Document ID: EPA-HQ-OPP-2011-0657-0006
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-08-15T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF	

CHEMICAL SAFETY AND

POLLUTION PREVENTION

Date: 	January 17, 2012

MEMORANDUM

SUBJECT:	S-Metolachlor. Human Health Risk Assessment for the Section 3
Requests for Use on Coriander (Cilantro) and Garden Beet Leaves.

PC Code:  108800	DP Barcode:  D396452

Decision No.:  451816	Registration No.: 100-816

Petition No.: 1E7898	Regulatory Action: Section 3

Risk Assessment Type: Single Chemical	Case No.: 0001

TXR No.:  NA	CAS No.: 87392-12-9

MRID No.:   NA	40 CFR:  180.368

FROM:	W. Cutchin, Chemist

Alternative Risk Integration Assessment Team (ARIA)

Inert Ingredients Assessment Branch (IIAB)

Registration Division (RD; 7505P)

THROUGH:	S. Hummel, Senior Scientist

		Registration Action Branch 4 (RAB4)

		Health Effects Division (HED; 7509P)

TO:	B. Madden, Risk Manager

	Minor Use and Emergency Response Branch

		RD (7505P)

RD of the Office of Pesticide Programs (OPP) has requested that ARIA
evaluate the Section 3 request for the use of the herbicide
S-metolachlor to control weeds on coriander (cilantro) and beet, garden,
leaves.

INTRODUCTION

Section 3 requests has been received from the Interregional Research
Project No.4 (IR-4), on behalf of the Agricultural Experiment Station of
IR-4 and the Agricultural Experiment Stations of New York, North
Carolina and South Carolina (coriander (cilantro)); and California,
Oklahoma, Texas and Tennessee (beet, garden, leaves), for use of the
herbicide S-metolachlor formulated as Dual Magnum® (EPA Reg. No.
100-816).

				Table of Contents  TOC \o "1-4" \h \z \u  

  HYPERLINK \l "_Toc313885193"  1.0  EXECUTIVE SUMMARY	  PAGEREF
_Toc313885193 \h  6  

  HYPERLINK \l "_Toc313885194"  2.0  DETAIL DISCUSSION	  PAGEREF
_Toc313885194 \h  12  

  HYPERLINK \l "_Toc313885195"  2.1  Proposed New Uses	  PAGEREF
_Toc313885195 \h  12  

  HYPERLINK \l "_Toc313885197"  2.2  Physical/Chemical Properties	 
PAGEREF _Toc313885197 \h  12  

  HYPERLINK \l "_Toc313885198"  3.0  HAZARD ASSESSMENT	  PAGEREF
_Toc313885198 \h  14  

  HYPERLINK \l "_Toc313885199"  3.1  Hazard Profile	  PAGEREF
_Toc313885199 \h  14  

  HYPERLINK \l "_Toc313885200"  3.2  FQPA Hazard Considerations	 
PAGEREF _Toc313885200 \h  15  

  HYPERLINK \l "_Toc313885201"  3.2.1  Developmental Toxicity	  PAGEREF
_Toc313885201 \h  15  

  HYPERLINK \l "_Toc313885202"  3.2.1.1  Rat Developmental Study –
Metolochlor	  PAGEREF _Toc313885202 \h  16  

  HYPERLINK \l "_Toc313885203"  3.2.1.1  Rabbit Developmental Study -
Metolochlor	  PAGEREF _Toc313885203 \h  16  

  HYPERLINK \l "_Toc313885204"  3.2.1.3  Rat Developmental Study –
S-Metolochlor	  PAGEREF _Toc313885204 \h  17  

  HYPERLINK \l "_Toc313885205"  3.2.1.4  Rabbit Developmental Study –
S-Metolochlor	  PAGEREF _Toc313885205 \h  17  

  HYPERLINK \l "_Toc313885206"  3.2.2  Reproductive Toxicity	  PAGEREF
_Toc313885206 \h  18  

  HYPERLINK \l "_Toc313885207"  3.2.3  Pre-and/or Postnatal Toxicity	 
PAGEREF _Toc313885207 \h  19  

  HYPERLINK \l "_Toc313885208"  3.2.4  Immunotoxicity	  PAGEREF
_Toc313885208 \h  19  

  HYPERLINK \l "_Toc313885209"  3.2.5  Neurotoxicity	  PAGEREF
_Toc313885209 \h  19  

  HYPERLINK \l "_Toc313885210"  3.2.6  FQPA Safety Factor	  PAGEREF
_Toc313885210 \h  19  

  HYPERLINK \l "_Toc313885211"  3.3  Toxicity Endpoint Selection	 
PAGEREF _Toc313885211 \h  20  

  HYPERLINK \l "_Toc313885212"  3.3.1  Acute Reference Dose (aRfD) -
General Population	  PAGEREF _Toc313885212 \h  20  

  HYPERLINK \l "_Toc313885213"  3.3.4  Dermal Exposure (Short-Term)	 
PAGEREF _Toc313885213 \h  22  

  HYPERLINK \l "_Toc313885214"  3.3.5  Inhalation Exposure (Short-Term)	
 PAGEREF _Toc313885214 \h  22  

  HYPERLINK \l "_Toc313885215"  3.3.6  Inhalation Exposure
(Intermediate-Term)	  PAGEREF _Toc313885215 \h  22  

  HYPERLINK \l "_Toc313885216"  3.3.7  Classification of Carcinogenic
Potential	  PAGEREF _Toc313885216 \h  23  

  HYPERLINK \l "_Toc313885217"  3.4  Margins of Exposure	  PAGEREF
_Toc313885217 \h  23  

  HYPERLINK \l "_Toc313885218"  3.5  Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc313885218 \h  23  

  HYPERLINK \l "_Toc313885219"  3.6  Summary of Endpoints Selected for
Risk Assessment	  PAGEREF _Toc313885219 \h  23  

  HYPERLINK \l "_Toc313885220"  3.7  Endocrine Disruption	  PAGEREF
_Toc313885220 \h  25  

  HYPERLINK \l "_Toc313885222"  4.0  RESIDUE CHEMISTRY CONSIDERATIONS	 
PAGEREF _Toc313885222 \h  25  

  HYPERLINK \l "_Toc313885223"  4.1  Metabolism in Plants/Livestock	 
PAGEREF _Toc313885223 \h  25  

  HYPERLINK \l "_Toc313885224"  4.2  Metabolism in Rotational Crops	 
PAGEREF _Toc313885224 \h  26  

  HYPERLINK \l "_Toc313885225"  4.3  Residue Analytical Methods	 
PAGEREF _Toc313885225 \h  27  

  HYPERLINK \l "_Toc313885237"  4.5  Residues in Processed Commodities	 
PAGEREF _Toc313885237 \h  29  

  HYPERLINK \l "_Toc313885238"  4.6  Residues in Rotational Crops	 
PAGEREF _Toc313885238 \h  29  

