Registered/Proposed Uses	9
2.2  Structure and Nomenclature	11
2.3  Physical and Chemical Properties	11
3.0  Hazard Characterization/Assessment	12
3.1  Mode of Action and Toxicological Studies Available for Evaluation	12
3.2  Absorption, Distribution, Metabolism, and Elimination (ADME)	12
3.3  Hazard Profile	13
3.4  FQPA Considerations	14
3.5  Toxicity Endpoint and Point of Departure Selection	15
3.6  Endocrine Disruption	17
4.0  Public Health and Pesticide Epidemiology Data	18
5.0  Dietary Exposure/Risk Characterization	18
5.1  Pesticide Metabolism and Environmental Degradation	18
5.1.1  Metabolism in Primary Crops	18
5.1.2  Metabolism in Rotational Crops	18
5.1.3  Metabolism in Livestock	19
5.1.4  Analytical Methodology	19
5.1.5  Environmental Degradation	19
5.1.6  Comparative Metabolic Profile	20
5.1.7  Toxicity Profile of Major Metabolites and Degradates	20
5.1.8  Pesticide Metabolites and Degradates of Concern	20
5.1.9  Drinking Water Residue Profile	20
5.1.10  Food Residue Profile	21
5.1.11  International Residue Limits	21
5.2  Dietary Exposure and Risk	22
5.2.1  Acute Dietary Exposure/Risk	22
5.2.2  Chronic Dietary Exposure/Risk	22
5.2.3  Cancer Dietary Risk	22
5.3  Anticipated Residue and %CT Information	23
6.0  Residential (Non-Occupational) Exposure/Risk Characterization	23
6.1  Spray Drift	23
6.2  Residential Bystander Post-application Inhalation Exposure	23
7.0  Aggregate Risk Assessments and Risk Characterization	23
8.0  Cumulative Risk Characterization/Assessment	24
9.0  Occupational Exposure/Risk Pathway	24
9.1  Short-/Intermediate-Term Occupational Handler Risk	24
9.2  Short-/Intermediate-Term Postapplication Risk	27
10.0  Data Needs and Label Recommendations	27
10.1  Toxicology	27
10.2  Residue Chemistry	28
10.3  Occupational and Residential Exposure	28
Appendix A:  Toxicology Assessment	29
A.1  Toxicology Data Requirements for Saflufenacil	29
A.2  Toxicity Profiles	30
Appendix B:  Tolerance Summary Table	35
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 proposal to amend the established tolerances for saflufenacil on cotton, dry bean, dry pea, and soybean (PP#0F7744).  The amended tolerances on these crops are the result of the proposed harvest aid/desiccation use pattern for Sharpen[(TM)] Powered by Kixor Herbicide (EPA Reg. No. 7969-278); the currently-registered uses are for preplant application.  In addition, BASF has submitted a proposal for a new use of Sharpen[(TM)] on Oilseeds, Rapeseed Subgroup 20A as harvest aid/desiccant (PP#0F7744).

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/d) 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)/ LOAELs were established for the developmental effects seen in rats and rabbits as well as for the offspring effects seen in the two-generation reproductive toxicity study; (2) the dose-response relationship for the effects of concern are also well-characterized and being used for assessing dermal and inhalation risks; and (3) the dose being used for the overall risk assessments would be protective of the developmental and offspring effects.  
   * 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 the acute and subchronic neurotoxicity study.  In the acute neurotoxicity study, a decrease in motor activity was observed on the first day of dosing at the limit dose (2000 mg/kg/day) in males only.  The finding was not accompanied by any other neuropathological changes and was considered a reflection of a mild and transient general systemic toxicity and not a substance-specific neurotoxic effect.  Additionally, it was not corroborated in the subchronic neurotoxicity study.  There is also no other indication of neurotoxicity in any study in the database.  In the subchronic neurotoxicity study, systemic toxicity was seen at 1000 (66.2 mg/kg/day) and 1350 (101 mg/kg/day) ppm in males and females, respectively.
   * 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.  A 3% dermal-absorption factor and a 100% inhalation-absorption factor were used in the route-to-route extrapolation.  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 30% 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.

Occupational Exposure/Risk:  There is potential for occupational handler and postapplication short- and intermediate-term exposure resulting from the proposed uses of saflufenacil.  Potential occupational handler exposure scenarios include mixing/loading liquids for aerial and ground applications, applications via aerial and ground equipment, and flagging.  There is no expectation of occupational post-application exposure associated with the proposed uses.

No chemical-specific handler exposure data were submitted in support of this Section 3 registration.  It is the policy of HED to use data from the Pesticide Handlers Exposure Database (PHED) Version 1.1 as presented in PHED Surrogate Exposure Guide (8/98) to assess handler exposures for regulatory actions when chemical-specific monitoring data are not available (HED Science Advisory Council for Exposure (ExpoSAC) Draft Standard Operating Procedure (SOP) # 7, dated 1/28/99).  In addition, no chemical-specific post-application data were submitted; therefore, exposures during post-application activities were estimated using default assumptions and dermal transfer coefficients from HED's ExpoSAC Policy Number 3.1 "Agricultural Transfer Coefficients" (August 2000).

