EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS 

PUBLISHED IN THE FEDERAL REGISTER

(Alfalfa Tolerance Petition, March 2014)

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

Team 23, 703-305-1243

BASF Corporation

Petition# 4F8256

EPA has received a pesticide petition (4F8256) 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 alfalfa, forage at 0.075 parts per million (ppm) and alfalfa, 

hay at 0.10 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 preharvest/desiccant application. An additional nature of residue study with a postemergence 

application in rice as a representative monocot (grass) species showed metabolism similar to 
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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 (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 either a single postemergence application or sequential 

postemergence applications of Saflufenacil made in alfalfa. Field trials were carried out using 

the maximum label rates, the maximum number of applications, and the minimum preharvest interval (PHI) for use in alfalfa. 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 
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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 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 demethylation of the uracil ring 

system, degradation of the N-methyl-N-isopropyl group to NH2, and cleavage of the uracil ring, 
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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 March 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); and the 

proposed new tolerances on alfalfa commodities.

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); and the proposed new 

tolerances on alfalfa 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 drinking water estimated concentrations were 

included directly into the acute dietary exposure analysis. 

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.
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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); and the proposed new 

tolerances on alfalfa 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 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 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 
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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.

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)
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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.

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);
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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; in February 2014, EFSA published their Reasoned 

Opinion in favor of establishing EU MRLs for Saflufenacil commodities