  HYPERLINK \l "_Toc313885239"  4.7  Drinking Water Profile	  PAGEREF
_Toc313885239 \h  29  

  HYPERLINK \l "_Toc313885242"  4.8  Dietary Exposure Analysis and Risk
Estimates	  PAGEREF _Toc313885242 \h  30  

  HYPERLINK \l "_Toc313885243"  5.0  NON-DIETARY, NON-OCCUPATIONAL
EXPOSURE	  PAGEREF _Toc313885243 \h  31  

  HYPERLINK \l "_Toc313885244"  6.0  AGGREGATE RISK	  PAGEREF
_Toc313885244 \h  32  

  HYPERLINK \l "_Toc313885245"  6.1  Acute Aggregate Risk	  PAGEREF
_Toc313885245 \h  32  

  HYPERLINK \l "_Toc313885246"  6.2  Short- & Intermediate-Term
Aggregate Risk	  PAGEREF _Toc313885246 \h  33  

  HYPERLINK \l "_Toc313885247"  6.3  Chronic Aggregate Risk	  PAGEREF
_Toc313885247 \h  33  

  HYPERLINK \l "_Toc313885248"  6.4  Cancer Aggregate Risk	  PAGEREF
_Toc313885248 \h  33  

  HYPERLINK \l "_Toc313885249"  7.0  OCCUPATIONAL EXPOSURE AND RISK	 
PAGEREF _Toc313885249 \h  34  

  HYPERLINK \l "_Toc313885260"  9.0  CONCLUSION	  PAGEREF _Toc313885260
\h  37  

  HYPERLINK \l "_Toc313885261"  10.0  DATA NEEDS	  PAGEREF _Toc313885261
\h  38  

  HYPERLINK \l "_Toc313885262"  10.1  Toxicology Data Requirements	 
PAGEREF _Toc313885262 \h  38  

  HYPERLINK \l "_Toc313885263"  10.2  Residue Chemistry Data
Requirements	  PAGEREF _Toc313885263 \h  38  

  HYPERLINK \l "_Toc313885264"  10.3  Occupational/Residential
Requirements	  PAGEREF _Toc313885264 \h  38  

  HYPERLINK \l "_Toc313885265"  References	  PAGEREF _Toc313885265 \h 
38  

 

1.0  EXECUTIVE SUMMARY

General Information

Metolachlor (PC Code 108801) is a racemic herbicide that consists of 50%
each of the R-enantiomer and the S-enantiomer which is the herbicidally
active isomer.  S-metolachlor (PC Code 108800) is an isomer enriched
formula comprised of 88% S-isomer and 12% R-isomer.  Permanent
tolerances are established at 40 CFR §180.638(a)(2) for S-metolachlor
in/on a variety of crop commodities, at levels ranging from 0.02 in/on
meat and dairy products to 20 ppm in/on peanut hay and includes
Brassica, leafy greens, subgroup 5A at 1.8 ppm and spinach at 0.5 ppm. 
Compliance with the tolerance levels is determined by measuring only the
sum of free and bound S-metolachlor,
S-2-chloro-N-(2-ethyl-6-methylphenyl)-N-(2-methoxy-1-methylethyl)acetami
de, its R-enantiomer, and its metabolites, determined as the
derivatives, 2- [(2-ethyl-6- methylphenyl)amino]-1-propanol (CGA-37913)
and 4-(2-ethyl-6-methylphenyl)-2- hydroxy-5-methyl-3-morpholinone
(CGA-49751) calculated as the stoichiometric equivalent of
S-metolachlor.  S-metolachlor is a selective, chloroacetanilide
herbicide used primarily for grassy weed control in many agricultural
food and feed crops, residential lawns, commercial turf (including golf
courses, sports fields, recreation areas, and sod farms), ornamentals
and horticultural nurseries.  S-metolachlor formulations include
emulsifiable and flowable concentrates, granular, and ready-to-use
products.  Application methods for agricultural uses include ground,
aerial, irrigation and chemigation.  Applications of S-metolachlor to
residential lawns or turf are limited to professional applicators using
backpack, hose-end, or handgun sprayers.   

IR-4 has proposed the use of the herbicide S-metolachlor formulated as
Dual Magnum® (EPA Reg. No. 100-816) on coriander (cilantro) as a
broadcast, foliar application (0.64-0.96 lbs ai/A) at 30 days before the
leaf harvest and 70 days before seed and on beets grown for leaves as a
broadcast, pre-emergence soil surface treatment at 0.63 -1.26 lbs ai/A
after the crop has been planted but before the crop and weeds emerge.  A
second application of S-metolachlor to beets may be made as one post
emergence, broadcast treatment at 0.63 -1.26 lbs ai/A when plants are at
1 to 2 true leaf stage.  

Toxicology

The existing toxicological database is primarily comprised of studies
conducted with metolachlor.  However, bridging studies indicate that the
metolachlor toxicology database can be used to assess toxicity for
S-metolachlor.  The toxicology database for S-metolachlor, when combined
with the metolachlor database, is complete for risk assessment purposes.
 However, neurotoxicity (870.6200 a and b) and immunotoxicity studies
(870.7800) are required in accordance with the revised 40 CFR Part 158
Toxicology Data Requirements.

S-Metolachlor exhibits low acute toxicity via the oral (Toxicity
Category III), inhalation (Toxicity Category IV), and dermal (Toxicity
Category III) routes of exposure.  It causes slight eye irritation, and
is non-irritating dermally but is a dermal sensitizer.  In subchronic
(metolachlor and S-metolachlor) and chronic (metolachlor) toxicity
studies in dogs and rats decreased body weight and body weight gain were
the most commonly observed effects.  No systemic toxicity was observed
when metolachlor was administered dermally.  No neurotoxicity studies
with metolachlor or S-metolachlor are available.  However, there was no
evidence of neurotoxic effects in the available toxicity studies. 
Prenatal developmental studies in the rat and rabbit with both
metolachlor and S-metolachlor revealed no evidence of a qualitative or
quantitative susceptibility in fetal animals.  A two-generation
reproduction study with metolachlor in rats showed no evidence of
parental or reproductive toxicity.  The FQPA safety factor was reduced
to 1X because there are no residual uncertainties with regard to pre-
and/or postnatal toxicity.  There was no evidence of mutagenic or
cytogenetic effects in vivo or in vitro. Metolachlor has been classified
as a Group C, possible human carcinogen based on liver tumors in rats at
the highest dose tested.  No cancer potency factor has been established,
as risks established based on the chronic reference dose are protective
of cancer effects.

Dose Response Assessment

Toxicological endpoints were selected for dietary/drinking water,
occupational and residential exposure scenarios.  An acute reference
dose (RfD) for assessment of food and drinking water exposures was
selected from a developmental toxicity study in rats.  A chronic RfD was
selected from a chronic toxicity study in dogs.  A point of departure
(POD) for dermal exposure was not selected because no dermal or systemic
toxicity was seen in rabbits following repeated dermal application at
the highest dose tested for 21 days.  An inhalation exposure POD was
selected from a developmental toxicity study in rats.  An uncertainty
factor of 100X was applied to endpoints selected for exposure routes
(10x for interspecies extrapolation, 10x for intraspecies variation).   

