EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE 

PETITIONS PUBLISHED IN THE FEDERAL REGISTER (7/1/2007)

(Saflufenacil- Olive Tolerance Petition, January 2014)

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

Manager, Team 23, 703-305-1243

BASF Corporation

4F8229

EPA has received a pesticide petition 4F8229 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 tolerances for residues of Saflufenacil in or on the 

raw agricultural plant commodity olive 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 postemergencedirected at the base of plants underneath the leaf canopy application, and a pre-
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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 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 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 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 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. 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 bodyweight 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. 
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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 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 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 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 sexdependent 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. 
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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 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 in the U.S. 40 CFR § 180.649. This analysis includes all the crops 

with established 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 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.

i. Food.

Acute Dietary Exposure Assessment

Acute dietary exposure estimates were conducted using the currently established tolerances 

for Saflufenacil (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 on rice 

commodities (pending EPA review, submitted December 2012); the proposed amended 
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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 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 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 intra-species 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 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 old) 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 0.05

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.
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Chronic Dietary Exposure Assessment

Chronic dietary exposure estimates were conducted using the currently established 

tolerances for Saflufenacil (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 on rice 

commodities (pending EPA review, submitted December 2012); 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 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 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 children 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 Saflufenacil 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 2.5
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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 Saflufenacil 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 highest acute Estimated Drinking 

Water Concentrations (EDWC’s) for Saflufenacil were estimated to be 111 ug/L (ppb) from 

ground water and the highest chronic EDWC’s for Saflufenacil were estimated to be 73 

ug/L (ppb) from ground water. 

Drinking water exposure contributions were assessed based on the maximum estimated 

Saflufenacil 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 Tables 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 Saflufenacil 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 0.12
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Table 4. Results for Saflufenacil Chronic Water Exposure 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 results demonstrate that the use of Saflufenacil does not result in an unacceptable acute 

risk.

Table 5. Estimated Acute Aggregate Exposure and Risk of Saflufenacil. 

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 0.018957 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 0.29
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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 0.005956 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 aggregate risk assessments include exposure from food, 

water, and residential uses. There are no residential uses for Saflufenacil therefore a shortand 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 6). 

The results demonstrate that the use of Saflufenacil does not result in an unacceptable 

chronic risk.

Table 6. Estimated Chronic Aggregate Exposure and Risk of Saflufenacil

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. 
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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.

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. 
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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?pesticideCode=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)

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)

An application for Saflufenacil MRLs in the European Union to support imported produce 

is currently under review by EU Commission and EFSA.