EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS

PUBLISHED IN THE FEDERAL REGISTER (Crayfish Tolerance Petition )

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

- 305

- 1243
BASF Corporation

2F8139

EPA has received a pesticide petition (2F8139) from BASF Corporation , 26 Davis Drive, P.O. Box 13528, Research Triangle Park, North Carolina 27709

- 3528 proposing, pursuant to section 408(d) of t he 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 in or on the raw agricultural commodities crayfish at 0. 0 1 parts per million (ppm). C ompliance with the tol erances levels is to be determined by measuring only 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 , in or on the commodit ies. EPA has determined th at 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 d a ta at this time or whether the data supports granting of the petition. Add itional 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 adequate to elucidate the nature of the

re sidue 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
pos temergence 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.2

Therefore, t he residues of concern 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/M S) methods D0603/02 (plants) and L0073/01 (livestock)) is available to enforce the tolerance expression

.

3. Magnitude of residues. An accumulation in crayfish was c onducted to determine the magnitude of the residue in crayfish following sequential applic ations of Saflufenacil made preplant/preemergence followed by postemergence in rice . The study w as c onducted using the maximum label rates, the maximum number of applications, and the minimum pre

harvest interval (PHI) for use in rice . Detected residues of Saflufenacil in the edible crayfish commodit y support the proposed tolerance.

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 ac tivation. 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 r at 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, indicatin g 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

-3

weaning body weight and/or body

- weight gain, and changes in hematological parameters

were observed at a dose resulting in less sev ere 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 ch ronic toxicity studies in rats, mice, and dogs identified the hematopoietic system as the target organ of saflufenacil. Protoporphyrinogen oxidase inhibition in the mammalian species may result in disruption of heme synthesis which in turn causes anemia. I n these studies, decreased hematological parameters (red blood cells (RBC), hematocrit (Ht), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC)) were seen at about the same dose level acro ss 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 th e 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 hematop oiesis 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 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 general systemic toxicity and not a substance

- specific neurotoxic effect. In the subchronic neurotoxicity study, systemic toxicity (anemia), but no e vidence 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 hematopoietic system rather than to the immune system

.4

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. Excretion of orally dosed Saflufenacil was essentially complete within 96 h, wi th 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 o f 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. Exhalation was not a relevant excr etion 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 parent molecule and 3 major metabolites were identified and isolated from ur ine and feces. There were no significant gender differences in metabolic profiles. Saflufenacil was metabolized 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 tes ts 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 othe r relevant toxicity studies (e.g., sub

- chronic and chronic toxicity, developmental toxicity and multi

- generation reproductive studies) which would suggest that S aflufenacil produces any endocrine disruption.5

C. Aggregate Exposure

1. Dietary exposure. Ex posure 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 analysis 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 (pending EPA review, submitted December 2012) on rice commodities , and plus the proposed tolerance value on crayfish

.

i. Food. Acute Dietary Exposure Assessment
Acute dietary exposure est imates 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
sugarc ane, refined sugar at 0.045 ppm, plus the proposed amended tolerance (pending EPA review, submitted December 2012) on rice commodities, and plus the proposed tolerance value on crayfish

. 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 endpoint is based on the NOAEL of 5 00 mg/kg/day with the standard i nter

- 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. Result s 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 0.0 1
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. utili zing 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 Saflufen acil (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 (pending EPA review, submitted December 2012) on rice commodities, and plus the proposed tolerance value on crayfish

. 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.7

The chronic Population Adjusted Dose (cPAD) us ed 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 highly expos ed pop ulation 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 us ing 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 ar e 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.8

ii. Drinking wate r

. 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 concentrations occurred from the M ississippi 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 maximu m 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, r espectively. 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 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 yea rs 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 0.019

Table 4. Results for S aflufenacil Chronic Water Exposure Analysis Conside ring 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) 0.00007 8 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 th e 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 0.001 313 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 0.0710

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 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 Exp osure 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 aggreg ate 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 subpopulati on 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) Tot al

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 2.811

Children 6

– 12 y ears 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 n ot 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 es tablish, 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 s hare 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 assume that S aflufenacil does not h ave 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 ag gregate 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
exposu re 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 h armonized MRLs are established for residues of S aflufenacil and its metabolites in similar
crops and livestock commodities in Canada

.