All risks for occupational handlers are above the target MOE of 100 with the use of gloves, and do not exceed the LOC as the proposed labels already require the use of protective gloves as personal protective equipment.  

Saflufenacil is classified as Toxicity Category III for acute oral toxicity, acute dermal toxicity, and acute eye irritation.  It is classified as toxicity Category IV for acute inhalation toxicity and acute dermal irritation.  It is not a dermal sensitizer.  The restricted-entry interval (REI) of 12 hours appearing on the Sharpen[(TM)] label complies with the Worker Protection Standard (WPS).  

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.

Review of Human Research:  This assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure.  Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases such as PHED and the Agricultural Reentry Task Force (ARTF) Database.  EPA has reviewed all the studies in these multi-pesticide generic exposure databases and, based on available evidence, has found them to be neither fundamentally unethical nor significantly deficient relative to standards of ethical research conduct prevailing when they were conducted.  There is no regulatory barrier to continued reliance on these studies, and all applicable requirements of EPA's Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied.

Recommendation for Tolerances and Registration:

Pending submission of a revised Section F (see requirements under Proposed Tolerances), and the submission of reference standards for the saflufenacil metabolites (see requirements under Submittal of Analytical Reference Standards), there are no residue chemistry, occupational exposure, or toxicology issues that would preclude granting an unconditional registration for the requested uses of saflufenacil on the requested crops.  

The proposed uses and the submitted data support:  "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 commodities."

Cotton, gin byproducts
0.45 ppm
Cottonseed Subgroup 20C
0.20 ppm
Sunflower Subgroup 20B
1.0 ppm
Pea, hay
17 ppm
Grain, aspirated fractions
10 ppm
Soybean, hulls
0.50 ppm
Soybean, seed
0.10 ppm
Pea and bean, dried shelled, except soybean, subgroup 6C
0.30 ppm
Rapeseed Subgroup 20A
0.45 ppm

Note to RD:  In conjunction with establishing these tolerances, the existing tolerance for "Vegetable, foliage of legume, group 7" should be modified to "Vegetable, foliage of legume, group 7 (except pea hay)"; the existing tolerance for "Vegetable, legume, group 6" should be replaced with "Vegetable, legume, edible podded, subgroup 6A" plus "Pea and bean, succulent shelled, subgroup 6B"; and the existing tolerances for "Sunflower, seed" and "Cotton, undelinted seed" should be deleted.
The proposed uses and the submitted data also support:  "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 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, in or on the commodities."

Cattle, liver
                                      2.5
Cattle, meat byproducts, except liver
                                     0.05
Goat, liver
                                      2.5
Goat, meat byproducts, except liver
                                     0.05
Sheep, liver
                                      2.5
Sheep, meat byproducts, except liver
                                     0.05
Horse, liver
                                      2.5
Horse, meat byproducts, except liver
                                     0.05

Data Gaps

See Section 10.0 for data needs and label recommendations.


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 proposal to amend the established tolerances for saflufenacil on cotton, dry bean, dry pea, and soybean (PP#0F7744).  The amended tolerances on these crops are the result of the proposed harvest aid/desiccation use pattern for Sharpen[(TM)] Powered by Kixor Herbicide (EPA Reg. No. 7969-278); the currently registered uses are for preplant application.  In addition, BASF has submitted a proposal for a new use of Sharpen[(TM)] on Oilseeds, Rapeseed Subgroup 20A as harvest aid/desiccant (PP#0F7744).

BASF has submitted draft labels dated 6/24/10 for the 2.85 lb ai/gal SC formulation [Sharpen[(TM)] Powered by Kixor Herbicide (EPA Reg. No. 7969-278)].  Information pertaining to the proposed end-use product is listed in Table 3.  A summary of the proposed use patterns on legume vegetables and oilseeds is detailed in Table 2.1.2.

Table 2.1.1.  Summary of Proposed End-Use Products.
Trade Name
                                   Reg. No.
                             ai (% of formulation)
                               Formulation Type
                                 Target Crops
                                 Target Pests
                                  Label Date
Sharpen[(TM)] Powered by Kixor Herbicide
                                   7969-278
                                     29.74
                                      SC
                          legume vegetables, oilseeds
                                Broadleaf weeds
                        Draft labels submitted 6/24/10

