EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE

PETITIONS PUBLISHED IN THE FEDERAL REGISTER ( 7 /1/200 7 )
( Saflufenacil

- Olive Tolerance Petition, J anuary 201 4 )

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

- 305

- 1243

BASF Corporation

4F8229

EPA has received a pesticide petition 4 F8229 from BASF Corporation , 26 Davis Drive, P.O. Box 135 28, 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 in or on t he raw agricultural plant commodit y olive at 0.03 parts per million (ppm)

. C ompliance with the plant commodity 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

- ({[(isopropylami no)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 FDDC A; 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. 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 adequate 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

-2

harvest/desiccant application

. An additional nature of residue study was also previously submitted with a postemergence application in rice as a representative monocot (grass) species . The metabolis m of Saflufenacil in plants following a postemergence application is similar to the metabolism of Saflufenacil in plants following a preplant/preemergence application. Therefore, t he residues of concern for the tolerance expression and risk assessment cons ist of Saflufenacil, M800H11, and M800H35.

2. Analytical method. Adequate enforcement methodology (liquid chromatography/mass spectrometry/mass spectrometry (LCMS/MS) methods for plant and livestock commodities are available to enforce the tolerance e xpression

.
3. Magnitude of residues. Field trials in the US were carried out to determine the magnitude of the residue following sequential postemergence

- directed application s of Saflufenacil made in olive trees . Field trials were carried out using the maximum label rate, the maximum number of applications, and the minimum pre

- harvest interval (PHI) for use in olive trees . Detected combined residues of Saflufenacil plus metabolites in the crop commodities support the proposed tolerances.

B. Toxicologi cal 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 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 effec ts 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 incre ased 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 hem atological 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.3

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 volume (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 h igher 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 mic e, 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 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 evidence of neurotoxicity, was seen in males and females.

There wa s no evidence of i mmu notoxity 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 re d 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 defectiv e 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 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 i n 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, with the majority eliminated within the first 24 to 48 h. There was a sex

- dependent d ifference 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 lo w - 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 remaini ng 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 urine and feces. There were no significant gender differences in metabolic profiles. S aflufenacil 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 Saf lufenacil 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 ha ve 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, developmenta l 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 c hronic 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 establishe d tolerances ; the proposed import tolerances for sugarcane, cane at 0.03 ppm, sugarcane, molasses at 0.075 ppm, and sugarcane, refined sugar at 0.045 ppm (pending EPA review, submitted July 2012) ; the proposed amended tolerance on rice commodities (pending EPA review, submitted December 2012) ; the propos ed amended tolerances on barley and wheat (pending EPA review, submitted June 2013); the proposed tolerances on forage grass commodities (pending EPA review, submitted July 2013); the proposed amended tolera nces in animal commodities (pending EPA review, submitted July 2013); and the proposed new tolerances on olive commodities

.
i. Food. Acute Dietary Exposure Assessment
Acute dietary exposure estimates were conducted using the curren tly established toler ances for S aflufenacil (40 CFR 180.649) ; the proposed import tolerances for sugarcane, cane at 0.03 ppm, sugarcane, molasses at 0.075 ppm, and sugarcane, refined sugar at 0.045 ppm (pending EPA review, submitted July 2012) ; the proposed amended tolerance o n rice commodities (pending EPA review, submitted December 2012) ; the proposed amended5

tolerances on barley and wheat (pending EPA review, submitted June 2013); the proposed tolerances on forage grass commodities (pending EPA review, submitted July 2013); the proposed amended tolerances in animal commodities (pending EPA review, submitted July 2013); and the proposed new tolerances on olive commodities. The assessment was conducted using tolerance values, default process factors, and 100% crop treatment fa ctors. 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 r esult 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 uncertainty f actors 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 0.004245 0.08
All Infants (< 1 year old) 0.005366 0.11
Children (1

