**EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR**

**PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER (**  **7 /1/200**  **7 )**  **EPA Registration**  **Division contact: [**  **Kathryn Montague**  **, Herbicide Branch,**  **Product Manager**  **, Team 23,**  **703 -** **305 -**  **1243 ]**  **BASF Corporation Petition No. 2E8065**  EPA has received a pesticide petition **( 2E8065)**  from **BASF Corporation ,**  **26 Davis Drive,**  **P.O. Box 13528, Research Triangle Park, North Carolina 27709**  **- 3528**  proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180. 649 by establishing a tolerance for **combined residues of S**  **aflufenacil (2 -**  **chloro -**  **5 -**  **[3,6 -**  **dihydro -** **3 -**  **methyl -**  **2,6 -**  **dioxo -**  **4 -**  **(trifluoromethyl) -**  **1(2 H** 

**) -** **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(2** **H )**  **- pyrimidinyl)**  **- 4**  **- fluorobenzoyl]**  **- N**  **' -**  **isopropylsulfamide and N**  **- [4**  **- chloro**  **- 2**  **- fluoro**  **- 5**  **- ({[(isopropylamino)sulfonyl]amino}**  **carbonyl)phenyl]urea , calculated as the stoichiometric equivalent of**  **S aflufenacil**  in or on the raw agricultural commodities **sugarcane, cane** at **0. 03**  parts per million (ppm) and **sugarcane, molasses** at **0.0 75**  parts per million (ppm) and **sugarcane ,**  **refined sugar** at **0.0 45**  parts per million (ppm)

. EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully

evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry 1. Plant metabolism

. **Previously submitted metabolism data for corn, soybean,**  **and tomato and a confined rotational crop study**  **are ade quate to elucidate the**  **nature of the residue in plants resulting from preplant/preemergence application**  **, a**  **postemergence -**  **directed at the base of plants underneath the leaf canopy application**  **, and a pre -**  **harvest/desiccant application .**  **An additional nature of residue**  **study was conducted with a postemergence application in rice as a representative**  **monocot (grass) species . T**  **he metabolism of Saflufenacil in plants following a postemergence application is similar to the metabolism of Saflufenacil in plants**  **followi ng a preplant/preemergence application.**  **Therefore, t he residues of concern** 2

**for the tolerance expression and risk assessment consist of Saflufenacil, M800H11, and M800H35.**  2. Analytical method. **Adequate enforcement methodology (liquid chromatography/mass**  **spectrometry/mass spectrometry (LCMS/MS) methods D0603/02 (plants) and L0073/01 (livestock)) is available to enforce the tolerance**  **expression .**  3. Magnitude of residues. **Field trials in**  **Brazil were carried out to determine**  **the magnitude of the residue fo**  **llowing a postemergence over** **- the**  **- top application o**  **f Saflufenacil**  **applied for**  **pre -**  **harvest weed**  **desiccation in sugarcane . Field trials were**  **carried out using the maximum label rates, the maximum number of applications, and the minimum pre**  **- harvest interval (P** **HI) for use in sugarcane**  **. Detected combined residues of**  **Saflufenacil plus metabolites in**  **the crop**  **commodities support**  **the proposed import**  **tolerances.** B. Toxicological Profile 1. Acute toxicity. **Saflufenacil has low acute toxicity via the oral, dermal, and**  **inhalation routes of exposure. It is slightly irritating to the eye but is neither a dermal irritant nor sensitizer**  **.** 2. Genotoxicty. **Saflufenacil is weakly clastogenic in the in vitro**  **chromosomal aberration assay in V79 cells in the presence of S9 ac** **tivation; however, the response was not evident in the absence of S9 activation. It is neither mutagenic in bacterial**  **cells nor clastogenic in rodents in vivo**  **.**

3. Reproductive and developmental toxicity. Increased fetal and offspring susceptibility

to S aflufenacil were 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 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 that were not maternally toxic, indicating increased quantitative susceptibility . In the 2

–generation reproduction study in rats, offspring effects such as 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 were observed at a dose resulting in less severe maternal toxicity

(decreased food intake, body weight/weight gain and changes in hematological parameters and organ weights indicative of anemia), indicating increased qualitative susceptibility

. 4. Subchronic toxicity. **Short -** **term, subchronic, and chronic toxicity studies in rats, mice, and dogs identified the hematopoietic system as the target organ of**  **saflufenacil. Protoporphyrinogen oxidase inhibition in the mammalian species ma y**  **result in disruption of heme synthesis which in turn causes anemia. In these studies,**3