Table 2.1.2.  Summary of Directions for Use of Saflufenacil.
                       Applic. Timing, Type, and Equip.
                                  Formulation
                                [EPA Reg. No.]
                                   App. Rate
                                 (lb ai/acre)
                           Max. No. App. per Season
                            Max. Seasonal App. Rate
                                 (lb ai/acre)
                                      PHI
                                    (days)
                        Use Directions and Limitations
                        Oilseeds, Rapeseed Subgroup 20A
                                  Preharvest
                                 Desiccation 
                                  Broadcast,
                               Ground or aerial
                                 Sharpen[(TM)]
                                   Herbicide
                                2.85 lb/gal SC
                                  [7969-278]
                                 0.0225-0.045
                                       2
                                     0.045
                                       3
Applications are to be made in >=10 gal/acre (ground) or >=3 gal/acre (aerial).  
                       Oilseeds, Sunflower Subgroup 20B
                                  Preharvest
                                 Desiccation 
                                  Broadcast,
                               Ground or aerial
                                 Sharpen[(TM)]
                                   Herbicide
                                2.85 lb/gal SC
                                  [7969-278]
                                 0.0225-0.045
                                       2
                                     0.090
                                       7
Applications are to be made in >=10 gal/acre (ground) or >=3 gal/acre (aerial).  
                       Oilseeds, Cottonseed Subgroup 20C
                                  Preharvest
                                 Desiccation 
                                  Broadcast,
                               Ground or aerial
                                 Sharpen[(TM)]
                                   Herbicide
                                2.85 lb/gal SC
                                  [7969-278]
                                 0.0112-0.045
                                       2
                                     0.045
                                       5
Applications are to be made in >=10 gal/acre (ground) or >=5 gal/acre (aerial).  
                               Dry Edible Beans
                                  Preharvest
                                 Desiccation 
                                  Broadcast,
                               Ground or aerial
                                 Sharpen[(TM)]
                                   Herbicide
                                2.85 lb/gal SC
                                  [7969-278]
                                 0.0225-0.045
                                       2
                                     0.045
                                       2
Applications are to be made in >=10 gal/acre (ground) or >=3 gal/acre (aerial).  Do not graze or feed treated hay or straw to livestock.
                                   Dry Peas
                                  Preharvest
                                 Desiccation 
                                  Broadcast,
                               Ground or aerial
                                 Sharpen[(TM)]
                                   Herbicide
                                2.85 lb/gal SC
                                  [7969-278]
                                 0.0225-0.045
                                       2
                                     0.045
                                       3
Applications are to be made in >=10 gal/acre (ground) or >=3 gal/acre (aerial).  Desiccation-treated pea vines may be grazed or fed to livestock
                                   Soybeans
                                  Preharvest
                                 Desiccation 
                                  Broadcast,
                               Ground or aerial
                                 Sharpen[(TM)]
                                   Herbicide
                                2.85 lb/gal SC
                                  [7969-278]
                                 0.0225-0.045
                                       2
                                     0.045
                                       3
Applications are to be made in >=10 gal/acre (ground) or >=3 gal/acre (aerial).  Do not graze or feed treated hay or straw to livestock.
Note:  Thorough spray coverage and a methylated seed oil (MSO) plus ammonium-based adjuvant system is required for optimum desiccation activity.

Conclusions:  The submitted use directions for Sharpen[(TM)] Herbicide are adequate to allow evaluation of the residue data relative to the proposed uses.  

2.2  Structure and Nomenclature

Table 2.2.  Saflufenacil and Metabolites 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


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 new 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.  For additional information, see Austin, et al. (7/22/09; D367317).

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, 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/day) 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/d) 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).

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/LOAELs were established for the developmental effects seen in rats and rabbits as well as for the offspring effects seen in the two-generation reproductive toxicity study; (2) the dose-response relationship for the effects of concern are also well-characterized and being used for assessing dermal and inhalation risks; and (3) the dose being used for the overall risk assessments would be protective of the developmental and offspring effects.  
   * 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 the acute and subchronic neurotoxicity study.  In the acute neurotoxicity study, a decrease in motor activity was observed on the first day of dosing at the limit dose (2000 mg/kg/day) in males only.  The finding was not accompanied by any other neuropathological changes and was considered a reflection of a mild and transient general systemic toxicity and not a substance-specific neurotoxic effect.  Additionally, it was not corroborated in the subchronic neurotoxicity study.  There is also no other indication of neurotoxicity in any study in the database.  In the subchronic neurotoxicity study, systemic toxicity was seen at 1000 (66.2 mg/kg/day) and 1350 (101 mg/kg/day) ppm in males and females, respectively.
   * 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 which 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 (10X) and intraspecies (10X) extrapolation.  Thus, the aPAD is estimated as the NOAEL of 500 mg/kg bw divided by 100 or 5.0 mg/kg bw.

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 (10X) and intraspecies (10X) extrapolation.  Thus, the cPAD is estimated as 4.6 divided by 100 or 0.046 mg/kg bw/day (Table 3.5a).

Incidental Oral (Short- and Intermediate-Term):  Selection of this endpoint is not warranted since residential uses of saflufenacil are not expected.