  

Acute Dietary			 aPAD = 3.0 mg/kg/day

(General Population)

Chronic Dietary	 		cPAD = 0.97mg/kg/day

(All Populations)

	

Cancer (all routes) 		Group C carcinogen

Incidental Oral Short-term 	NOAEL=50 mg/kg/day

	(1-30 days)

	Inhalation Short-Term 		NOAEL=50 mg/kg/day

	(1-30 days)

	Inhalation Short-Term 		NOAEL=8.8 mg/kg/day

(1-30 days)

Residue Chemistry

The qualitative nature of metolachlor residues in plants is adequately
understood.  Residues of concern in plants, livestock, and rotational
crops include metolachlor and its metabolites, determined as the
derivatives CGA-37913 and CGA-49751.  The Agency previously concluded
that the residues of concern for S-metolachlor are the same as for
metolachlor.  The residues of concern for S-metolachlor in drinking
water include the parent, CGA-354743 (metolachlor ethanesulfonic acid
(ESA)) and CGA-51202 (metolachlor oxanilic acid (OA)).

Adequate methodology is available for enforcing the established and
recommended tolerances.  PAM Vol. II, Pesticide Regulation Section
180.368, lists a gas chromatography with nitrogen-phosphorus detector
(GC/NPD) method (Method I) for determining residues in/on plant
commodities and a gas chromatography with mass selective detector
(GC/MSD) method (Method II) for determining residues in livestock
commodities.  These methods determine residues of metolachlor and its
metabolites as either CGA-37913 or CGA-49751 following acid hydrolysis. 
Adequate data are also available on the recovery of metolachlor through
FDA’s Multiresidue Method Testing Protocols which indicate that
metolachlor is completely recovered through Method 302.  IR-4 and
Syngenta have proposed a high pressure liquid chromatography with mass
spectroscopy/mass spectroscopy (HPLC/MS/MS) enantiomer-specific method
for the enforcement of the proposed tolerances, Method 1848-01.  The
method uses a chiral HPLC column to separate out the S-enantiomers
(SYN506357 and SYN508500) of the hydrolysis products CGA-37913 and
CGA-49751.  This method has been determined to be adequate for
enforcement purposes.

Coriander (cilantro) fresh, dried and seed samples were analyzed using
“Working Method for PR 09595: Analysis of s-Metolachlor in Cilantro as
Metabolites s-CGA-37913 (SYN-506357) and s-CGA-49751 (SYN-508500),” a
modification of Syngenta Method No. 1848-01.  Samples of the raw
agricultural commodities, leaves and stems, and seed were refluxed in
acid and partitioned into dichloromethane (DCM).  An aliquot was
purified with column chromatography and concentrated into aqueous
acetonitrile.  The lower limit of method validation (LLMV) for residues
of SYN 506357 and SYN 508500 was 0.05 ppm in all matrices.  Based on the
LLMV, the calculated limits of detection (LOD) ranged from 0.0132-0.0175
ppm for SYN 506357 and SYN 508500 in coriander (cilantro) fresh, dried
and seed samples.  The calculated limits of quantitation (LOQ) ranged
from 0.0359-0.0526 ppm for SYN 506357 and SYN 508500 in coriander
(cilantro) fresh, dried and seed samples, respectively.  The method is
adequate for data collection.

Previously submitted storage stability data indicates that the residues
of metolachlor are stable on a variety of commodities for up to 2 yrs. 
Coriander (cilantro) fresh leaves and stems, dried leaves and stems and
seed samples were stored frozen for a maximum of 708 days, 702 days, and
416 days, respectively.  The results of the storage stability study with
coriander (cilantro) samples and previously submitted storage stability
data are adequate to show that residues of S-metolachlor were stable for
the duration of this study.

There are no coriander (cilantro) or garden beet leaf livestock feed
items of regulatory interest; therefore, a discussion of S-metolachlor
residues on livestock food items is not germane to this petition.

The submitted coriander (cilantro) study is adequate in number and
geographic location of the residue field trials.  At all sites, two
plots received a single broadcast application of S-metolachlor at the
approximate rate of 0.64 lb ai/A or 0.96 lb ai/A.  Coriander (cilantro)
fresh leaf and stem samples were harvested approximately 30 (27-34) days
pre-harvest interval (PHI), after the application and placed into frozen
storage shortly after harvest.  At one site, additional treated plots
received a single broadcast application of S-metolachlor at the
approximate rate of 0.64 lb ai/A or 0.96 lb ai/A, where coriander
(cilantro) seed were collected.  At another site, additional treated
plots received a single broadcast application of S-metolachlor at the
approximate rate of 0.64 lb ai/A or 0.96 lb ai/A, and coriander
(cilantro) leaves and stems were collected at 27 days and dried in an
oven.  No spray adjuvant was used at the trials.  No residue decline
studies were submitted.

The analytical results show that after a single foliar broadcast
application of S-metolachlor at the approximate rate of 0.64 lb ai/A and
0.96 lb ai/A with a 27 to 34-days PHI, the maximum total S-metolachlor
residues as parent equivalents were approximately 3.7 ppm and 4.1 ppm in
coriander (cilantro) fresh leaves and stems, respectively.  The maximum
total S-metolachlor residues as parent equivalents were increased from
approximately <0.131 ppm (fresh samples) to 0.834 ppm (dried samples) in
the 0.64 lb ai/A treated plot.  The maximum total S-metolachlor residues
as parent equivalents were increased from approximately 0.170 ppm (fresh
samples) to 2.031 ppm (dried samples) in the 0.96 lb ai/A treated plot. 
The maximum total S-metolachlor residues as parent equivalents were
<0.131 ppm in coriander (cilantro) seed at both application rates. 
Based on the results of these trials, the appropriate tolerance for
residues of S-metolachlor in/on coriander (cilantro) leaves is 8.0 ppm. 
However, the Agency uses the preferred name coriander not cilantro for
this raw agricultural commodity and, in addition, does not differentiate
between dry and fresh leaves for coriander (cilantro).  Therefore, a
revised Section F should be submitted to indicate a request for
coriander, leaves at 8.0 ppm and the cilantro dried and fresh leaves
should be removed.  The study data indicates that the requested
tolerance on coriander, seed at 0.13 ppm is adequate.  

No new data have been submitted in support of the requested tolerance on
beet, garden, leaves.  The request is based on the currently established
tolerance for residues of S-metolachlor on Brassica leafy vegetables
(Sub-group 5B), of 1.8 ppm.  The Chemistry Science Advisory Council
(ChemSAC) has considered the issue and determined that since the use
pattern for beet greens is the same as that for leafy Brassica (sub
group 5B), and beet greens are similar to the commodities in the leafy
Brassica subgroup 5B, it is appropriate to translate this tolerance of
1.8 ppm to beet greens.  Based on the CHEMSAC determination and that the
proposed use pattern for beet, garden, leaves is the same as leafy
Brassica greens, subgroup 5B, ARIA recommends for the proposed tolerance
of 1.8 ppm on beet, garden, leaves.

