EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS

PUBLISHED IN THE FEDERAL REGISTER ( 7 /1/200 7 ) (Rice Tolerance Petition, December 2012)

EPA Registration Division contact: Kathryn Montague , Herbicide Branch, Product Manager , Team 23, 703

- 305

- 1243

BASF Corporation

2F8129

EPA has received a pesticide petition ( 2F8129 ) 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 amending tolerance s for residues of Saflufenacil, including its metabolites and degradates, in or on the raw agri cultural commodities rice straw at 0.3 0 parts per million (ppm). Compliance with the tolerances levels is to be determined by measuring only the sum 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 commodit ies. 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

. Prev iously submitted metabolism data for corn, soybean, and
tomato and a confined rotational crop study are adequate to elucidate the nature of the2

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 following a preplant/preemergence application. Therefore, the residues of concern for the tolerance expression and risk assessment consist of Saflufenac il, 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 the US were carried out to determine the magnitude of the residue following sequential applications of Saflufenacil made preplant/preemergence followed by postemergence in rice . Field trials were carried out using the maximum label rates, the maximum number of applications, and the minimum pre

harvest interval (PHI) for use in both drill ed

- /dry

- seed ed rice and water

- seeded rice cultures

. Detected combined residues of Saflufenacil plus metabolites in the crop commodities support the proposed 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 activation; 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 developm ental toxicity. Increased fetal and offspring susceptibility
to S aflufenacil were observed in the developmental toxicity studies in the rat and rabbit and3

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 obse rved 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 an d 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 safluf enacil. Protoporphyrinogen oxidase inhibition in the mammalian species may result in disruption of heme synthesis which in turn causes anemia. In these studies, decreased hematological parameters (red blood cells (RBC), hematocrit (Ht), mean corpuscular vo lume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin 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 s pleen 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 throug h 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 first 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 gener al systemic toxicity and not a substance

- specific neurotoxic effect. In the subchronic neurotoxicity study, systemic toxicity (anemia), but no evidence of neurotoxicity, was seen in males and females.

There was no evidence of immunotoxity in the toxicity database for Saflufenacil. In the immunotoxicity study conducted in male mice, systemic toxicity (signs of anemia and liver4

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 hematopoietic 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 dos es. 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

rea ched within 1 hour (h) of dosing and declined rapidly after 24 h. Excretion 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 male rats was via the feces, while urinary excretion was the major route of elimination in females. The sex

- dependent excretion was more pronounced at the low

- dose level than at the h igh

- dose level. Also, males had significantly higher biliary excretion of Saflufenacil residues than females. Exhalation was not a relevant excretion pathway of Saflufenacil. At 168 h after dosing, Saflufenacil residues remaining in tissues were very lo w and occurred mainly in carcass, liver, skin, and gut
contents.

The parent molecule and 3 major metabolites were identified and isolated from urine and feces. There were no significant gender differences in metabolic profiles. Saflufenacil was metaboliz ed by three major transformation steps, which were demethylation of the uracil 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 toxicological 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 effect5

produced by a naturally occurring estrogen or other endocrine effects. However, there were no significant findings in other relevant toxicity studies (e.g., sub

- c hronic and chronic toxicity, developmental toxicity and multi

- generation reproductive studies) which would suggest that S aflufenacil produces any 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 M800H11 and M800H35. The current established tolerance values are listed in the U.S. 40 CFR § 180.649. Th is a nalysis include s all the crops with established tolerances , plus the proposed import tolerances (pending EPA review, submitted July 2012) for sugarcane, cane at 0.03 ppm, sugarcane, molasses at 0.075 ppm, and sugarcane, refined sugar at 0.045 ppm , plus the proposed amended tolerance values on rice commodities

.

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 import tolerances (pending EPA review, submitted July 2012) for sugarcane, cane at 0.03 ppm, sugarcane, molasses at 0.075 ppm, and sugarcane, refined sugar at 0.045 ppm, plus the proposed amended tolerance values on rice commodities

. The assessment was conducte d 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) usin g 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 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 1.6

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
Children (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 analysis 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 import tolerances (pending EPA review, submitted July 2012) for sugarcane, cane at 0.03 ppm, sugarcane, molas ses at 0.075 ppm, and sugarcane, refined sugar at 0.045 ppm, plus the proposed amended tolerance values on rice commodities . The assessment was conducted using tolerance values, default process factors, and 100% crop treatment factors. The consumption dat a 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.7

The chronic Population Adjusted Dose (cPAD) used for 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 hig hly expos ed population 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 Propose d Tolerances using DEEM

- FCID , food only

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 years 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 far 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

. All 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 concentrations8

oc curred from the Mississippi 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 est imated 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 ba sed on the maximum estimated 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, respectively. 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 Co ncentration using DEEM

- 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
Children (3

- 5 years old) 0.000607 0.01
Children (6

- 12 years old) 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

- FCID9

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 Exposure 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 FQPA 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 0.0610

Children 6

– 12 years 0.001485 0.000422 0.001907 0.04

Youth 13

- 19 years 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
aPAD = 5 mg/kg bw/day

Short

- and Intermediate

- Term Aggregate Exposure 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 years 0.000716 0.000051 0.000767 1.711

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. Ther efore, 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 establish, modify, or revoke a tolerance, the Agency consider “available information'' concern ing 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 share a common mechanism of toxicity with any other substances, and S aflufenacil does not app ear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance petition , therefore, EPA will assume that S aflufenacil does not have 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 aggregate exposure to Saflufenacil residues from the proposed uses.12

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 maximum residue limits (MRLs) established for residues of S aflufenacil and its metabolites in crops or livestock commodities. The residue definition and harmonized MRLs are established for residues of S aflufenacil and its metabolites in similar crops and livestock commodities in Canada

.