Dermal (Short- and Intermediate-Term):  Although a 28-day dermal toxicity study with non-pregnant adult rats yielded no evidence of toxicity (dermal or systemic), there is concern for developmental toxicity following exposure to saflufenacil.  Decreased fetal weights and increased skeletal variations were observed in the rat oral prenatal developmental toxicity study at the LOAEL of 20 mg/kg/day (NOAEL was 5 mg/kg/day).  The concern for developmental toxicity is also supported by findings at higher doses from the rabbit developmental toxicity study and the rat 2-generation reproductive toxicity study.  In the previous risk assessment (Austin, et al., 7/22/09; D367317), a dermal-absorption factor of 3% was used based on a dermal-penetration study.  Thus, the equivalent dermal NOAEL based on the rat prenatal developmental toxicity study can be estimated as 5 mg/kg/day/ 0.03 or 166.7 mg/kg/day.  The LOC is for a MOE <100, based on a combined UF of 100 to account for interspecies (10X) and intraspecies (10X) extrapolation.

Inhalation (Short- and Intermediate-Term):  Besides the required acute inhalation toxicity study that resulted in only minimal toxicity (Category IV), no other inhalation toxicity studies are available for saflufenacil.  Based on the available toxicity database and the Agency's current practices, the inhalation risk for saflufenacil is being assessed using the rat oral prenatal developmental toxicity study with a 100% absorption assumption.  The Agency sought expert advice and input on issues related to this route-to-route extrapolation approach (i.e., the use of oral toxicity studies for inhalation risk assessment) from its Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009.  The Agency received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The Agency is in the process of evaluating the SAP report and may, as appropriate, re-examine and develop new policies and procedures for conducting inhalation risk assessments, including route-to-route extrapolation of toxicity data.  If any new policies or procedures are developed, the Agency may revisit the need for an inhalation toxicity study for saflufenacil and/or a re-examination of the inhalation toxicity risk assessment.

Table 3.5a.  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. 

Table 3.5b.  Summary of Toxicological Doses and Endpoints for Saflufenacil for Occupational Human-Health Risk Assessment.
Exposure/
Scenario
Point of Departure
UFs
LOC for Risk Assessment
Study and Toxicological Effects
Dermal Short-and Intermediate- Term (1-30 days and 1-6 months, respectively)
NOAEL=5 mg/kg/day

Dermal absorption factor = 3%
UFA = 10X
UFH = 10X

FQPA SF = 1X
Occupational LOC for MOE = 100
Developmental study  -  Rat.
NOAEL = 5 mg/kg bw/day.
LOAEL = 20 mg/kg bw/day based on decreased fetal bodyweight and increased skeletal variations.  

Inhalation Short- and Intermediate- Term (1-30 days and 1-6 months, respectively)
NOAEL=5 mg/kg/day

Inhalation-absorption rate = 100%
UFA = 10X
UFH = 10X

FQPA SF = 1X
Occupational LOC for MOE = 100
Developmental study  -  Rat.
NOAEL = 5 mg/kg bw/day.
LOAEL = 20 mg/kg bw/day based on decreased fetal bodyweight and increased skeletal variations.  
Cancer (oral, dermal, inhalation)
Classification:  Not likely carcinogenic to humans based on the lack of tumors in the mouse and rat carcinogenicity studies and lack of mutagenicity. 
               No long-term uses are expected for saflufenacil.
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).  A dermal-absorption factor of 3% was estimated from a dermal-penetration study (See last risk assessment (Austin, et al., 7/22/09; D367317))
UFH = potential variation in sensitivity among members of the human population (intraspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  MOE = margin of exposure.  LOC = level of concern.  

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  Public Health and Pesticide Epidemiology Data

No public health/epidemiology data were used in developing this risk assessment.  Since saflufenacil is a new chemical, data are not available.  


5.0  Dietary Exposure/Risk Characterization

The following references apply to this section: 
Residue Chemistry Summary - D381129, G. Kramer, 24-MAR-2011
Dietary Exposure - D381976, G. Kramer, 24-MAR-2011
Drinking Water Degradates Identification - D356619, G. Orrick, 01-DEC-2008
Estimated Drinking Water Concentrations - D349860, G. Orrick, 15-APR-2009

5.1  Pesticide Metabolism and Environmental Degradation

5.1.1  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 preplant/preemergence application.  The main reactions involved in the metabolic pathway of saflufenacil were N-demethylation at the uracil ring, stepwise degradation (N-dealkylation) of the N-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).  The proposed metabolic pathway of radiolabeled saflufenacil in soybean following post-emergence treatment follows the same initial pathways, but is not as extensive.  No new metabolites were observed following post-emergence treatment; however, an additional major metabolite (M800H02), that is not included in the tolerance expression, was observed in soybean seed.  As the structure of M800H02 is closely related to the parent compound and it is the precursor of the regulated metabolite M800H11, HED concludes that M800H02 is a residue of concern for risk-assessment purposes in seed crops following post-emergence treatment.

5.1.2  Metabolism in Rotational Crops

The metabolism of saflufenacil in rotational crops appears to be consistent with the pathway observed in the plant metabolism studies.  Unless the petitioner requests plantback intervals (PBIs) shorter than 4 months, no additional data are required, and tolerances for inadvertent residues in/on rotational crops need not be established in conjunction with the currently proposed uses.