- 2 years o ld) 0.008178 0.16
Children (3

- 5 years old) 0.00715 0.14
Children (6

- 12 years old) 0.005251 0.11
Youth (13

- 19 years old) 0.003346 0.07
Adults (20

- 49 years old) 0.003179 0.06
Adults (50+ years old) 0.002275 0.05
Females (13

– 49 years old) 0.002658 0.0 5

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 cr op treated values) would further reduce the estimated exposure values.6

Chronic Dietary Exposure Assessment

Chronic dietary exposure estimates were conducted using the currently established tolerances for Saflufenacil (40 CFR 180.649) ; the proposed import t olerances for sugarcane, cane at 0.03 ppm, sugarcane, molasses at 0.075 ppm, and sugarcane, refined sugar at 0.045 ppm (pending EPA review, submitted July 2012) ; the proposed amended tolerance on rice commodities (pending EPA review, submitted December 201 2) ; the proposed amended tolerances on barley and wheat (pending EPA review, submitted June 2013); the proposed tolerances on forage grass commodities (pending EPA review, submitted July 2013); the proposed amended tolerances in animal commodities (pending EPA review, submitted July 2013); and the proposed new tolerances on olive commodities

. The assessment was conducted using tolerance values, default process factors, and 100% crop treatment factors. The consumption data was from the USDA Continuing Surve y 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 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 uncertainty factors of 100X and with a FQPA safety factor of 1. The most highly expos ed population sub

- group was c hildren 1

- 2 years of age which utilized 9.7 % 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

Population Exposure Estimate %cPAD
Subgroups (mg/kg b.w./day)

U.S. Population 0.001592 3.5
All Infants (< 1 year old) 0.002049 4.5
Children (1

- 2 years old) 0.004472 9.7
Children (3

- 5 years old) 0.003711 8.1
Children (6

- 12 years old) 0.002515 5.5
Youth (13

- 19 years old) 0.001471 3.2
Adults (20

- 49 years old) 0.00134 2.9
Adults (50+ years old) 0.001113 2.4
Females (13

- 49 years old) 0.001167 2.57

The results of the analysis show that for all populations, the exposures are far below a level of con cern (< 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. Based on results from the PRZM

- GC and PRZM /EXAMS models estimates, the highe st acute Estimated Drinking Water Concentrations (EDWC ’s ) for S aflufenacil were estimated to be 111 ug/L (ppb) from ground water and th e highest chronic EDWC’s for S aflufenacil were estimated to be 73 ug/L (ppb) from ground water

. Drinking water exposure contributions were assessed based on the maximum estimated S aflufenacil water concentrations, and water consumption and body weights reported in CSFII, using DEEM

- FCID software. The acute and chronic estimated water exposure values are summarized in Tabl es 3 and 4, respectively. Drinking water exposure accounts for less than 1 % of the aPAD and up to 8.6 % 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 0.006053 0.12
All Infants (< 1 year old) 0.018957 0.38
Children (1

- 2 years old) 0.009333 0.19
Children (3

- 5 years old) 0.007573 0.15
Children (6

- 12 years old) 0.005786 0.12
Youth (13

- 19 years old) 0.005041 0.10
Adults (20

- 49 years old) 0.005956 0.12
Adults (50+ years old) 0.005306 0.11
Females (13

- 49 years old) 0.006041 0.128

Table 4. Results for S aflufenacil Chronic Water Exposu re 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 0.001529 3.3
All Infants (< 1 year old) 0.003941 8.6
Children (1

- 2 years old) 0.002205 4.8
Children (3

- 5 years old) 0.001858 4.0
Children (6

- 12 years old) 0.001340 2.9
Youth (13

- 19 years old) 0.001115 2.4
Adults (20

- 49 years old) 0.001525 3.3
Adults (50+ years old) 0.001508 3.3
Females (13

- 49 years old) 0.001519 3. 3

Acute Aggregate Exposure and Risk (food and water)
The aggregate acute risk includes exposure of Saflufenacil from food and water (Table 5). The result s demonstrate that the use of S aflufenacil does not result in an unacceptable acute risk.