There is no crop associated with this petition which requires residue
data for processed fractions.  

The rotational crop restrictions listed on the label are appropriate for
these proposed uses.

Drinking Water

Environmental fate data indicate that parent metolachlor/S-metolachlor
is moderately persistent to persistent.  It is mobile to highly mobile
in different soils and has been detected extensively in surface water
and groundwater.  Major degradates identified in groundwater include
metolachlor ethanesulfonic acid (ESA) and metolachlor oxanilic acid (OA)
in both groundwater and surface water.  Environmental Fate and Effects
Division (EFED) calculated conservative, Tier I Estimated Drinking Water
Concentrations (EDWCs) of metolachlor and S-metolachlor in ground water
and surface water for use in the last human health risk assessment. 
Since there are existing uses of S-metolachlor with higher application
rates than the proposed Section 3 uses, those EDWCs will not increase. 
EDWCs for metolachlor and S-metolachlor were calculated for both the
parent compound, metolachlor ESA and metolachlor OA degradates (see
metabolites table, Appendix 1).  EDWCs were calculated using drinking
water models PRZM/EXAMS and FIRST for surface water and SCIGROW for
ground water.  Current NAWQA monitoring data was also used to determine
EDWCs.  Based on monitoring and modeling data, total EDWCs for peak and
average surface water respectively are 219 ppb and 119 ppb.  Recommended
groundwater EDWCs (peak and average) are 126 ppb.

Dietary Exposure

For acute and non-cancer chronic exposures, ARIA is concerned when
estimated dietary risk exceeds 100% of the population adjusted dose
(PAD).  S-metolachlor is classified as a Group C carcinogen, so no
separate dietary assessment was performed for cancer.  For acute and
chronic dietary exposures an unrefined assessment was conducted,
assuming 100% crop treated, and tolerance level residues.  The acute and
chronic dietary risk estimates are below the Agency’s level of concern
for the general U.S. population and all population subgroups with the
most highly exposed subgroups being all infants (<1 year old) at 1.5% of
the acute PAD (aPAD) and 11.6% of the chronic PAD (cPAD). 

Non-Dietary, Non-Occupational Exposure

There are no residential user exposures for the proposed new use of
S-metolachlor for this Section 3 assessment.  However, there is
potential for residential exposure to S-metolachlor from use of other
registered products which are applied to residential lawns or turf by
professional applicators.  Therefore, the only potential short-term
residential risk scenario anticipated is post-application exposure of
children playing on treated lawns.  S-metolachlor incidental oral
exposure is assumed to include hand-to-mouth exposure, object-to-mouth
exposure and exposure through incidental ingestion of soil.  The
residential exposure to toddlers for this scenario was calculated to be
0.046 mg/kg/day resulting in an MOE of 1100.  Based on this analysis,
the short-term oral MOEs are not of concern.

Aggregate Risk

The aggregate acute and chronic risk estimates include exposure to
residues of S-metolachlor in food and drinking water, and does not
include dermal, inhalation or incidental oral exposure.  Since the
dietary exposure assessment already includes the highest acute and
chronic exposures from the drinking water modeling data, no further
calculations are necessary.  The acute and chronic risk estimates for
all populations, resulting from aggregate exposure to S-metolachlor in
food and drinking water is below ARIA’s level of concern.  The food
and drinking water exposure estimates for the most highly exposed
subgroup, all infants (< 1 year old), is 1.5% of the aPAD and 11.6% of
the cPAD.

There are no residential user exposures for the proposed new use of
S-metolachlor for this Section  3 assessment.  No intermediate-term risk
scenarios are anticipated for the existing and proposed uses of
S-metolachlor.  However, there is potential for short-term residential
exposure to S-metolachlor from use of other registered products which
are applied to residential lawns or turf by professional applicators via
post-application exposure to children playing on treated lawns including
hand-to-mouth exposure, object-to-mouth exposure and exposure through
incidental ingestion of soil.  Results from that assessment have been
used to assess aggregate risk from exposure to food, drinking water, and
residential lawns.  Based on this analysis, short-term aggregate MOE of
860 for toddlers is not of concern.

As estimated risks are calculated based on the chronic reference dose
are protective of cancer effects, no separate cancer risk assessment is
necessary.  

Occupational Exposure

The occupational exposure scenario of mixing, loading, and applying
S-metolachlor as an herbicide on crops has been assessed.  The proposed
uses may result in short-/intermediate-term (i.e., 1-30 days or up to 6
months) dermal and inhalation exposures during mixing, loading,
applying, and postapplication activities.  Long-term exposures (i.e., 6
months of continuous exposure) are not expected to occur based on the
proposed use pattern.  Dermal toxicological endpoints of concern were
not identified (i.e., no systemic toxicity was seen following dermal
exposure at the limit dose) therefore, no dermal exposures were
calculated.  Short- and intermediate-term exposures from inhalation
exposure routes were assessed for all exposure scenarios.  Occupational
and residential exposure and risk estimates were conducted using maximum
application rates and surrogate exposure data.  Based on the Agency's
current practices, a quantitative postapplication inhalation exposure
was also not assessed.  

Data from Occupational Pesticide Handler Unit Exposure Surrogate
Reference Table, which summarizes data from the Pesticide Handlers
Exposure Database (PHED) was used to assess handler and post-application
exposures in the absence of chemical-specific data.  At the baseline
level, all inhalation MOEs are above the target MOE of 100, thus, risks
are not of concern.  The handler exposure estimates in this assessment
are based on a central tendency estimate of unit exposure and an
upper-percentile assumption for the application rate, and thus assumed
to represent high-end exposures.  The uncertainties associated with this
assessment stem from the use of surrogate exposure data (e.g.,
differences in use scenario and data confidence), and assumptions
regarding the amount of chemical handled.  The estimated exposures are
believed to be reasonable high-end estimates based on observations from
field studies and professional judgment.  

Use of Human Studies

This risk assessment relies in part on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical.  These studies have been determined to require a review of
their ethical conduct.  Some of these studies are also subject to review
by the Human Studies Review Board.  All of the studies used have
received the appropriate review.

Environmental Justice

Potential areas of environmental justice concerns, to the extent
possible, were considered in this human health risk assessment, in
accordance with U.S. Executive Order 12898, "Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations,"   HYPERLINK
"http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf" 
http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

Conclusion

Pending resolution of the toxicology and residue chemistry concerns
outlined in Section 10 below, ARIA has no concerns regarding human
health exposure and risk from the proposed Section 3 use of
S-metolachlor on coriander and garden beet leaves.