5.1.3  Metabolism in Livestock

The nature of the residue in livestock is adequately understood based on acceptable metabolism studies conducted on lactating goats and laying hens.  Saflufenacil was metabolized by several dealkylation steps occurring at two different sites in the molecule (N-isopropyl-N-methylsulfamide side chain and at the uracil ring) and via hydrolytic opening of the uracil ring (goat only).  In the ruminant metabolism study, saflufenacil was a major residue in all matrices.  M800H04, a ring opening product, was the only significant metabolite (>10% total radioactive residue, TRR) found (liver).  In the poultry metabolism study, saflufenacil was a major residue in all matrices and no significant metabolites were found.  

5.1.4  Analytical Methodology

The petitioner has submitted two liquid chromatography/mass spectroscopy/mass spectroscopy (LC-MS/MS) analytical methods for the determination of residues of the parent and its metabolites in/on plant and livestock commodities.  BASF Method D0603/02 was developed for determination of residues of saflufenacil and its metabolites M800H11 and M800H35 in different plant matrices using LC-MS/MS.  The limit of quantitation (LOQ) was 0.01 ppm for each analyte in food matrices and 0.025 ppm for each analyte in feed matrices.  BASF analytical Method No. L0073/01 was developed for determination of saflufenacil in livestock matrices using LC-MS/MS.  The LOQ was 0.01 ppm in all matrices.  These methods were used as the data-collection methods in the analysis of samples for residues of concern from the various studies associated with the current petition.  Each method has been adequately validated by the petitioner as well as by independent laboratories.  Method No. L0073/01 was also adequately radiovalidated using weathered samples obtained from metabolism studies.

HED has determined that Methods D0603/02 and L0073/01 are suitable enforcement methods for plant and livestock commodities, respectively, as defined in SOP No. ACB-019 (9/15/08).  

5.1.5  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).

5.1.6  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.

5.1.7  Toxicity Profile of Major Metabolites and Degradates

Toxicity data were not submitted for the metabolites of saflufenacil.

5.1.8  Pesticide Metabolites and Degradates of Concern

Table 5.1.8.  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

5.1.9  Drinking Water Residue Profile

The Estimated Drinking Water Concentrations (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 5.1.9) 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 5.1.8).  

Table 5.1.9.  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
                                      173

5.1.10  Food Residue Profile

The submitted magnitude of the residue data for the raw and processed commodities of cotton, dry bean, dry pea, canola, and soybean are adequate.  There are also adequate storage stability data to validate the storage conditions and intervals of samples collected from the field and processing trials.  With the exception of soybean hulls and aspirated grain fractions (AGFs), no concentration of the total saflufenacil residue was found in any processed commodity, separate tolerances for residues in/on processed commodities are not required.

An adequate dairy cow feeding study has been submitted; this study is acceptable for determining tolerance levels for ruminant commodities.  The increased reasonably-balanced dietary burdens (RBDBs) resulting from the proposed uses necessitate that the established tolerances be increased to 2.5 ppm for residues in liver and 0.05 ppm for residues in meat byproducts except liver of cattle, goats, horses, and sheep.

Analytical standards of saflufenacil, M800H11, and M800H35 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), 10/28/10].  However, since the standards for M800H11 and M800H35 expired on 10/1/10, the petitioner is requested to provide a new supply to the Repository.  

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.

5.1.11  International Residue Limits

There are no Codex maximum residue limits (MRLs) established for residues of saflufenacil and its metabolites in crop or livestock commodities.  Canadian MRLs are established for vegetable, legume, subgroup 6c; cotton, undelinted seed; and livestock commodities, all at levels lower than those recommended to support the current action.  Canada is currently in the process of reviewing the proposed harvest-aid uses use of saflufenacil.  EPA and Canadian tolerance/MRL recommendations are harmonized as a result of the joint-review process.
5.2  Dietary Exposure and Risk

5.2.1  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 0.010370 mg/kg/day for the general U.S. population (<1% of the aPAD) and 0.038353 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 5.2).

5.2.2  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 0.004219 mg/kg/day for the general U.S. population (9.2% of the cPAD) and 0.013999 mg/kg/day (30% 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 5.2).

