**EPA REGISTRA** 

**TION DIVISION COMPA NY NOTICE OF FILING FOR PESTICIDE**  **PETITIONS PUBLISHED IN THE FEDERA L REGISTER**  **( 7**  **/1/200 7**  **)** ( Pomegranate Tolerance Petition, August 201 4 )

**EPA Registration**  **Division contact: Kathryn Montague**  **, Herbicide Branch,**  **Product Manager**  **, T**  **eam 23, 703**  **- 305**  **- 1243**  **BA SF Corporation**  **Petition 4F8305**

EPA has received a pesticide petition **( 4F8305**  **)** from **BA SF Corporation**  **, 26 Davis**  **Drive, P.O. Box 13528,**  **Research Triangle Park, North Carolina 27709 -**  **3528** proposing, pursuant to section 408(d) of the Fed eral Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180. 649 by establishing tolerance s for residues of **Saflufenacil in or on the raw agricultural**  **plant commodit** **y pomegranate**  **at 0.0**  **3 parts**  **per million (ppm)**
**. Compliance with th**  **e plant commodity**  **tolerances levels 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(2 H**  **) -**  **py rimidinyl]**  **- 4**  **- fluoro**  **- N** **- [[methyl(1**  **- methylethyl)amino]sulfonyl]benzamide, and its metabol**  **ites N** **- [2**  **- chloro**  **- 5**  **- (2,6**  **- dioxo**  **- 4**  **- (trifluoromethyl)**  **- 3,6**  **- dihydro**  **- 1(2**  **H )**  **- py**  **rimidinyl) -** **4 -** **fluorobenzoyl] -**  **N '**  **- isopropylsulfamide and**  **N -**  **[4 -**  **chloro -** **2 -** **fluoro -**  **5 -**  **({[(isopropylamino)sulfonyl]amino} carbonyl)phenyl]urea, calculated as the stoichiometric equivalent of Saflu**  **fenacil ,**  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 m etabolism

. **Previously submitted metabolism data for corn, soybean,**  **and tomato**  **, and a confined rotational c**  **rop 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**  **- harvest/desiccant application** 
**. An**  **add itional nature of residue study with a**  **postemergence application in rice as a representative monocot (grass) species showed metabolism**  **similar to the metabolism of Saflufenacil in plants following a preplant/preemergence application. Therefore, the residue**  **s of concern for the tolerance expression and risk assessment consist of Saflufenacil, M800H11, and**  **M800H35.**2

2. Analytical m ethod. **Ad equate enforcement methodology (liquid**  **chromatography/mass spectrometry/mass spectrometry (LC /**  **MS/ MS) methods**  **for plant and**  **livestock commodities are 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 postemergence**  **- directed applications of**  **Saflufenacil made in pomegranate 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 pomegranate trees. 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 derma**  **l 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**  **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**  **- we**  **ight gain,**  **and changes**  **in hematological**  **parameters were**  **observed at**  **a dose**  **resulting in**  **less severe**  **maternal toxicity**  **(de creased**  **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 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** 3

**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 d ogs. 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 ne**  **urotoxicity 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 ne**  **uropathological 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, w**  **as 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 liver effects) w**  **as seen, but the effects were not ind**  **icative 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 i n 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 r ats 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. Anim al m etabolism

. **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, with the majority eliminated wit**  **hin 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 high**  **- 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 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 si gnificant gender differences in metabolic profiles.**  **Saflufenacil was metabolized by three major transformation steps, which were**4

