Document ID: EPA-HQ-OPP-2010-1026-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2011-02-04T05:00Z

<COMPANY NOTICE OF FILING OF PETITION TO ESTABLISH IMPORT TOLERANCES FOR
SAFLUFENACIL>

<EPA Registration Division contact: Kathryn Montague, Herbicide Branch,
Product Manager, Team 23, 703-305-1243>

<BASF Corporation (PP 0E7806)>

<	EPA has received a pesticide petition (0F7806) 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 import tolerances for residues of saflufenacil,
including its metabolites and degradates, in or on the raw agricultural
commodities banana, whole fruit at 0.03 parts per million (ppm) and
coffee, green bean at 0.03 ppm and mango, fruit at 0.03 ppm. Compliance
with the tolerance 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>)-p
yrimidinyl]-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(2<H>)-pyrim
idinyl)-4-fluorobenzoyl]-<N'>-isopropylsulfamide and
<N>-[4-chloro-2-fluoro-5-({[(isopropylamino)sulfonyl]amino}carbonyl)phen
yl]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 or a postemergence-directed at the
base of plants underneath the leaf canopy. application. 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
D0603/02 (plants) and L0073/01 (livestock)) is available to enforce the
tolerance expression.>

<	3. Magnitude of residues. Field trials in Central and South America
were carried out to determine the magnitude of the residue following a
postemergence-directed spray at the base of plants underneath the leaf
canopy of Saflufenacil applied for weed control in banana, coffee and
mango plantations. The number and locations of field trials are in
accordance with OPPTS Guideline 860.1500. Field trials were carried out
using the maximum label rates, the maximum number of applications, and
the minimum pre-harvest interval (PHI) for each of the crops. Detected
combined residues of Saflufenacil plus metabolites in the crop 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>

<	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 tolerance values are listed in the U.S. 40 CFR
§ 180.649. This analysis includes all the crops with established
tolerances values as of November 2010, plus the proposed tolerance
values (pending EPA review, submitted June 2010 and July 2010 for
legumes vegetables crop subgroup 6C beans and peas, soybean, cotton, and
canola) plus the proposed tolerance values for banana, coffee and
mango.>

<	i. Food. 

Acute Dietary Exposure Assessment

Acute dietary exposure estimates were conducted using the currently
established tolerances for Saflufenacil (40 CFR 180.649), plus the
pending proposed tolerances for soybean, soybean hulls, legume
vegetables crop subgroup 6C dried shelled pea and bean (except soybean),
cotton undelinted seed, cotton gin byproducts, crop group 7 foliage of
legume vegetables group (based on pea vine data), crop group 20A
oilseeds rapeseed, plus the currently proposed tolerances for banana,
coffee, mango, and plus the higher residue levels in meat-by-products
(except liver) from goat, hog, sheep, horse, cattle, and liver from
cattle, goat, hog, sheep, and horse based on the re-calculation of the
feed burden containing feedstuffs with proposed tolerances.  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 uncertainity 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	0.001313	0.03

All Infants (< 1 year old)	0.002468	0.05

Children (1-2 years old)	0.003014	0.06

Children (3-5 years old)	0.002407	0.05

Children (6-12 years old)	0.001485	0.03

Youth (13-19 years old)	0.000949	0.02

Adults (20-49 years old)	0.000772	0.02

Adults (50+ years old)	0.000679	0.01

Females (13 – 49 years old)	0.000759	0.02

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 were conducted using the currently established
tolerances for Saflufenacil (40 CFR 180.649), plus the pending proposed
tolerances for soybean, soybean hulls, legume vegetables crop subgroup
6C dried shelled pea and bean (except soybean), cotton undelinted seed,
cotton gin byproducts, crop group 7 foliage of legume vegetables group
(based on pea vine data), crop group 20A oilseeds rapeseed, plus the
currently proposed tolerances for banana, coffee, mango, and plus the
higher residue levels in meat-by-products (except liver) from goat, hog,
sheep, horse, cattle, and liver from cattle, goat, hog, sheep, and horse
based on the re-calculation of the feed burden containing feedstuffs
with proposed tolerances.  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 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
uncertainity 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 3.3% 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	0.000459	1.0

All Infants (< 1 year old)	0.001051	2.3

Children (1-2 years old)	0.001537	3.3

Children (3-5 years old)	0.001196	2.6

Children (6-12 years old)	0.000716	1.6

Youth (13-19 years old)	0.000413	0.9

Adults (20-49 years old)	0.000328	0.7

Adults (50+ years old)	0.000298	0.6

Females (13-49 years old)	0.000321	0.7

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.  The highest water concentrations occurred from the
Mississippi corn scenario (model) from an aerial application at 0.134 lb
ai/A.  Based on results from the PRZM/EXAMS and SCI-GROW models
estimates, the highest acute Estimated Drinking Water Concentrations
(EDWC) for Saflufenacil were estimated to be 8.1 ug/L (ppb) in surface
water and 0.36 ug/L in ground water.  The highest chronic EDWC’s for
Saflufenacil were estimated to be 2.5 ug/L in surface water and 0.36
ug/L in ground water.  