 Table 5.2.  Summary of Dietary (Food and Drinking Water) Exposure and Risk for Saflufenacil.
                              Population Subgroup
                                 Acute Dietary
                              (95[th] Percentile)
                                Chronic Dietary
                                        
                          Dietary Exposure (mg/kg/day)
                                     % aPAD
                                Dietary Exposure
                                  (mg/kg/day)
                                     % cPAD
 General U.S. Population
                                    0.010370
                                     <1
                                    0.004219
                                      9.2
 All Infants (<1 year old)
                                    0.038353
                                     <1
                                    0.013999
                                       30
 Children 1-2 years old
                                    0.017102
                                     <1
                                    0.007234
                                       16
 Children 3-5 years old
                                    0.015406
                                     <1
                                    0.006506
                                       14
 Children 6-12 years old
                                    0.010475
                                     <1
                                    0.004370
                                       10
 Youth 13-19 years old
                                    0.008429
                                     <1
                                    0.003159
                                      6.9
 Adults 20-49 years old
                                    0.009246
                                     <1
                                    0.003811
                                      8.3
 Adults 50+ years old
                                    0.008373
                                     <1
                                    0.003945
                                      8.6
 Females 13-49 years old
                                    0.009310
                                     <1
                                    0.003793
                                      8.2

5.2.3  Cancer Dietary Risk

Saflufenacil is classified as "not likely carcinogenic to humans."  Therefore, cancer risk is not a concern for this chemical.

5.3  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.


6.0  Residential (Non-Occupational) Exposure/Risk Characterization

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

6.1  Spray Drift

Spray drift is always a potential source of exposure to residents nearby spraying operations.  This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for saflufenacil.  The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices.  On a chemical-by-chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling.  The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT[(R)] computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods.  After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drift with specific products with significant risks associated with drift.

6.2  Residential Bystander Post-application Inhalation Exposure

Based on the Agency's current practices, a quantitative residential bystander post-application inhalation exposure assessment was not performed for saflufenacil at this time.  However, volatilization of pesticides may be a potential source of post-application inhalation exposure to individuals nearby to pesticide applications.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA SAP in December 2009.  The Agency received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are put into place, then the Agency may revisit the need for a quantitative post-application inhalation exposure assessment for saflufenacil.

7.0  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.


8.0  Cumulative Risk Characterization/Assessment

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to saflufenacil and any other substances and saflufenacil does not appear to produce a toxic metabolite produced by other substances.  For the purposes of this tolerance action, therefore, EPA has not assumed that saflufenacil has a common mechanism of toxicity with other substances.  For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.


9.0  Occupational Exposure/Risk Pathway

The following reference applies to this section:
Occupational and Residential Exposure Assessment - D381978, A. Nowotarski, 24-FEB-2011 

A risk assessment has already been performed for sunflower subgroup 20B, soybean, dry peas, cottonseed subgroup 20C, and dry edible beans (Austin, et al., 7/22/09; D367317).  The maximum use rate has not increased for the proposed new use and, therefore, the previous assessment still covers any occupational handler/postapplication exposure from use on these crops.  An assessment for rapeseed subgroup 20A (canola) is included below since this use has not been assessed previously. 

9.1  Short-/Intermediate-Term Occupational Handler Risk

Potential occupational exposure scenarios include:  1) mixing/loading liquids for aerial application; 2) mixing/loading liquids for groundboom application; 3) applicators using aerial equipment; 4) open-cab groundboom equipment; and 5) flaggers. 

Handler exposure is expected to be short- and intermediate-term based on information provided on proposed labels (e.g., maximum application rate of 0.0445 lb ai/A).  Typically, HED completes short- and intermediate-term assessments for occupational scenarios in all cases because these kinds of exposures are likely and acceptable use/usage data are not available to justify deleting intermediate-term scenarios.  Based on use data and label instructions, HED believes that occupational exposures may occur over a single day or up to weeks at a time for many use-patterns and that intermittent exposure over several weeks may also occur.  Some applicators may apply these products over a period of weeks, because they are commercial applicators who are completing multiple applications for multiple clients.  The average adult body weight of 60 kg was used for estimating dermal and inhalation dose because the endpoint is from a developmental study and was observed in offspring.  Long-term exposures are not expected; therefore, a long-term assessment was not conducted.

No chemical-specific data are available with which to assess potential exposure to pesticide handlers.  The estimates of exposure to pesticide handlers are based upon surrogate study data available in PHED (August, 1998).  For pesticide handlers, it is HED standard practice to present estimates of dermal exposure for "baseline;" that is, for workers wearing a single layer of work clothing consisting of a long-sleeved shirt, long pants, shoes plus socks and no protective gloves, as well as for "baseline" and the use of protective gloves or other personal-protective equipment (PPE) as might be necessary.  The proposed product label involved in this assessment directs applicators and other handlers to wear protective eyewear, long-sleeved shirt and long pants, socks, shoes, and chemical-resistant gloves. 

Daily handler exposures are estimated for each applicable handler task with the application rate, the area treated in a day, and the applicable unit exposure using the following formula:

Daily Exposure (mg ai/day) = Unit Exposure (mg ai/lb ai handled) x Application Rate (lbs ai/area) x Daily Area Treated (area/day)

Where:

Daily Exposure		=	Amount (mg ai/day) inhaled that is available for inhalation absorption;
Unit Exposure 		=	Unit exposure value (mg ai/lb ai) derived from August 1998 PHED data;
Application Rate		=	Normalized application rate based on a logical unit treatment, such as acres; and
Daily Area Treated 	=	Normalized application area based on a logical unit treatment such as acres (A/day).

