Document ID: EPA-HQ-OPP-2014-0284-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2014-12-17T05:00Z

Interregional Research Project Number 4 (IR-4)

Petition #4E8248

	EPA has received a pesticide petition (4E8248) from Interregional
Research Project No. 4 (IR-4), 500 College Road East, Suite 201 W,
Princeton, NJ 08540  requesting, 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 by establishing a tolerance for residues of
S-metolachlor in or on the raw agricultural commodity lettuce at 1.5
parts per million (ppm), cucurbit vegetable crop group 9 at 0.50 ppm,
vegetable, fruiting, group 8-10, except tabasco pepper, low growing
berry subgroup 13-07G excluding cranberry at 0.40 ppm, and sunflower
subgroup 20B at 0.50 ppm and the concurrent deletion of the existing
tolerance for okra.  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. The qualitative nature of S-metolachlor residues
in plants is adequately understood for the purpose of the proposed
tolerances, based upon acceptable corn, potato and soybean metabolism
studies.  The metabolism of S-metolachlor involves conjugation with
glutathione, breakage of this bond to form the mercaptan, conjugation of
the mercaptan with glucuronic acid, hydrolysis of the methyl ether, and
conjugation of the resultant alcohol with a neutral sugar.  EPA has
determined that, for S-metolachlor, residues of concern in plants
include parent and metabolites, determined as the derivatives CGA-37913
and CGA-49751.

	2. Analytical method. Syngenta has developed and validated analytical
methodology for enforcement purposes.  A gas chromatography-nitrogen
phosphorus detection (GC/NPD) method has been submitted to the Agency
for determining residues in/on crop commodities and is published in PAM
Vol. II, Method I.  A gas chromatography-mass selective detection
(GC/MSD) method has been submitted to the Agency for determining
residues in livestock commodities and is published in PAM Vol. II,
Method II.  These methods determine residues of S-metolachlor and its
metabolites as either CGA-37913 or CGA-49751 following acid hydrolysis. 
An extensive database of method validation data using these methods on
various crop commodities is available.

	3. Magnitude of residues. Complete residue data to support the
requested tolerances are submitted or referenced with this petition. 
The residue studies were conducted per EPA Test Guidelines 860.1000 and
860.1500.

B. Toxicological Profile

	1. Acute toxicity.  The database for acute toxicity of S-metolachlor is
considered to be complete.  S-metolachlor is moderately acutely toxic
(toxicity category III) by the oral and dermal routes of exposure and
relatively non-toxic (toxicity category IV) by the inhalation route of
exposure.  It causes slight eye irritation (toxicity category III) and
is non-irritating dermally (toxicity category IV).  The active
ingredient was found to be positive in a dermal sensitization test but
this effect is mitigated in end-use product formulations.

	2. Genotoxicty. Gene mutation (Guideline 870.5100), micronucleus
(Guideline 870.5395) and unscheduled DNA synthesis (Guideline 870.5550)
studies conducted with S-metolachlor have been reviewed and approved by
EPA.  There is no evidence of a mutagenic or cytogenetic effect in vivo
or in vitro with S-metolachlor.

	3. Reproductive and developmental toxicity. Prenatal developmental
studies in the rat and rabbit with S-metolachlor revealed no evidence of
a qualitative or quantitative susceptibility in fetal animals.  No
significant developmental toxicity was observed in most studies even at
the highest dose tested.  In a two-generation reproduction study, there
was no evidence of parental or reproductive toxicity at the highest dose
tested (80 mg/kg/day).  The results indicate that S-metolachlor is not
embryotoxic or teratogenic in either species at maternally toxic doses.

	4. Subchronic toxicity. In a 90-day dietary study in rats with
S-metolachlor, no effects were observed in males or females at 209 and
236 mg/kg/day, respectively.  In another 90-day dietary study in rats,
decreased body weight, reduced food consumption and food efficiency in
both sexes and increased kidney weight gain in males was observed at 150
mg/kg/day; the NOAEL was 15 mg/kg/day.  A 90-day dog study with
S-metolachlor has been accepted by EPA; no effects were observed in
males and females at 62 mg/kg/day and 74 mg/kg/day, respectively, which
were the highest doses tested.