**decreased hematological parameters (red blood cells (RBC), hematocrit (Ht), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean**  **corpuscular hemog lobin concentration (MCHC)) were seen at about the same dose**  **level across species, except in the case of the dog, where the effects were seen at a slightly higher dose. These effects occurred around the same dose level from the**  **short -** **term through long -** **term exposures without increasing in severity. Effects were**  **also seen in the liver (increased weight, centrilobular fatty change, and lymphoid infiltrate) in mice, the spleen (increased spleen weight and extramedullary**  **hematopoiesis) in rats, and in both these organs (increased iron storage in the liver**  **and extramedullary hematopoiesis in the spleen) in dogs. These effects also occurred around the same dose level from the short** **- term through long**  **- term exposures**  **without increasing in severity. No dermal toxicity was seen at the limit dose in a 28** 

**– day dermal toxicity study in rats.**  **There was no evidence of neurotoxicity or neuropathology in the toxicity database fo**  **r S aflufenacil. In the acute neurotoxicity study, a decrease in motor activity was**  **observed on the fi rst day of dosing at the limit dose 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. In t he subchronic neurotoxicity study, systemic toxicity**  **(anemia), but no evidence of neurotoxicity, was seen in males and females. There**  **wa s no evidence of i**  **mmunotoxity in the toxicity database for S aflufenacil.**  **In the immunotoxicity study conducted in male**  **mice, systemic toxicity (signs of anemia and liver effects) w**  **as seen, but the effects were not indicative of immunotoxicity.**  **There were no effects on sheep red blood cell (SRBC) IgM antibody titers or immune system organ weights (spleen and thymus) in the**  **treated mice. In the 90**  **- day oral toxicity study in rats, t**  **he increase in spleen weight seen only in rats is attributable to an increased clearance of defective RBCs (i.e., defective hemoglobin**  **synthesis) and is thus an indication of toxicity to the hemato poietic system rather**  **than to the immune system .**  ] 5. Chronic toxicity. **Carcinogenicity studies in rats and mice showed no evidence of increased incidence of tumors at the tested doses. Saflufenacil is**  **classified as not likely to be carcinogenic to humans .**  6. Animal metabolism. **Rat metabolism data indicate that Saflufenacil is well absorbed and rapidly excreted. The maximum concentration of Saflufenacil in**  **blood and plasma was reached within 1 hour (h) of dosing and declined rapidly after 24 h. Excreti**  **on of orally dosed Saflufenacil was essentially complete within 96 h, with the majority eliminated within the first 24 to 48 h. There was a sex** **** **dependent difference in the excretion of orally administered Saflufenacil. The main route of elimination in ma** **le rats was via the feces, while urinary excretion was the ma** **jor route of elimination in females. The sex -**  **dependent excretion was more pronounced at the low**  **- dose level than at the high**  **- dose level. Also, males had**  **significantly higher biliary excretion of Saflufenacil residues than females.** 4

**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. The pare**  **nt molecule and 3 major metabolites were identified and isolated from urine and feces. There were no significant gender differences in metabolic profiles.**  **Saflufenacil was metabolized by three major transformation steps, which were demethylation of the ur**  **acil ring system, degradation of the N**  **- methyl** **- N**  **- isopropyl**  **group to NH 2**  **, and cleavage of the uracil ring, forming a sulfonylamide group. The**  **metabolism of Saflufenacil**  **in the animals is well understood.** 7. Metabolite toxicology

. **No metabolites of toxicolo gical concern**  **are identified.**  8. Endocrine disruption