The daily dermal or inhalation dose is calculated by normalizing the daily exposure by body weight and adjusting, if necessary, with an appropriate inhalation absorption factor using the following formula:

Average Daily Dose (mg/kg/day) = Daily Exposure (mg ai/day) x (Absorption Factor (%/100)) / Body Weight (kg)

Where:

Average Daily Dose 		= 	Absorbed dose received from exposure to a pesticide in a given scenario (mg ai/kg body weight/day);
Daily Exposure 		=	Amount (mg ai/day) deposited on surface of skin that is available for dermal absorption, or the amount inhaled that is available for inhalation absorption;
Absorption Factor 			= 	A measure of the amount of chemical that crosses a biological boundary such as the skin or lungs (% of the total available absorbed); and
Body Weight 			= 	Body weight determined to represent the population of interest in a risk assessment (kg).

Non-cancer dermal and inhalation risks for each applicable handler scenario are calculated using an MOE, which is a ratio of the NOAEL to the daily dose.  All MOE values were calculated using the formula below:

MOE= NOAEL (mg/kg/day) / Average Daily Dose (mg/kg/day)

Table 9.1 provides a summary of the estimated exposures and risks to occupational pesticide handlers.  An MOE >=100 is adequate to protect occupational pesticide handlers.  Since all the estimated MOEs are >100 with baseline protection or the addition of gloves (as already required by the label), the proposed uses are not of concern for HED.

Table 9.1.  Occupational Dermal and Inhalation Exposures and Risks.
                                Crop or Target
                                   App. Rate
                                 (lb ai/A)[a]
      Area Treated Daily or Amount Handled (acres or gallons per day)[b]
                     Dermal and Inhalation Unit Exposures
                                  (mg/lb ai)
                      Short- and Intermediate-Term Doses
                                (mg/kg/day)[e]
                                    MOEs[f]
                                       
                                       
                                       
                                       
                                       
                         Short- and Intermediate-Term
                        Combined Dermal and Inhalation
                     Mixer/Loader for Aerial Applications
                        Rapeseed subgroup 20A (canola)
                                    0.0445 
                                     1200
                                    Dermal
                               Baseline[c]:  2.9
                                 PPE-G:  0.023
                                    Dermal
                               Baseline:  0.078
                              PPE-G[g]:  0.00062
                                       
                                    Dermal
                                 Baseline:  64
                                 PPE-G: 8,100
                     Baseline Dermal +Baseline Inhal:  63 
                                       
                     PPE-G Dermal + Baseline Inhal: 2,900
                                       
                                       
                                       
                                  Inhalation
                             Baseline[d]:  0.0012
                                  Inhalation
                               Baseline:  0.0011
                                       
                                    Inhal.
                                  Baseline: 
                                     4,600
                                       
                   Mixer/Loader for Groundboom Applications
                        Rapeseed subgroup 20A (canola)
                                    0.0445
                                      200
                                    Dermal
                               Baseline[c]:  2.9
                                       
                                    Dermal
                               Baseline:  0.013
                                       
                                    Dermal
                                Baseline:  380
                    Baseline Dermal + Baseline Inhal:  380
                                       
                                       
                                       
                                  Inhalation
                             Baseline[d]:  0.0012
                                  Inhalation
                              Baseline:  0.00018
                                    Inhal.
                               Baseline: 28,000
                                       
                   Applying Sprays via Groundboom Equipment
                        Rapeseed subgroup 20A (canola)
                                    0.0445
                                      200
                                    Dermal
                                Baseline: 0.014
                                    Dermal
                              Baseline: 0.000063
                                       
                                    Dermal
                                  Baseline: 
                                    79,000
                   Baseline Dermal + Baseline Inhal: 29,000
                                       
                                       
                                       
                                  Inhalation
                               Baseline: 0.00074
                                  Inhalation
                              Baseline:  0.00011
                                       
                                    Inhal.
                               Baseline: 45,000
                                       
                     Applying Sprays via Aerial Equipment
                        Rapeseed subgroup 20A (canola)
                                    0.0445
                                     1200
                                    Dermal
                                 Eng cont[h]: 
                                     0.005
                                    Dermal
                              Eng cont:  0.00014
                                    Dermal
                               Eng cont: 37,000
                   Eng cont Dermal + Eng cont Inhal: 25,000 
                                       
                                       
                                       
                                  Inhalation
                                  Eng cont: 
                                   0.000068
                                  Inhalation
                              Eng cont:  0.000061
                                  Inhalation
                               Eng cont: 82,000
                                       
                                    Flagger
                        Rapeseed subgroup 20A (canola)
                                    0.0445
                                      350
                                    Dermal
                               Baseline:  0.011
                                    Dermal
                              Baseline:  0.000087
                                    Dermal
                               Baseline: 58,000
                       Baseline Dermal + Baseline Inhal:
                                    28,000
                                       