	5. Chronic toxicity. Chronic studies in both the rat and dog with
S-metolachlor revealed no significant chronic toxicity.  In the rat, a
decrease in body weight was observed at the highest dose tested.  In the
dog, the only adverse effect was decreased body weight gain in females
at 33 mg/kg/day; the NOAEL was 10 mg/kg/day.

	6. Animal metabolism. Animal metabolism studies have shown that
S-metolachlor is extensively absorbed, rapidly metabolized and almost
totally eliminated following oral administration in rats, goats and
poultry.  S-metolachlor was primarily absorbed from the gastrointestinal
tract and ultimately eliminated in the excreta of the species tested. 
Metabolism in animals proceeds through common Phase 1 intermediates and
glutathione conjugation.

	7. Metabolite toxicology. The metabolism of S-metolachlor has been well
characterized in standard FIFRA metabolism studies.  S-metolachlor does
not readily undergo dealkylation to form an aniline or quinone imine as
has been reported for other members of the chloroacetanilide class of
chemicals.  Therefore, as EPA has agreed, it is not appropriate to
include S-metolachlor with the group of chloroacetanilides that readily
undergo dealkylation, producing a common toxic metabolite (quinone
imine).  EPA has reviewed toxicology data submitted by Syngenta
demonstrating that the S-metolachlor metabolites ethane sulfonic acid
(CGA 354743) and oxanilic acid (CGA 51202) are not absorbed by mammalian
systems and/or have a significantly lower level of mammalian toxicity
when compared to parent.

	8. Endocrine disruption. S-metolachlor does not belong to a class of
chemicals known or suspected of having adverse effects on the endocrine
system.  There is no evidence that S-metolachlor has any effect on
endocrine function in developmental or reproduction studies. 
Furthermore, histological investigation of endocrine organs in the
chronic dog, rat and mouse studies did not indicate that the endocrine
system is targeted by S-metolachlor, even at maximally tolerated doses
administered for a lifetime.  There is no evidence that S-metolachlor
bioaccumulates in the environment.

C. Aggregate Exposure

	1. Dietary exposure. Acute (Tier I) and chronic (Tier II) dietary
exposure evaluations were made for S-metolachlor using the Dietary
Exposure Evaluation Model software with the Food Commodity Intake
Database (DEEM-FCID™, version 3.15).  DEEM-FCID software incorporates
food consumption data from the National Health and Nutrition Examination
Survey “What We Eat in America” (NHANES/WWEIA) dietary survey
conducted in 2003-2008.  These aggregate human health assessments
include all current and pending uses as well as proposed new IR-4 uses
on head lettuce, leaf lettuce, low-growing berries (Subgroup 13-07G),
cucurbits (Crop Group 9), and revised crop groupings for fruiting
vegetables (Group 8-10, except tabasco peppers), and sunflowers
(Subgroup 20B).  The acute exposure assessments were based on
established or proposed tolerances for S-metolachlor.  The chronic
exposure assessments were based on average field trial residues,
established tolerances, or market basket survey data (potato and
tomato).  The percent of crop treated (%CT) was assumed to be 100% for
all commodities.  Secondary residues in animal commodities were
estimated based on “maximum reasonably balanced dietary burdens” and
transfer information from metabolism and feeding studies.

	i. Food. Acute Risk.  The acute dietary risk assessments were performed
for all population subgroups with an acute reference dose of 3.0
mg/kg-bw/day based on an acute no observed adverse effect level (NOAEL)
of 300 mg/kg/day prenatal developmental toxicity study in rats and an
uncertainly factor of 100X.  The 100X safety factor includes intra- and
interspecies variations.  No additional FQPA safety factor was applied. 
The acute assessments were run using DEEM-FCID™ software using
established tolerances for S-metolachlor and 100% crop treated values. 
For the purpose of the aggregate risk assessments, the exposure values
were expressed in terms of margin of exposure (MOE), which was
calculated by dividing the NOAEL by the exposure for each population
subgroup.  In addition, exposures were expressed as a percent of the
acute reference dose (% aRfD).  Acute food exposure to the U.S.
population resulted in a MOE of 60,235 or 0.2% of the aRfD (Benchmark
MOE =100; aRfD = 3.0 mg/kg-bw/day).  Acute food exposure to the most
sensitive subpopulation (children 1 to 2 years old) resulted in a MOE of
26,373 or 0.4% of the aRfD (Benchmark MOE =100; 3.0 mg/kg-bw/day).  

