EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE 

PETITIONS PUBLISHED IN THE FEDERAL REGISTER

(7/1/2007)(Pomegranate Tolerance Petition, August 2014)

EPA Registration Division contact: Kathryn Montague, Herbicide Branch, Product 

Manager, Team 23, 703-305-1243

BASF Corporation

Petition 4F8305

EPA has received a pesticide petition (4F8305) 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 tolerances for residues of

Saflufenacil in or on the raw agricultural plant commodity pomegranate at 0.03 parts 

per million (ppm). Compliance with the 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(2H)-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(2H)-pyrimidinyl)-4-fluorobenzoyl]-N'-

isopropylsulfamide and N-[4-chloro-2-fluoro-5-({[(isopropylamino)sulfonyl]amino} 

carbonyl)phenyl]urea, calculated as the stoichiometric equivalent of Saflufenacil, in or 

on the commodities. 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 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 additional 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 residues of concern for the 

tolerance expression and risk assessment consist of Saflufenacil, M800H11, and 

M800H35.
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2. Analytical method. Adequate 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 preharvest 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 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 Saflufenacil 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 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 
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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 for 

Saflufenacil. 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 substancespecific 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 

liver effects) was 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, the 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 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, 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 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 significant gender differences in metabolic profiles. 

Saflufenacil was metabolized by three major transformation steps, which were 
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demethylation of the uracil ring system, degradation of the N-methyl-N-isopropyl 

group to NH2, 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 Saflufenacil

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 Saflufenacil 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 Saflufenacil and metabolites M800H11 and M800H35. The 

current established tolerance values are listed as of August 1 2014 in the U.S. 40 CFR 

§ 180.649. This analysis includes all the crops with established tolerances 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 (pending 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 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 

(pending EPA review, submitted March 2014); and the proposed new tolerances on 

pomegranate. 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 drinking water estimated 

concentrations were included directly into the acute dietary exposure analysis. 
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The resulting exposure estimates were compared against the Saflufenacil acute 

Population Adjusted Dose (aPAD) of 5 mg/kg b.w./day for all populations. This 

endpoint is based on the NOAEL of 500 mg/kg/day with the standard inter- and intraspecies uncertainty factors of 100X and an FQPA safety factor of 1. The exposure 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 Saflufenacil Acute Dietary Exposure Analysis Considering all 

Proposed Tolerances using DEEM-FCID at the 95th 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 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) 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 
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(pending EPA review, submitted March 2014); and the proposed new tolerances on 

pomegranate. 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 drinking water estimated 

concentrations were included directly into the chronic dietary exposure analysis. 

The chronic Population Adjusted Dose (cPAD) used for U.S. population and all subpopulations 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 exposed population sub-group was infants 

(< 1 year old) which utilized 18.5 % cPAD. The results of the chronic dietary 

assessment are presented in Table 2. 

Table 2. Results for Saflufenacil Chronic Dietary Exposure Analysis Considering all 

Proposed Tolerances using DEEM-FCID, food and drinking 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% 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.
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ii. Drinking water. [The drinking 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 Assessment in Support of 

Tolerances for Residues in/on Fish, Crayfish, and Imported Sugarcane”. The highest

Estimated Drinking Water Concentrations (EDWC’s) for Saflufenacil occurred with the 

rice use. The EDWCs used in the dietary exposure analysis were 133 μg/L (ppb) for 

acute risk assessment and 120 μg/L (ppb) for the chronic risk assessment. 

Acute Aggregate Exposure and Risk (food and water)

The aggregate acute risk includes exposure of Saflufenacil from food and water (Table 

1). The results demonstrate that the use of Saflufenacil does not result in an 

unacceptable acute risk.

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 registered or proposed residential uses for 

Saflufenacil 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 Saflufenacil from food and water 

(Table 2). The results demonstrate that the use of Saflufenacil does not result in an 

unacceptable chronic risk. 

2. Non-dietary exposure. The term ‘‘residential exposure’’ is used to refer to nonoccupational, 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 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 

Saflufenacil to share a common mechanism of toxicity with any other substances, and 

Saflufenacil does not appear to produce a toxic metabolite produced by other 

substances. For the purposes of this tolerance petition, therefore, EPA will assume 

that Saflufenacil does not have a common mechanism of toxicity with other 

substances.
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E. Safety Determination

1. U.S. population. Based on the current risk assessments, BASF concludes

that the acute aggregate and the chronic aggregate exposure from the use of 

Saflufenacil does not result in an unacceptable risk.

2. Infants and children. Based on the current risk assessments, BASF concludes

that the acute aggregate exposure and the chronic aggregate exposure from the use 

of Saflufenacil does not result in an unacceptable risk.

F. International Tolerances

National maximum residue limits (MRLs) for Saflufenacil are available in a 

number of countries as referenced below. 

Codex CXLs 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 

harmonized 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)

South Korean MRLs for Saflufenacil are established for numerous plant commodities

(website 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)

Brazilian MRLs for Saflufenacil are established for a few plant commodities (website 

reference: 

http://portal.anvisa.gov.br/wps/wcm/connect/db5a2c804b9a7f57afa2bfaf8fded4db/S16

+-+Saflufenacil.pdf?MOD=AJPERES)

European Union MRLs for Saflufenacil are established for numerous plant and animal 

commodities (website reference: 

http://ec.europa.eu/sanco_pesticides/public/?event=homepage)