. **No specific tests have been conducted with S**  **aflufenacil to determine whether the chemical may have an effect in humans that is**  **similar to an effect produced by a naturally occurring estrogen or other endocrine**  **effects. However, there were no significant findings in other relevant toxicity studies (e.g., sub**  **- chronic and chronic toxicity, developmental toxicity and multi** **- generation**  **reproductive studies) which would suggest that S aflufenacil**  **produces an y endocrine**  **disruption.** C. Aggregate Exposure 1. Dietary exposure. **Exposure assessments were conducted to evaluate the potential risk due to acute and chronic dietary exposure of the U.S. population to**  **combined residues of S aflufenacil**  **and metabolites M 800H11 and M800H35.**  **The current**  **established tolerance values are listed in the U.S. 40 CFR § 180.649.**  **Th is**  **analysis include s**  **all the crops with established tolerances**  **and proposed new import tolerances for sugarcane, cane**  **at 0.03 ppm, sugarcane, molasses**  **at 0.075 ppm, and**  **sugarcane, refined sugar at**  **0.045 ppm.** i. Food. **Acute Dietary Exposure Assessment Acute dietary exposure estimates were**  **conducted using the curren tly established**  **tolerances for S aflufenacil (40 CFR 180.649)**  **, plus the proposed new**  **impor t**  **tolerances for sugarcane, cane at**  **0.03 ppm, sugarcane, molasses at**  **0.075 ppm, and sugarcane, refined sugar**  **at 0.045 ppm.**  **The assessment was conducted using tolerance values, default process factors, and 100% crop**  **treatment factors. The**  **consumption data was from the USDA Continuing Survey of Food Intake by**  **Individuals (CSFII 1994 -**  **1996, 1998) and the EPA Food Commodity Ingredient Database (FCID) using Exponent's Dietary Exposure Evaluation Module (DEEM** **** **FCID) software. The result** **ing exposure estimates**  **were compared against the S aflufen**  **a cil**  **acute Population Adjusted Dose (aPAD) of 5 mg/kg b.w./day for all populations. This** 5

**endpoint is based on the NOAEL of 5 00**  **mg/kg/day with the standard inter** **- and**  **intra -**  **species uncertainity factors of 100X and an FQPA**  **safety factor of 1. The expos**  **ure for all sub**  **- population was less than**  **1.0 % utilization of the aPAD. The**  **results of the acute dietary assessment are presented in Table 1. Table 1.**  **Results for**  **S aflufenacil**  **Acute Dietary**  **Exposure Analysis**  **Considering all**  **Proposed Tolerances using DEEM -**  **FCID at the 95 th**  **Percentile , food only** 

**Population Exposure Estimate**  **%aPAD Subgroups**  **(mg/kg b.w./day) U.S. Population**  **0.001313 0.03**  **All Infants (< 1 year old) 0.002468**  **0.05 Children (1**  **- 2 years old)**  **0.003014 0.06**  **Childr en (3**  **- 5 years old)**  **0.002407 0.05**  **Children (6 -**  **12 years old) 0.001485**  **0.03 Youth (13**  **- 19 years old)**  **0.000949 0.02**  **Adults (20 -**  **49 years old) 0.000772**  **0.02 Adults (50+ years old)**  **0.000679 0.01**  **Females (13**

**– 49 years old)**  **0.000759 0.02**  **The results of the a nalysis show that for all populations, the estimated exposures are**  **well below the Agency's level of concern (< 100% aPAD). Additional refinements in the dietary risk assessment (i.e. utilizing anticipated residue values, percent crop**  **treated values) would further reduce the estimated exposure values.**  **Chronic Dietary Exposure Assessment Chronic**  **dietary exposure estimates were conducted using the currently established tolerances for Saflufenacil (40 CFR 180.649)**  **, plus the proposed new import**  **tolerances f** 

**or sugarcane, cane**  **at 0.03 ppm, sugarcane, molasses**  **at 0.075 ppm, and**  **sugarcane, refined sugar at**  **0.045 ppm. The assessment was conducted using**  **tolerance values, default process factors, and 100% crop treatment factors. The**  **consumption data was from the USDA Continuing Survey of Food Intake by**  **Individuals (CSFII 1994 -**  **1996, 1998) and the EPA Food Commodity Ingredient Database (FCID) using Exponent's Dietary Exposure Evaluation Module (DEEM** **** **FCID) software. The chronic Population Adjusted Dose (cPAD) used f**  **or U.S. population and all sub**   ** populations is 0.046 mg/kg bw/day. This endpoint is based on the NOAEL value of** **4.6 using the standard inter** **- and intra** **- species uncertainity factors of 100X and with**  **a FQPA safety factor of 1. The most highly expos ed**  **populat ion sub**  **- group was**  **children 1 -**  **2 years of age which utilized 3.3**  **% cPAD. The results of the chronic dietary assessment are presented in Table 2.**  **Table 2. Results for S**  **aflufenacil Chronic**  **Dietary Exposure Analysis Considering all**  **Proposed Tolerances using DEEM** **- FCID**  **, food only**6 **Population Exposure Estimate**  **%cPAD Subgroups**  **(mg/kg b.w./day) U.S. Population**  **0.000459 1.0**  **All Infants (< 1 year old) 0.001051**  **2.3 Children (1**  **- 2 years old)**  **0.001537 3.3**  **Children (3 -**  **5 years old) 0.001196**  **2.6 Children (6**  **- 12 year**  **s old) 0.000716**  **1.6 Youth (13**  **- 19 years old)**  **0.000413 0.9**  **Adults (20 -**  **49 years old) 0.000328**  **0.7 Adults (50+ years old)**  **0.000298 0.6**  **Females (13 -**  **49 years old) 0.000321**  **0.7 The results of the analysis show that for all populations, the exposures are fa**  **r below a level of concern (< 100% cPAD). Additional refinements in the chronic dietary**  **risk assessment (i.e. utilizing anticipated residue values and percent crop treated values) would further reduce the estimated exposure values.**  ii. Drinking water