Chronic Risk.  The chronic assessments were run using DEEM-FCID™
software using average field trial residue values, USDA-PDP residues,
SMBS data, and 100% crop treated values.  The chronic dietary risk
assessments were performed for all population subgroups with a chronic
reference dose of 0.1 mg/kg-bw/day based on a one-year feeding study in
dogs with a NOAEL of 9.7 mg/kg/day and an uncertainly factor of 100X. 
The 100-fold safety factor includes intra- and interspecies variations. 
No additional FQPA safety factor was applied.  For the purpose of the
aggregate risk assessments, the exposure values were expressed in terms
of margin of exposure (MOE), which was calculated by dividing the NOAEL
by the exposure for each population subgroup.  In addition, exposures
were expressed as a percent of the reference dose (% cRfD).  Chronic
food exposure to the U.S. population resulted in a MOE of 13,860 or 0.7%
of the cRfD (Benchmark MOE = 100; cRfD = 0.1 mg/kg-bw/day).  Chronic
food exposure to the most exposed sub-population (children, 1-2 years
old) resulted in a MOE of 5,829 or 1.7% of the cRfD (Benchmark MOE =
100; cRfD = 0.1 mg/kg-bw/day).  

Cancer.  S-metolachlor has been classified as a Group C, possible human
carcinogen based on the occurrence of liver tumors in rats.  The NOAEL
that was established based on tumors in rats (15 mg/kg/day) is
comparable to the NOAEL of 9.7 mg/kg/day selected for the chronic
reference dose.  Therefore the chronic dietary end point is protective
for cancer dietary exposure.

	ii. Drinking water. [The estimated drinking water concentrations
(EDWCs) for surface water and groundwater were taken from the First
Index Reservoir Screening Tool (FIRST), Pesticide Root Zone
Model/Exposure Analysis Modeling System (PRZM/EXAMS) and Screening
Concentration in Ground Water (SCI-GROW) models; as well as monitoring
data from two National Water Quality Assessment (NAWQA) programs.  The
maximum concentration of parent metolachlor / S-metolachlor detected in
a nationwide NAWQA surface water monitoring program (that did not
analyze for the degradates) was used as the peak surface water EDWC for
the acute assessment; the one-in-ten-year maximum annual average
PRZM/EXAMS concentration was used as the chronic surface water EDWC. 
For the metolachlor ethanesulfonic acid (ESA) and metolachlor oxanilic
acid (OA) metabolites, the one-in-ten-year maximum FIRST concentrations
were used as peak surface water EDWCs for the acute assessment;
one-in-ten-year annual averages were used as the chronic surface water
EDWCs.  Groundwater EDWCs for parent metolachlor / S-metolachlor and
the ESA metabolite were taken from the nationwide and Iowa / Illinois
NAWQA groundwater monitoring programs; maximum (upper bound) detections
were used for both acute and chronic groundwater EDWCs, since time
weighted means were not available.  For the OA metabolite, the SCI-GROW
concentration was used.

For surface water, the EDWCs of parent metolachlor / S-metolachlor and
its degradates were estimated to be 218.78 ppb (parent: 77.60 ppb, ESA:
47.61 ppb, and OA: 93.57 ppb) for acute exposure and 118.81 ppb (parent:
18.15 ppb, ESA: 34.04 ppb, and OA: 66.62 ppb) for chronic exposure. 
For ground water the EDWCs of parent metolachlor / S-metolachlor and its
degradates were estimated to be 126.2 ppb (parent: 32.8 ppb, ESA: 63.7
ppb, and OA: 29.7 ppb) for both acute and chronic exposure.

Acute Exposure from Drinking Water.  The acute EDWC of 218.78 ppb for
surface water was used in the DEEM-FCID™ software as “water, direct
and indirect, all sources” to model the acute drinking water
exposures.  The acute drinking water exposure contributions at the
95%-ile of exposures were determined by taking the difference between
the aggregate (food + drinking water) exposures and the food exposures
for each population subgroup.  Acute drinking water exposure to the
U.S. population resulted in an MOE of 29,101 or 0.3% of the aRfD
(Benchmark MOE = 100; aRfD = 3.0 mg/kg-bw/day).  Acute drinking water
exposure to the most exposed sub-population (infants, <1 year old)
resulted in an MOE of 9,465 or 1.1% of the aRfD (Benchmark MOE = 100;
aRfD = 3.0 mg/kg-bw/day).  