**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 aflu**  **fenacil 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 any endocrine disruption.**  C. Aggregate Exposure 1. Dietary exposure. **Exposure assessments were conducted to ev aluate**  **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**  **as of Au**  **gust 1 2014**  **in the U.S. 40 CFR § 180.649.**  **Th is**  **analysis include s**  **all the crops with established tolerances**  **and: 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**  **, submit ted July 2013); the proposed amended**  **tolerances in animal commodities (pending EPA**  **review, submitted July 2013); the**  **proposed tolerances on olive**  **commodities (pending EPA**  **review, submitted January 2014); the proposed**  **tolerances on alfalfa commodities (pend ing EPA review, submitted March 2014);**  **and the proposed new tolerances on**  **pomegranate**
**.** 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)**  **and: 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 (pendi ng EPA**  **review, submitted July 2013); the proposed tolerances on olive commodities (pending EPA**  **review , submitted January 2014);**  **the proposed tolerances on alfalfa commodities (pending EPA** 

**review, submitted March 2014); and the proposed new tolerances on**  **po megranate** 
**. 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 Co**  **mmodity Ingredient Database (FCID) using Exponent's Dietary Exposure Evaluation Module (DEEM**  **- FCID) software.**  **The drinking water estimated concentrations were included**  **directly into the acute dietary exposure analysis.** 5

**The result ing**  **exposure estimates w ere compared against the S**  **aflufen a**  **cil acute**  **Population A djusted Dose (aPA**  **D) of 5 mg/kg b.w./day for all populations. This endpoint is based on the NOA**  **EL of 5 00**  **mg/kg/day with the standard inter**  **- and intra**  **** **species uncertainty factors of 100X and an FQPA sa**  **fety factor of 1. The expos ure for**  **all sub**  **- population was less than**  **1.0 %**  **utilization of the aPA D. The results of the acute**  **dietary assessment are presented in Table 1. Table 1.**  **Results for S aflufenacil**  **Acute Dietary Exposure Analysis Considering all Prop**  **osed Tolerances using DEEM**
**- FCID at the 95**  **th Percentile**  **, food and drinking water** 



### Population **Exposure Estimate %aPAD**  **Subgroups (mg/kg b.w./day)**  **U.S. Population 0.008199**  **0.16** 

### All Infants (< 1 year old) **0.026256 0.53**  

### Children (1
**- 2 years old)**  **0.014271 0.**  **29** 

### Children (3
**- 5 years old)**  **0.011052 0.22**  

### Children (6
**- 12 years old)**  **0.008171 0.16**  

### Youth (13
**- 19 years old)**  **0.006825 0.14**  

### Adults (20
**- 49 years old)**  **0.007652 0.15**  

### Adults (50+ years old) **0.006909 0.14**  

### Females (13 **– 49 years old)**  **0.007849 0.16** 

**The result s of the analysis show that for all populations, the estimated exposures are**  **well below the A gency**  **'s level of concern (< 100% aPA**  **D). A dditional refinements in**  **the dietary risk assessment (i.e. utilizing anticipated residue values, percent crop treated val**  **ues) would further reduce the estimated exposure values. Chronic Dietary Exposure A**  **ssessment Chronic dietary exposure estimates were conducted using the currently established**  **tolerances for Saflufenacil (40 CFR 180.649) and: 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);**  **the proposed tolerances on olive commodities (pending EPA review**  **, submitted January 2014); the proposed tolerances on alfalfa commodities** 6

**(pending EPA**

**review, submitted March 2014); and the proposed new tolerances on**  **pomegranate**
**. The assessment was conduc**  **ted 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) usi**  **ng Exponent's Dietary Exposure Evaluation Module (DEEM**  **- FCID) software.**  **The drinking water estimated concentrations were included directly into the chronic dietary exposure analysis.**  **The chronic Population Adjusted Dose (cPA D) used for U.S. population a**  **nd all sub**   ** populations is 0.046 mg/kg bw/day. This endpoint is based on the NOA** **EL 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**  **inf ants**  **(< 1 year old) which utilized**  **18.5 % cP**  **AD . 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 and drin**  **king water**