Drinking water exposure contributions were assessed based on the maximum
estimated Saflufenacil water concentrations (acute 8.1 ug/L, chronic 2.5
ug/L), 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 1% 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	0.000423	0.01

All Infants (< 1 year old)	0.001535	0.03

Children (1-2 years old)	0.000664	0.01

Children (3-5 years old)	0.000607	0.01

Children (6-12 years old)	0.000422	0.01

Youth (13-19 years old)	0.000343	0.01

Adults (20-49 years old)	0.000392	0.01

Adults (50+ years old)	0.000354	0.01

Females (13-49 years old)	0.000394	0.01

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	0.000053	0.1

All Infants (< 1 year old)	0.000173	0.4

Children (1-2 years old)	0.000078	0.2

Children (3-5 years old)	0.000073	0.2

Children (6-12 years old)	0.000051	0.1

Youth (13-19 years old)	0.000038	0.1

Adults (20-49 years old)	0.000049	0.1

Adults (50+ years old)	0.000052	0.1

Females (13-49 years old)	0.000049	0.1

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 there are no safety
concerns for any subpopulation based on the proposed uses and the
results meet the FQPA standard of reasonable certainty of no harm.   

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

Population Subgroup	aPAD (mg/kg/day)	Food Exposure (mg/kg/day)	Water
Exposure (mg/kg/day)	Total Exposure (mg/kg/day)	% aPAD

U.S. Population	5	0.001313	0.000423	0.00174	0.03

All Infants (< 1 yr old)	5	0.002468	0.001535	0.00400	0.08

Children 1-2 years	5	0.003014	0.000664	0.00368	0.07

Children 3-5 years	5	0.002407	0.000607	0.00301	0.06

Children 6 – 12 years	5	0.001485	0.000422	0.00191	0.04

Youth 13-19 years	5	0.000949	0.000343	0.00129	0.03

Adults 20-49 years	5	0.000772	0.000392	0.00116	0.02

Adults + 50	5	0.000679	0.000354	0.00103	0.02

Females 13-49 years	5	0.000759	0.000394	0.00115	0.02

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 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 6). The results demonstrate there are no safety
concerns for any subpopulation based on the proposed uses and the
results meet the FQPA standard of reasonable certainty of no harm. 

Table 6. 	Estimated Chronic Aggregate Exposure and Risk of Saflufenacil 

Population Subgroup	cPAD (mg/kg/day)	Food Exposure (mg/kg/day)	Water
Exposure (mg/kg/day)	Total Exposure (mg/kg/day)	% cPAD

U.S. Population	0.046	0.000459	0.000053	0.00051	1.1

All Infants (< 1 yr old)	0.046	0.001051	0.000173	0.00122	2.7

Children 1-2 years	0.046	0.001537	0.000078	0.00162	3.5

Children 3-5 years	0.046	0.001196	0.000073	0.00127	2.8

Children 6 – 12 years	0.046	0.000716	0.000051	0.00077	1.7

Youth 13-19 years	0.046	0.000413	0.000038	0.00045	1.0

Adults 20-49 years	0.046	0.000328	0.000049	0.00038	0.8

Adults + 50	0.046	0.000298	0.000052	0.00035	0.8

Females 13-49 years	0.046	0.000321	0.000049	0.00037	0.8

]>

<	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, EPA may
conclude that there is a reasonable certainty that no harm will result
to the general population from aggregate exposure to Saflufenacil
residues from the proposed uses.>

<	2. Infants and children. Based on the current risk assessments, EPA
may conclude that there is a reasonable certainty that no harm will
result to infants and children from aggregate exposure to Saflufenacil
residues from the proposed uses.>

<F. International Tolerances>

<	There are no Codex maximum residue limits (MRLs) established for
residues of Saflufenacil and its metabolites in crops or livestock
commodities. The residue definition and harmonized MRLs are established
for residues of Saflufenacil and its metabolites in similar crops and
livestock commodities in Canada.>

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