Chronic Exposure from Drinking Water.  The predicted chronic ground
water value of 126.2 ppb was input directly into the DEEM-FCID™
software as water, direct and indirect, all sources to model the chronic
drinking water exposure.  Chronic drinking water exposure to the U.S.
population resulted in an MOE of 3,677 or 2.6% of the cRfD (Benchmark
MOE = 100; cRfD = 0.1 mg/kg-bw/day).  Chronic drinking water exposure
to the most exposed subpopulation (infants, <1 year old) resulted in an
MOE of 1,426 or 6.8% of the cRfD (Benchmark MOE = 100; cRfD = 0.1
mg/kg-bw/day).  

	2. Non-dietary exposure. There is a potential for post-application
exposure to adults and children resulting from professionally-applied
treatments of S-metolachlor on residential lawns.  Post-application
exposure is considered to be short-term based on label directions
limiting application to one time per season.  Since toxicity was not
observed in a dermal toxicity study, up to a dose level of 1,000
mg/kg/day, the only parameter of short-term residential risk that needs
to be addressed is the possible oral exposure of toddlers and children
from treated turf or soil.  Using these exposure assumptions, the
short-term residential exposures from metolachlor/S-metolachlor resulted
in an aggregate MOE of 1,314 for children, 1-2 years.  Note that there
are no non-dietary contributions to the aggregate MOE for adults or
infants (<1 year) from turf uses since none of the oral exposure
scenarios (hand-to-mouth, object-to-mouth, soil ingestion) would be
applicable to these subpopulations.

D. Cumulative Effects

	Cumulative Exposure to Substances With a Common Mechanism of Toxicity. 
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”.  The EPA has examined the common
mechanism potential for S-metolachlor and has concluded that
S-metolachlor should not be included with the chloroacetanilide
pesticides designated as a “Common Mechanism Group.”  The Agency’s
position is that only some chloroacetanilides, namely acetochlor,
alachlor and butachlor should be considered as a “Common Mechanism
Group” due to their ability to cause nasal turbinate tumors.

E. Safety Determination

	1. U.S. population. Using the conservative assumptions described above,
and based on the completeness and reliability of the toxicity data, the
acute aggregate exposure calculation for all current, pending, and
proposed uses of S-metolachlor provided an MOE of 19,621 or 0.5% of the
aRfD (Benchmark MOE = 100; aRfD = 3.0 mg/kg-bw/day) for the U.S.
population.  The chronic aggregate exposure calculation for all current,
pending, and proposed uses of S-metolachlor provided an MOE of 2,906 or
3.3% of the cRfD (Benchmark MOE = 100; cRfD = 0.1 mg/kg-bw/day) for the
U.S. population.

	2. Infants and children. Using the conservative assumptions described
in the exposure section above, and based on the completeness and
reliability of the toxicity data, the acute aggregate exposure
calculation for all current, pending, and proposed uses of S-metolachlor
provided an MOE of 7,357 or 1.4% of the aRfD (Benchmark MOE = 100; aRfD
= 3.0 mg/kg-bw/day) for infants < 1 year old (the most sensitive
subpopulation for the acute assessment).  The short-term aggregate
assessment resulted in an MOE of 1,149 for the children (1-2 years old)
population subgroup (Benchmark MOE = 100).  The chronic aggregate
exposure calculation for all current, pending, and proposed uses of
S-metolachlor provided an MOE of 1,220 or 7.9% of the cRfD (Benchmark
MOE = 100; cRfD = 0.1 mg/kg-bw/day) for infants <1 year old (the most
sensitive subpopulation for the chronic assessment).

F. International Tolerances

	There are currently no Maximum Residue Limits (MRLs) set for
S-metolachlor for crops by the Codex Alimentarius Commission. 
International MRLs for the herbicide S-metolachlor have been established
for various agricultural commodities in a number of countries including
Argentina, Australia, Austria, Belarus, Belgium, Brazil, Canada, Czech
Republic, France, Georgia, Germany, Greece, Hungary, India, Italy,
Japan, Korea (South), Luxembourg, Malaysia, Moldova, Morocco,
Netherlands, New Zealand, Russia, Serbia and Montenegro, Slovak
Republic, Slovenia, Spain, Switzerland, Taiwan, and Ukraine.

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