### Population **Exposure Estimate %cPAD**  **Subgroups (mg/kg b.w./day)**  **U.S. Population 0.003105**  **6.8** 

### All Infants (< 1 year old) **0.008506 18.5**  

### Children (1
**- 2 years old)**  **0.005786 12.6**  

### Children (3
**- 5 years old)**  **0.004637 10.1**  

### Children (6
**- 12 years old)**  **0.003098 6.7**  

### Youth (13
**- 19 years old)**  **0.002347 5.1**  

### Adults (20
**- 49 years old)**  **0.002943 6.4**  

### Adults (50+ years old) **0.002867 6.2**  

### Females (13
**- 49 years old)**  **0.002923 6.4** 

**The results of the analysis show that for all populations, the exposures are far below a**  **level of concern (< 100% cPA**  **D). A dditional 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.** 7

**ii. Drinking**  **water**

**.** [**The drink ing water values used in this assessment were**  **from the most recent human health risk assessment conducted by US EPA on**  **January 23, 2014 ,**  **“Saflufenacil. Human -**  **Health Risk A ssessment in Support of**  **Tolerances for Residues in/on Fish, Crayfish, and Imported Su garcane”. The highest**  **Estimated Drinking Water Concentrations (EDWC ’s**  **) for S aflufenacil**  **occurred with the rice use. The EDWCs used in the dietary exposure analysis were 133**  **μ g/L (ppb)**  **for acute risk assessment and 120**  **μ g/L (ppb) for the chronic risk asse**  **ssment. Acute A** **ggregate Exposure and Risk (food and water) The aggregate acute risk includes exposure of**  **Saflufenacil from food and water (Table**  **1 ). The result** **s demonstrate that the use of S aflufenacil does not result in an**  **unacceptable acute risk. Shor**  **t -**  **and Intermediate -** **Term A ggregate 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**  **registered or proposed residential uses for**  **S aflufenacil**  **therefore a short -**  **and intermediate -** **term aggregate risk assessment is not required.**  **Chronic A ggregate Exposure and Risk (food and water)**  **The aggregate chronic risk includes exposure of S aflufenacil**  **from food and water (Table**  **2 )**  **. The result s de**  **monstrate that the use of S aflufenacil does not result in an**  **unacceptable chronic risk.** 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. Cum ulativ

e Effects **"Section 408(b)(2)(D)(v) requires that, when considering whether to establish, modify, or revoke a tolerance, the A** **gency consider “available information''**  **concerning the cumulative effects of a particular pesticide's residues and “other substanc**  **es 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.**8

E. Safety Determination 1. U.S. population. **Based on the current risk assessments, BA** **SF conclude**  **s that the**  **acute ag gregate 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, BA** **SF conclude**  **s that the**  **acute aggregate exposure and the chronic aggregat e exp**  **osure from the use of S**  **aflufenacil does not result in an unacceptable risk.**

F. International Tolerances **N ational**  **maximum residue limits (**  **MR Ls**  **) for Saflufenacil**  **are available in a number of countries as referenced below.**  **Codex CXLs for Saflufenacil are a**  **vailable for numerous plant and animal commodities (w**  **ebsite reference: http://www.codexalimentarius.net/pestres/data/pesticides/details.html?id=251**  **); Canadian MRLs for Saflufenacil (including its metabolites) are established and**  **harmonized with US Toleran ces 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.squarest** **art.ne.jp/foundation/agrdtl.php?a_inq=24250 )**  **S outh**  **Korean MRLs for Saflufenacil are established for numerous plant commodities (w**  **ebsite reference: http://fse.foodnara.go.kr/residue/pesticides/pesticides_mrl_korea_view.jsp?pesticideC**  **ode=P01627 )**  **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 plant commodities**  **(w ebsite**  **r eference:**  **http://portal.anvisa.gov.br/wps/wcm/connect/db5a2c804b9a7f57afa2bfaf8fded4db/S16 +**  **- +Saflufenacil.pdf?MOD=A**  **JPERES )**  **European Union MRLs for Saflufenacil are established for numerous plant and animal**  **commodities (website reference: http://ec.europa.**  **eu/sanco_pesticides/public/?event=homepage)**