2.0  DETAIL DISCUSSION

2.1  Proposed New Uses

S-metolachlor is to be applied to coriander (cilantro) formulated as
Dual MAGNUM (EPA Reg. No.: 100-816) as a broadcast, foliar application
(0.64-0.96 lbs ai/A) at 30 days before the leaf harvest and 70 days
before seed.  Use the lower end of S-metolachlor rate range for soils
that are relatively coarse textured and the higher rates on fine
textured soils.  Apply S-metolachlor to beets grown for leaves as a
broadcast, pre-emergence soil surface treatment at 0.63 -1.26 lbs ai/A
after the crop has been planted but before the crop and weeds emerge.  A
second application of S-metolachlor to beets may be made as one post
emergence, broadcast treatment at 0.63 -1.26 lbs ai/A when plants are at
1 to 2 true leaf stage.  Use the lower end of S-metolachlor rate range
for soils that are relatively coarse textured and the higher rates on
fine textured soils.

	2.2  Physical/Chemical Properties 

Table 2.2.a  Nomenclature of S-Metolachlor and its Regulated Hydrolytic
Derivatives.

Compound

 - CGA-37913

Common name	None

Company experimental names	SYN506357 (S-enantiomer of CGA 37913)

Chemical name	2-[(2-ethyl-6-methylphenyl) amino]-1-propanol

CAS registry number	61520-53-4

 - CGA-49751

Common name	None

Company experimental names	CGA-49751

SYN508500 (S-enantiomer of CGA 49751)

Chemical name	4-(2-ethyl-6-methylphenyl)-2-hydroxy-5-methyl-3-morpholine

CAS registry number	61520-54-5

Table 2.2.b  Physicochemical Properties of the Technical Grade Test
Compound

Parameter	Value	Reference

Melting point/boiling point	N/A	Registration Division: Physical and
Chemical Characteristics

(DP Num: 225258)

UV/visible absorption spectrum λmax	Neutral:	534 L/mol•cm @ 266.4 nm

	443 L/mol•cm @ 274.4 nm

Acidic:	534 L/mol•cm @ 266.4 nm

	444 L/mol•cm @ 274.4 nm

Basic:	531 L/mol•cm @ 266.4 nm

	411 L/mol•cm @ 274.4 nm

	

3.0  HAZARD ASSESSMENT

3.1  Hazard Profile

The existing toxicological database is comprised primarily of studies
conducted with metolachlor.  Metabolism studies were inadequate for
comparing the metabolic pathways of metolachlor and S-metolachlor. 
However, based on a comparison of the findings in toxicity studies with
both chemicals, S-metolachlor is considered to be of comparable toxicity
to metolachlor and data can be bridged between the two compounds.  The
metolachlor toxicology database is complete.  The combined metolachlor
and S-metolachlor toxicity data bases are adequate to characterize the
toxicity of S-metolachlor for risk assessment purposes.  

	

In subchronic oral studies on metolachlor, the only evidence of toxicity
was decreased body weight/body weight gain in rats and dogs in both
sexes.  There was no evidence of systemic toxicity at the limit dose in
a 21 day dermal toxicity metolachlor study in rabbits, however dermal
irritation was observed at lower doses.  In the chronic dog study on
metolachlor, the only adverse effect was decreased body weight gain in
females.  

In the mouse carcinogenicity study, possible treatment-related deaths in
females and decreased body weight/body weight gain in both sexes were
observed.  In the rat combined chronic toxicity/ carcinogenicity study,
decreased body weight gain and food consumption were observed.  There
was no evidence of carcinogenicity in mice; however, there were
statistically significant increases in liver adenomas and combined
adenomas/carcinomas in female rats.  In male rats, there was a
statistically significant trend but no pair-wise significance for liver
tumors.  There was no evidence of a mutagenic or cytogenetic effect in
vivo or in vitro in studies with either metolachlor or S-metolachlor. 
Metolachlor has been classified as a Group C carcinogen with risk
quantitated using a non-linear (Margin of Exposure (MOE)) approach.  

There was no evidence of increased quantitative or qualitative fetal
susceptibility in the prenatal developmental studies in rats and rabbits
with either metolachlor or S-metolachlor.  In general, significant
developmental toxicity was not seen in rats or rabbits with either
compound.  In the metolachlor rabbit prenatal developmental toxicity
study, maternal animals had persistent anorexia and decreased body
weight gain.  There were no developmental effects.  In the rat prenatal
developmental toxicity study on metolachlor, death, clinical signs
(clonic and/or tonic convulsions, excessive salivation, urine-stained
abdominal fur and/or excessive salivation) and decreased body weight
gain was observed at the limit dose in maternal animals.  Developmental
effects at the limit dose included slightly decreased number of
implantations per dam, decreased number of live fetuses/dam, increased
number of resorptions/dam and significant decrease in mean fetal body
weight.  In the S-metolachlor rat study, maternal toxicity, including
increased clinical signs (pushing head through bedding), and decreased
body weight/weight gain, food consumption and food efficiency, was
observed at the mid-dose.  There were no developmental effects at the
highest dose tested.  In the rabbit, clinical signs of toxicity
(little/none/soft stool) were observed at the mid-dose in maternal
animals tested with S-metolachlor.  No developmental effects were
observed at the highest dose tested.

In the two-generation reproduction study in rats conducted with
metolachlor, there was no evidence of parental or reproductive toxicity
at the highest dose tested (80 mg/kg/day). At this dose, there was a
minor decrease in fetal body weight beginning at lactation day 4.  Since
a similar body weight decrease was not seen on lactation day 0, the
cause of the effect on later lactation days is most likely due to
exposure of the pups to metolachlor in the diet and/or milk and
therefore is not evidence of an increased quantitative susceptibility in
post-natal animals.

Both compounds are extensively absorbed and metabolized following oral
administration. Elimination is via the urine and feces. Tissue residues
were highest in red blood cells.  

	

Neurotoxicity battery (870.6200 a and b) and immunotoxicity studies
(870.7800) are required in accordance with the revised 40 CFR Part 158
Toxicology Data Requirements. 

3.2  FQPA Hazard Considerations

The toxicity database for S-metolachlor/metolachlor is sufficient for a
full hazard evaluation and is considered adequate to evaluate risks to
infants and children.  Acceptable developmental toxicity studies in the
rat and rabbit and an acceptable reproduction study in the rat are
available.  Based on the results of the available toxicity studies,
there is no evidence for neurotoxicity or immunotoxicity.  However, in
accordance with the revised 40 CFR Part 158 Toxicology Data
Requirements, neurotoxicity battery (870.6200) and immunotoxicity
(870.7800) studies are required.

3.2.1  Developmental Toxicity 

3.2.1.1  Rat Developmental Study – Metolochlor

In a prenatal developmental toxicity study (MRID 00151941), metolachlor
(96.4% ai) in 0.5% (w/v) aqueous hydroxymethylcellulose was administered
by gavage (10 mL/kg) to 25 presumed pregnant BR rats from gestation days
(GD) 6 through 15, inclusive, at dose levels of 0, 30, 100, 300 or 1000
mg/kg/day.  The animals were sacrificed on GD 20 and the fetuses
examined for evidence of developmental effects.