. **A ll S**  **aflufenacil uses were examined at maximum use rates,**  **maximum number of applications, and all proposed application methods to determine which use would result in the highest water concentrations. The highest**  **water concentrations occurred from the Missi ssippi corn scenario**  **(model) from an**  **aerial application at 0.134 lb ai/A. Based on results from the PRZM/EXAMS and SCI**  **- GROW models estimates, the highest acute Estimated Drinking Water**  **Concentrations (EDWC ’s**  **) for S aflufenacil**  **were estimated to be 8.1 ug/L (ppb) in**  **surface water and 0.36 ug/L in ground water. The highest chronic EDWC’s for S**  **aflufenacil were estimated to be 2.5 ug/L in surface water and 0.36 ug/L in ground**  **water. Drinking water exposure contributions were assessed based on the maximum**  **es timated S**  **aflufenacil water concentrations (acute 8.1 ug/L, chronic 2.5 ug/L), and**  **water consumption and body weights reported in CSFII, using DEEM -** **FCID software. The acute and chronic estimated water exposure values are summarized**  **in Tables 3 and 4, respe ctively. Drinking water exposure accounts for less than**  **1 %**  **of the aPAD and 1% of the cPAD for all populations. Table**  **3. Results**  **for S**  **aflufenacil Acute**  **Water Exposure**  **Analysis Considering**  **the Maximum Estimated Acute Drinking Water Concentration using DEE**  **M -**  **FCID**

**Population Water Exposure Estimate**  **% aPAD Subgroups**  **(mg/kg b.w./day) U.S. Population**  **0.000423 0.01**  **All Infants (< 1 year old) 0.001535**  **0.03 Children (1**  **- 2 years old)**  **0.000664 0.01** 7

**Children (3 -**  **5 years old) 0.000607**  **0.01 Children (6**  **- 12 years o**  **ld) 0.000422**  **0.01 Youth (13**  **- 19 years old)**  **0.000343 0.01**  **Adults (20 -**  **49 years old) 0.000392**  **0.01 Adults (50+ years old)**  **0.000354 0.01**  **Females (13 -**  **49 years old) 0.000394**  **0.01**

**Table 4.**  **Results for**  **S aflufenacil**  **Chronic Water**  **Exposure Analysis**  **Considering the**  **Maximum Estimated Chronic Drinking Water Concentration using DEEM -**  **FCID**

**Population Water Exposure Estimate**  **%cPAD Subgroups**  **(mg/kg b.w./day) U.S. Population**  **0.000053 0.1**  **All Infants (< 1 year old) 0.000173**  **0.4 Children (1**  **- 2 years old)**  **0.000078 0.**  **2 Children (3**  **- 5 years old)**  **0.000073 0.2**  **Children (6 -**  **12 years old) 0.000051**  **0.1 Youth (13**  **- 19 years old)**  **0.000038 0.1**  **Adults (20 -**  **49 years old) 0.000049**  **0.1 Adults (50+ years old)**  **0.000052 0.1**  **Females (13 -**  **49 years old) 0.000049**  **0.1 Acute Aggregate Ex** **posure and Risk (food and water) The aggregate acute risk includes exposure of**  **Saflufenacil from food and water**  **(Table 5). The results demonstrate that there are no safety concerns for any subpopulation based on the proposed uses and the results meet the F**  **QP A standard**  **of reasonable certainty of no harm. Table 5.**  **Estimated Acute Aggregate Exposure and Risk of S aflufenacil**  **. Population Subgroup**  **Food Exposure**  **(mg/kg/day) Water** 

