Document ID: EPA-HQ-OPP-2014-0640-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-02-11T05:00Z

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)-pyr
imidinyl]-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)-pyrimidin
yl)-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.

	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 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 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 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, 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

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.   

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 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 (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 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 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)

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 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. 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);

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.j
sp?pesticideCode=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/db5a2c804b9a7f57afa2bfaf8fde
d4db/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)

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