There were four treatment-related deaths in animals treated at 1000
mg/kg/day.  Clinical signs of toxicity, including clonic and/or toxic
convulsions, excessive salivation, urine-stained abdominal fur and/or
excessive lacrimation, were observed in animals treated at 1000
mg/kg/day.  There was also an increase in excessive salivation in the
300 mg/kg/day group.  However, as this effect was most likely due to
gastric irritation and there was no other evidence of treatment-related
toxicity, the finding is not considered toxicologically significant. 
Body weight gain was significantly decreased in the 1000 mg/kg/day group
during GD 6-16, GD 6-20and GD 0-20.  Food consumption was not affected. 
In the 1000 mg/kg/day group, there were a slightly decreased number of
implantations per dam, decreased live fetuses/dam and increased number
of resorptions/dam.  There was also a statistically significant decrease
in mean fetal body weight.

The maternal toxicity LOAEL was 1000 mg/kg/day based on an increased
incidence of death, clinical signs of toxicity (clonic and/or toxic
convulsions, excessive salivation, urine- stained abdominal fur and/or
excessive lacrimation) and decreased body weight gain. The NOAEL was 300
mg/kg/day.  The developmental toxicity LOAEL was conservatively
established at 1000 mg/kg/day based on slightly decreased number of
implantations per dam, decreased number of live fetuses/dam, increased
number of resorptions/dam and significant decrease in mean fetal body
weight.  The NOAEL was 300 mg/kg/day.

3.2.1.1  Rabbit Developmental Study - Metolochlor

In a prenatal developmental toxicity study (MR1D 00041283), metolachlor
(95.4% ai) in 0.75% aqueous hydroxy methylcellulose was administered by
gavage to 16 pregnant New Zealand White rabbits/group from gestation
days (GD) 6 through 18, inclusive, at dose levels of 0, 36, 120 or 360
mg/kg/day.  The animals were sacrificed on GD 30 and the fetuses
examined for evidence of developmental effects.

One doe at 36 mg/kg/day and another at 360 mg/kg/day died on GDs 24 and
29, respectively.  The cause of death in both animals was attributed to
persistent anorexia.  Two rabbits aborted, one at 120 mg/kg/day (GD 25)
and another at 360 mg/kg/day (GD 17).  The high-dose animal had
persistent anorexia.  One rabbit in each group delivered prior to GD 30;
the control, low- and high-dose animals on GD 29 and the mid-dose animal
on GD 30.  There was a treatment-related increase in the incidence of
persistent anorexia in the does treated at 360 mg/kg/day, which was
defined as less than one-half of the daily food allotment consumed. 
However, food consumption data were not provided to support this
finding.  There was a treatment-related decrease in body weight gain in
the 360 mg/kg/day group for GD 6-18 and GD 6-30.  There was no
treatment-related increase in gross pathological findings in maternal
animals at necropsy.  No treatment-related increase in external,
visceral or skeletal developmental effects were observed. 

The maternal toxicity LOAEL was 360 mg/kg/day based on an increased
incidence of clinical observations (persistent anorexia) and decreased
body weight gain.  The NOAEL was 120 mg/kg/day.  The developmental
toxicity LOAEL was not established.  The NOAEL was 360 mg/kg/day.

3.2.1.3  Rat Developmental Study – S-Metolochlor

In a developmental (teratology) study (MRID# 43928925), rats (Strain:
Tif: RAI f (SPF)) received either 0, 5, 50, 500, or 1000 mg/kg/day
S-metolachlor (95.6% ai) suspension in 0.5% (w/w) aqueous solution of
sodium carboxymethylcellulose by oral gavage from gestation days 6
through 15.

No treatment related mortality was noted.  There was a dose related
increase in clinical signs seen as all 500 and 1000 mg/kg/day animals
and 9/24 of the 50mg/kg/day animals exhibited as pushing head through
bedding for about one hour.  This was noted throughout the dosing period
and may be an indication of neurotoxicity.  The 500 and 1000 mg/kg/day
dose groups had lower overall body weights at gestation days 15 and 21
and gained less weight than the control during the dosing period
(gestation days 6-16) and for the calculated periods of gestation days
6-21 and 0-21, also for corrected body weight gains from gestation days
6-21.  Also the 500 and 1000 mg/kg/day dose groups had reduced food
consumption during the dosing period (gestation days 6-16, statistically
significantly different), reduced food consumption following the dosing
period and for the overall periods (gestation days 6-21 and 0-2 1). 
This is also reflected in reduced food efficiency for the same periods
(6-16, 6-21, 6-21, and 0-21). 

The maternal toxicity NOEL was 50 mg/kg/day with a LOEL of 500 mg/kg/day
based on increased clinical signs of toxicity, decreased body weights
and body weight gains and reduced food consumption and reduced food
efficiency.  No significant treatment related developmental toxicity was
noted at the dose levels tests.  The developmental toxicity was equal to
or greater than 1000 mg/kg/day, a LOEL was not reached. 

3.2.1.4  Rabbit Developmental Study – S-Metolochlor

In a developmental (teratology) study (MRID# 43928924), female New
Zealand White. S.P.F. Rabbits received either 0, 20, 100, or 500
mg/kg/day S-metolachlor (89.6% ai (93.7% S isomer)) suspension in 3%
corn starch by oral gavage from gestation days 7 through 19. 

No treatment related mortality was noted.  There was a dose related
increase in the 500 mg/kg/day dose group had lower overall body weights
at gestation days 19, 29 and corrected body weights at day 29 gained
less weight than the control during the dosing period (gestation days
7-19) with a rebound weight gain following the dosing period (gestation
days 19-29), an indicator of toxicity.  This group also had lower
overall weight gain for the calculated periods of gestation days 7-29,
0-29 and corrected body weight gains for 0-29.  This was supported by
reduced little/none/soft stool observations at the 100 and 500 mg/kg/day
dose levels, food consumption during the dosing period (gestation days
7-19) and for the overall periods (gestation days 7-28 and 0-28) with a
rebound in food consumption following dosing (gestation days 19-28) at
the 500 mg/kg/day dose level.  This is also reflected in reduced food
efficiency for the same periods (719, 7-28, and 0-28) and increased food
efficiency following dosing (19-28) at the 500 mg/kg/day dose level. 
The maternal toxicity NOEL was 20 mg/kg/day with a LOEL of 100 mg/kg/day
based on clinical signs of toxicity.

No significant treatment related developmental toxicity was noted at the
dose levels tests.  The developmental toxicity was equal to or greater
than 500 mg/kg/day, a LOEL was not reached.

3.2.2  Reproductive Toxicity 

In a two-generation reproduction study (MRID 00080897), metolachlor
(95.4% ai) was administered in the diet to two consecutive generations
of 15 male/30 female CD albino rats at dose levels of 0, 30, 300 or 1000
ppm (F0 males: 0,2.4,23.5 and 75.8 mg/kg/day; F0 females: 0, 2.5, 26.0
and 85.7 mg/kg/day; F1males: 0, 2.3, 23.7 and 76.6 mg/kg/day; F1
females: 0, 2.6, 25.7 and 84.5 mg/kg/day).