**Exposure (mg/kg/day)**  **Total**

**Exposure (mg/kg/day)**  **% aPAD U.S. Population**  **0.001313 0.000423**  **0.001736 0.03**  **All Infants (< 1 yr old) 0.002468**  **0.001535 0.004003**  **0.08 Children 1**  **- 2 years**  **0.003014 0.000664**  **0.003678 0.07**  **Children 3 -**  **5 years 0.002407**  **0.000607 0.003014**  **0.06 Children 6** 

**– 12 years**  **0.001485 0.000422**  **0.001907 0.04**  **Youth 13 -**  **19 ye ars**  **0.000949 0.000343**  **0.001292 0.03**  **Adults 20 -**  **49 years 0.000772**  **0.000392 0.001164**  **0.02 Adults + 50**  **0.000679 0.000354**  **0.001033 0.02**  **Females 13 -**  **49 years 0.001313**  **0.000423 0.001736**  **0.03**8

**aPAD = 5 mg/kg bw/day**

**Short -**  **and Intermediate -**  **Term Aggregate Exposu re and Risk (food, water, and**  **residential) Short** **- and intermediate**  **- term**  **aggregate risk assessments include exposure from food, water, and residential uses. There are no residential uses for S**  **aflufenacil ,**  **therefore, a short -**  **and intermediate -** **term aggregate risk assessment is not required.**  **Chronic Aggregate Exposure and Risk (food and water) The aggregate chronic risk includes exposure of S**  **aflufenacil from food and water**  **(Table 6). The results demonstrate there are no safety concerns for any subpopulation**  **based on the proposed uses and the results meet the FQPA standard of reasonable certainty of no harm.**  **Table 6. Estimated Chronic Aggregate Exposure and Risk of S**  **aflufenacil Population Subgroup**  **Food Exposure**  **(mg/kg/day) Water** 

**Exposure (mg/kg/day)**  **Total**

**Exposure (mg/kg/day)**  **% cPAD U.S. Population**  **0.000459 0.000053**  **0.000512 1.1**  **All Infants (< 1 yr old) 0.001051**  **0.000173 0.001224**  **2.7 Children 1**  **- 2 years**  **0.001537 0.000078**  **0.001615 3.5**  **Children 3 -**  **5 years 0.001196**  **0.000073 0.001269**  **2.8 Children 6** 

**– 12 year**  **s 0.000716**  **0.000051 0.000767**  **1.7 Youth 13**  **- 19 years**  **0.000413 0.000038**  **0.000451 1.0**  **Adults 20 -**  **49 years 0.000328**  **0.000049 0.000377**  **0.8 Adults + 50**  **0.000298 0.000052**  **0.000350 0.8**  **Females 13 -**  **49 years 0.000459**  **0.000053 0.000512**  **1.1 cPAD = 0.046 mg/kg bw/day**  **. ]**  2. Non

- dietary exposure

. **[ The term ‘‘residential exposure’’ is used to refer to**  **non -**  **occupational, non -**  **dietary exposure (e.g., for lawn and garden pest control, indoor pest control, termiticides, and flea and tick control on pets). Saflufenacil is**  **not registered for any specific use patterns that would result in residential exposure.**  **Therefore, a non -**  **dietary exposure and risk evaluation was not conducted.** D. Cumulative Effects **"Section 408(b)(2)(D)(v) requires that, when considering whether to esta** **blish, modify, or revoke a tolerance, the Agency consider “available information'' concerning the cumulative effects of a particular pesticide's residues**  **and “other substances that have a common mechanism of toxicity." EPA has not**  **found S**  **aflufenacil to sha re a common mechanism of toxicity with any other**  **substances, and S**  **aflufenacil does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance**  **petition , therefore, EPA**  **will**9

**assume that S**  **aflufenacil does not hav e a common mechanism of toxicity with**  **other substances**  **.** E. Safety Determination 1. U.S. population. **Based on the current risk assessments, EPA may conclude that there is a reasonable certainty that no harm will result to the general**  **population from aggr egate exposure to Saflufenacil residues**  **from the proposed uses.**  2. Infants and children

. **Based on the current risk assessments, EPA may conclude that there is a reasonable certainty that no harm will result to infants and**  **children from aggregate exposure to Saflufenacil residues**  **from the proposed uses.** F. International Tolerances **There are no Codex ma**  **ximum residue limits (MRLs) established for residues**  **of S**  **aflufenacil and its metabolites in crops or livestock commodities.**  **The residue definition and**  **har monized MRLs**  **are established**  **for residues of S**  **aflufenacil and its metabolites in similar crops**  **and livestock commodities**  **in Canada .**