                                       
                                       
                                  Inhalation
                              Baseline:  0.00035
                                  Inhalation
                              Baseline:  0.000092
                                  Inhalation
                               Baseline: 54,000
                                       
a	Application rates are the maximum application rates determined from proposed labels for saflufenacil.
b	Amount handled per day values are HED estimates of acres treated per day or gallons handled per day based on ExpoSAC SOP #9 "Standard Values for Daily Acres Treated in Agriculture," industry sources, and HED estimates.
c	Baseline Dermal:  Long-sleeved shirt, long pants, and no gloves.
d	Baseline Inhalation:  no respirator.
      e	Dose (mg/kg/day) = Unit Exposure(mg/lb ai) x App. Rate (0.0445 lb ai/acre) x Area Treated (acres/day) or Amount Handled (gallons) / Body Weight (60 kg).  
f	MOE = NOAEL/Dose; where the short- and intermediate-term dermal NOAEL = 5 mg/kg/day; short- and intermediate-term inhalation NOAEL = 5 mg/kg/day.
g	PPE-G = long-sleeve shirt, long pants, and gloves.
h	Engineering control:  enclosed cockpit and baseline attire (long-sleeve shirt, long pants, shoes, and socks).

9.2  Short-/Intermediate-Term Postapplication Risk

Dermal

The proposed use is for application of saflufenacil as a pre-harvest desiccant.  As such, postapplication exposure to foliage is not expected because harvesting is done mechanically.  Therefore, occupational post-application dermal exposure was not assessed at this time.

Inhalation 

Based on the Agency's current practices, a quantitative occupational post-application inhalation exposure assessment was not performed for saflufenacil at this time.  However, there are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated fields.  These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA SAP in December 2009.  The Agency received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html).  The Agency is in the process of evaluating the SAP report as well as available post-application inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for saflufenacil.

REI 

Saflufenacil is classified as acute Toxicity Category III for acute dermal toxicity and primary eye irritation.  It is classified as Toxicity Category IV for primary skin irritation.  Therefore, the interim WPS REI of 12 hours is adequate to protect agricultural workers from post-application exposures to saflufenacil.


10.0  Data Needs and Label Recommendations

10.1  Toxicology

   * none

10.2  Residue Chemistry

860.1650 Submittal of Analytical Reference Standards

   * Analytical standards of saflufenacil, M800H11, and M800H35 are currently available in the National Pesticide Standards Repository [source:  personal communication with T. Cole of ACL/BEAD, 10/28/10].  However, since the standards for M800H11 and M800H35 expired on 10/1/10, the petitioner is requested to provide a new supply to the Repository.  

860.1550 Proposed Tolerances

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

   * Revised tolerance levels and commodity definitions are presented in Appendix B:  Tolerance Summary Table.

10.3  Occupational and Residential Exposure

   * none
























cc:  G. Kramer (RAB1)
RDI:  RAB1 (3/16/11)
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
Oilseeds, Cottonseed Subgroup 20C, gin byproducts
                                      3.5
                                     0.45
Cotton, gin byproducts
Oilseeds, Cottonseed Subgroup 20C, undelinted seed
                                      0.2
                                     0.20
Cottonseed Subgroup 20C
Oilseeds, Sunflower Subgroup 20B, seed
                                      1.0
                                      1.0
Sunflower Subgroup 20B
Pea, vines
                                      8.0
                                      17
Pea, hay
Soybean, aspirated grain fractions
                                     4.52
                                      10
Grain, aspirated fractions
Soybean, hulls
                                     0.42 
                                     0.50

Soybean, seed
                                      0.1
                                     0.10

Vegetable, Legume, Subgroup 6C, beans, dry
                                      0.5
                                     0.30
Pea and bean, dried shelled, except soybean, subgroup 6C
Vegetable, Legume, Subgroup 6C, peas, dry
                                      0.1
                                       

Oilseeds, Rapeseed Subgroup 20A, seed 
                                      0.8
                                     0.45
Rapeseed Subgroup 20A
Cattle, liver
                                       -
                                      2.5

Cattle, meat byproducts, except liver
                                       -
                                     0.05

Goat, liver
                                       -
                                      2.5

Goat, meat byproducts, except liver
                                       -
                                     0.05

Sheep, liver
                                       -
                                      2.5

Sheep, meat byproducts, except liver
                                       -
                                     0.05

Horse, liver
                                       -
                                      2.5

Horse, meat byproducts, except liver
                                       -
                                     0.05


Note:  In conjunction with establishing these tolerances, the existing tolerance for "Vegetable, foliage of legume, group 7" should be modified to "Vegetable, foliage of legume, group 7 (except pea hay)"; the existing tolerance for "Vegetable, legume, group 6" should be replaced with "Vegetable, legume, edible podded, subgroup 6A" plus "Pea and bean, succulent shelled, subgroup 6B"; and the existing tolerances for "Sunflower, seed" and "Cotton, undelinted seed" should be deleted.