There were no deaths in the F0 generation.  Two females of the F1
generation died during the premating period, one in the 300 ppm group at
32 days and the other in the 1000 ppm group at 52 days.  One female in
the 300 ppm group was found dead on gestation day 19 and a control group
female was sacrificed in a moribund condition on lactation day 1.  Based
on necropsy examinations, none of the deaths was treatment-related.
There were no treatment-related clinical signs of toxicity in either
generation.  Body weight, body weight gain and food consumption were
unaffected in the F0 generation.  In the F1 generation, food consumption
was significantly decreased in females of the 1000 ppm group at several
time points; however, there was no effect on body weight/body weight
gain.  Therefore, this finding was not considered toxicologically
significant.  There were no treatment-related effects on organ weights
or gross/microscopic necropsy examinations in either generation.

There was no evidence of a treatment-related effect on any of the
reproductive parameters for either generation.  Offspring body weight
was significantly decreased in the F1 litter on lactation days 14 and
21(91-96% of control value) and in the F, litter on lactation days 4, 7,
14 and 21 (92 - 95% of control value).  Although the magnitude of the
decrease is small, the finding is regarded as toxicologically
significant.

The parental toxicity LOAEL was not established.  The NOAEL was 1000 ppm
(F0 males/females: 75.8/85.7 mg/kg/day; F1males/females: 76.6/84.5
mg/kg/day).  The reproductive toxicity LOAEL was not established. The
NOAEL was 1000 ppm (F0 males/females: 75.8/85.7 mg/kg/day;
F1males/females: 76.6/84.5 mg/kg/day).  The offspring LOAEL was
conservatively established at 1000 ppm (F0 males/females:  75.8/85.7
mg/kg/day; F1males/females: 76.6/84.5 mg/kg/day) based on decreased body
weight in F1 and F2 litters.  The NOAEL is 300 ppm (F0 males/females:
23.5/ 26.0 mg/kg/day; F1males/females: 23.7/25.7 mg/kg/day).

3.2.3  Pre-and/or Postnatal Toxicity

The database is considered adequate for selection of study endpoints and
determination of a dose/response to characterize the potential prenatal
or postnatal toxicity of metolachlor or S-metolachlor to infants and
children.  No increase in susceptibility was seen in developmental
toxicity studies in rat and rabbit or reproductive toxicity studies in
the rat.  Toxicity to offspring was observed at dose levels the same or
greater than those causing maternal or parental toxicity.  Based on the
results of developmental and reproductive toxicity studies, there is not
a concern for increased qualitative and/or quantitative susceptibility
following in utero exposure to metolachlor or S-metolachlor. 

3.2.4  Immunotoxicity

There are no indications in the available studies that organs associated
with immune function, such as the thymus and spleen, are affected by
metolachlor or S-metolachlor.  There are no effects seen on the
developing immune system in the existing studies.  An immunotoxicity
study is required, however, under 40 CFR Part 158 as a part of the new
data requirements for registration of a pesticide (food and non-food
uses).

3.2.5  Neurotoxicity

There is no evidence in the toxicology database that metolachlor or
S-metolachlor is neurotoxic.  In the rat developmental toxicity study
with S-metolachlor (MRID 43928925), 6/24 animals in the 1000 mg/kg/day
group and 3/24 in the 500 mg/kg/day group were described as exhibiting
discomfort (pushing head through bedding for one hour after each dose);
the sign was first observed after the initial treatment.  No control
animals were affected. In the rat prenatal developmental toxicity study
with metolachlor, clinical signs of clonic and/or tonic convulsions and
excessive salivation, possible neurotoxic signs, were observed at 1000
mg/kg/day.  However, the signs were prior to death in some of the
treated animals and could be agonal effects.  Acute and subchronic
neurotoxicity studies (870.6200) are required in accordance with the
revised 40 CFR Part 158 Toxicology Data Requirements.  

3.2.6  FQPA Safety Factor

There is low concern (and no residual uncertainty) for pre- and/or
postnatal toxicity resulting from exposure to S-metolachlor.  Data
available on metolachlor and S-metolachlor provided no indication of
increased susceptibility (quantitative or qualitative) to rats or
rabbits exposed in utero.  The metolachlor rat reproduction study showed
no evidence of reproductive toxicity.  The dietary exposure from food
and water and residential exposure are not understated.  Therefore, the
special FQPA safety factor is reduced to 1x for risk assessment for this
chemical.  A developmental neurotoxicity study is not required since
there was no evidence of neurotoxicity or neuropathology from the
available studies and there is no concern or residual uncertainty for
pre/post-natal toxicity.  Based on the results of the available toxicity
studies, there is no evidence for immunotoxicity.

  

Since there are adequate developmental studies in rats and rabbits and
an adequate multi-generation study in rats, and no residual
uncertainties in toxicity or exposure databases that indicate the need
for a factor, the FQPA factor has been reduced to 1X.  

3.3  Toxicity Endpoint Selection

3.3.1  Acute Reference Dose (aRfD) - General Population

Selected Study: Developmental Toxicity in Rats - Metolachlor (MRID
00151941).  

In a prenatal developmental toxicity study with metolachlor on rats, the
maternal toxicity LOAEL was 1000 mg/kg/day based on an increased
incidence of death, clinical signs of toxicity (clonic and/or toxic
convulsions, excessive salivation, urine- stained abdominal fur and/or
excessive lacrimation) and decreased body weight gain.  The NOAEL was
300 mg/kg/day.  The developmental toxicity LOAEL was conservatively
established at 1000 mg/kg/day based on slightly decreased number of
implantations per dam, decreased number of live fetuses/dam, increased
number of resorptions/dam and significant decrease in mean fetal body
weight. The NOAEL was 300 mg/kg/day.

Dose and Endpoint for Establishing an aRfD:  300 mg/kg/day based on a
NOAEL of 1000 mg/kg/day and an LOAEL of 1000 mg/kg/day based on an
increased incidence of death, clinical signs of toxicity (clonic and/or
tonic convulsions, excessive salivation, urine-stained abdominal fur
and/or excessive lacrimation) and decreased body weight gain.  

Uncertainty Factor (UF): 100 – 10x for interspecies extrapolation and
10x for intraspecies variation.

Comments about Study/Endpoint:  Since clinical signs are observed after
a single oral dose of metolachlor, the duration and route of
administration are appropriate for the risk assessment.  Developmental
effects observed are not attributable to a single exposure and
therefore, a separate acute endpoint has not been identified for females
13-50.  Although increased incidence of death is one of the effects
seen, it was seen at a dose (1000 mg/kg/day) approximately three times
higher than the dose (300 mg/kg/day) selected for risk assessment;
therefore, the Agency is confident that adequate safety is provided to
protect the public from dietary exposure to residues of metolachlor.   