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 0.004245 0.006053 0.01030 0.21
All Infants (< 1 yr old) 0.005366 0.0 18957 0.02432 0.49

Children 1

- 2 years 0.008178 0.009333 0.01751 0.35

Children 3

- 5 years 0.00715 0.007573 0.01472 0.299

Children 6

– 12 years 0.005251 0.005786 0.01104 0.22

Youth 13

- 19 years 0.003346 0.005041 0.00839 0.17

Adults 20

- 49 years 0.003179 0.0 05956 0.00914 0.18

Adults + 50 0.002275 0.005306 0.00758 0.15

Females 13

- 49 years 0.002658 0.006041 0.00870 0.17
aPAD = 5 mg/kg bw/day

Short

- and Intermediate

- Term Aggregate Exposure and Risk (food, water, and residential)

Short

- and intermediate

- term a ggregate 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 (foo d and water)
The aggregate chronic risk includes exposure of S aflufenacil from food and water (Table 6)

. The result s demonstrate that the use of S aflufenacil does not result in an unacceptable chronic risk.

Table 6. Estimated Chronic Aggregate Exposure an d 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 0.001592 0.001529 0.00312 6.8
All Infants (< 1 yr old) 0.002049 0.003941 0.00599 13.0

Children 1

- 2 years 0 .004472 0.002205 0.00668 14.5

Children 3

- 5 years 0.003711 0.001858 0.00557 12.1

Children 6

– 12 years 0.002515 0.001340 0.00386 8.4

Youth 13

- 19 years 0.001471 0.001115 0.00259 5.6

Adults 20

- 49 years 0.00134 0.001525 0.00287 6.2

Adults + 50 0.001113 0. 001508 0.00262 5.7

Females 13

- 49 years 0.001167 0.001519 0.00269 5.8
cPAD = 0.046 mg/kg bw/day.10

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 con trol, 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 establish, 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 share 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 have a common mechanism of toxicity with other substances.

E. Safety Determination

1. U.S. population. Based on the current risk assessments, BASF conclude s that the acute aggregate and the chronic aggregate exposure from the use of S aflufenacil does not result in an unacceptable risk.

2. Infants and children

. Based on the current risk assessments, BASF conclude s that the acute aggregate exposure and the chronic aggregat e exposure from the use of S aflufenacil does not result in an unacceptable risk.

F. International Tolerances

N ational maximum residue limits ( MRLs ) for Saflufenacil are available in a number of countries as referenced below.11

Codex CXL s for Saflufenacil are available for numerous plant and animal commodities (website reference: http://www.codexalimentarius.net/pestres/data/pesticides/details.html?id=251 );
Canadian MRLs for Saflufenacil (including its metabolites) are established and ha rmonized with US Tolerances for various crops and livestock commodities (website reference: http://pr

- rp.hc

- sc.gc.ca/mrl

- lrm/results

- eng.php )
Japanese MRLs for Saflufenacil are established for numerous plant and animal commodities (website reference: http ://www.m5.ws001.squarestart.ne.jp/foundation/agrdtl.php?a_inq=24250 )

S outh Korean MRLs for Saflufenacil are established for numerous plant commodities (website reference: http://fse.foodnara.go.kr/residue/pesticides/pesticides_mrl_korea_view.jsp?pesticide Code=P 01627 )
Australian MRLs for Saflufenacil are established for numerous plant and animal commodities (website reference: http://www.apvma.gov.au/residues/docs/mrl_table1_december_2012.pdf )

B razilian MRLs for Saflufenacil are established for a few plan t commodities (website reference: http://portal.anvisa.gov.br/wps/wcm/connect/db5a2c804b9a7f57afa2bfaf8fded4db/S16+

- +Saflufenacil.pdf?MOD=AJPERES )
An application for Saflufenacil MRLs in the European Union to support imported produce is currently under re view by EU Commission and EFSA

.