3.3.2  Chronic Reference Dose (RfD) – General Population

Selected Study:  Chronic Feeding Study in Dogs (MRID 43744201).  

In a one year metolachlor oral feeding study in dogs, the NOAEL was 9.7
mg/kg/day and the LOAEL was 33 mg/kg/day based on stomach lesions in 75%
of the males and by slight sinusoidal histiocytosis in the liver of 50%
of the males.  

Dose and Endpoint for Establishing an aRfD:  9.7 mg/kg/day based on a
NOAEL of 9.7 mg/kg/day and a LOAEL of 33 mg/kg/day based on decreased
body weight gain in females.

variation.

3.3.3  Incidental Oral Exposure (Short-Term)

Selected Study: Developmental Toxicity Study in Rats (MRID 43928925).  

In a developmental study conducted with S-metolachlor in rats the
maternal toxicity NOAEL was 50 mg/kg/day with a LOAEL of 500 mg/kg/day
based on increased clinical signs of toxicity, decreased body weights
and body weight gains and reduced food consumption and reduced food
efficiency.  No significant treatment related developmental toxicity was
noted at the dose levels tests. The developmental toxicity NOAEL was
equal to or greater than 1000 mg/kg/day; a LOAEL was not reached.

Dose and Endpoint:  50 mg/kg/day based on an offspring NOAEL of 50
mg/kg/day and a LOAEL of 500 mg/kg/day based on increased incidence of
clinical signs, decreased body weight/body weight gain, food consumption
and food efficiency seen in maternal animals.

Uncertainty Factor (UF): 100 – 10x for interspecies extrapolation and
10x for intraspecies variation.

Comments about Study/Endpoint:  The NOAEL (20 mg/kg/day) for the
prenatal developmental toxicity study in rabbits with S-metolachlor
(MRID 43928924) was lower than the 50 mg/kg/day from the rat
developmental study.  However, the endpoint was based on weak clinical
signs of toxicity (increase in little/none/soft stool observations) at
100 mg/kg/day.  Although there was a dose-related increase in this
effect, it is not evidence of frank toxicity and was judged not be
appropriate for risk assessment.  Therefore, the rabbit study with
S-metolachlor was not selected for this exposure scenario.

3.3.4  Dermal Exposure (Short-Term)

No hazard was identified for quantification of risk following dermal
exposure.  In a 21-day dermal toxicity study (MRID 41833101), no
systemic toxicity was seen following repeated dermal application of
metolachlor (96.4% ai) to the intact skin of five New Zealand
rabbits/sex/group at doses of 0, 10, 100 or 1000 mg/kg/day for 21 days. 

3.3.5  Inhalation Exposure (Short-Term)

Selected Study: Developmental Toxicity Study in Rats (MRID 43928925).  

Dose and Endpoint:  50 mg/kg/day based on an offspring NOAEL of 50
mg/kg/day and a LOAEL of 500 mg/kg/day based on is based on increased
incidence of clinical signs, decreased body weight/body weight gain,
food consumption and food efficiency seen in maternal animals.

Uncertainty Factor (UF): 100 – 10x for interspecies extrapolation and
10x for intraspecies variation.

Comments about Study/Endpoint:  Since an oral study was selected, a 100%
absorption factor should be applied.

3.3.6  Inhalation Exposure (Intermediate-Term)

Selected Study: Subchronic (6 month) Toxicity Study in the Dog  (MRID
00032174)

In a subchronic oral toxicity study (MRID5 00032174 and 43244001),
metolachlor (96.8% ai) was administered in the diet to Beagle dogs
(8/sex/group for control and high dose groups; 6/sex/group for low- and
mid-dose groups) at dose levels of 0, 100, 300 or 1000 ppm (males: 0,
2.92, 9.71 and 29.61 mg/kg/day, respectively; females: 0, 2.97, 8.77 and
29.42 mg/kg/day, respectively) for six months.  There were no deaths or
clinical signs of toxicity.  Mean body weight gain was decreased during
weeks 0-13 and 0-26 in the 1000 ppm group males (55-63% decrease) and
females (44-50% decrease), although the changes were not statistically
significant.  Mean overall food consumption was not affected in the 1000
ppm group males but was slightly decreased (9%) in the 1000 ppm females.
 There was a significant decrease in the activated partial
thromboplastin time (APTT) in the 300 and 1000 ppm group males and 300
ppm group females but the findings were not considered toxicologically
significant because the decrease was slight and not dose-related. 
Alkaline phosphatase was significantly increased in the 300 ppm and 1000
ppm group males and females at week 26; however, the effect was not
considered toxicologically significant due to the small magnitude of the
increase and the lack of accompanying necropsy findings.  The LOAEL was
1000 ppm (males/females: 29.61/29.42 mg/kg/day) based on decreased body
weight gain.  The NOAEL was 300 ppm (males/females: 9.71/8.77
mg/kg/day).  Dose and Endpoint for Risk Assessment: NOAEL of 8.8
mg/kg/day based on decreased body weight gain at 29.4 mg/kg/day

Dose and Endpoint:  NOAEL of 8.8 mg/kg/day based on decreased body
weight gain at 29.4 mg/kg/day

Comments about Study/Endpoint: Since an oral study was selected, a 100%
absorption factor should be applied.

3.3.7  Classification of Carcinogenic Potential

HED’s Cancer Assessment Review Committee (CARC) classified metolachlor
as a Group C carcinogen with risk quantitated using a non-linear
approach.  The NOAEL of 15 mg/kg/day from the rat combined chronic
toxicity/carcinogenicity study is based on neoplastic
nodules/hepatocellular carcinomas seen at the highest dose tested of 150
mg/kg/day.  The Agency notes that the tumor NOAEL of 15 mg/kg/day is
comparable to the NOAEL of 9.7 mg/kg/day selected for establishing the
chronic reference dose for metolachlor (TXR 014691, 9/28/01).  The
recommendation for a non-linear approach should be followed since no new
data were submitted for a re-evaluation by the CARC.

3.4  Margins of Exposure

Table 3.4  Target Levels of Concern/Margin of Exposure S-Metolachlor

Route/Duration	Short-Term

(1-30 Days)	Intermediate-Term

(1 - 6 Months)	Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal	NA	NA	N/A

Inhalation	100	100	N/A

Residential (Non-Dietary) Exposure

Oral	100	N/A	N/A

Dermal	NA	N/A	N/A

Inhalation	N/A	N/A	N/A

3.5  Recommendation for Aggregate Exposure Risk Assessments

When there are potential residential exposures to the pesticide,
aggregate risk assessment must consider exposures from three major
sources: oral, dermal and inhalation exposures.  There are potential
residential incidental oral exposures to S-metolachlor via
post-application hand-to-mouth exposure of children playing on treated
lawns.  In addition, dietary and incidental oral endpoints for
S-metolachlor are based on common toxicological effects.  Therefore,
exposures from food and non-food oral routes should be aggregated for
this assessment.  

3.6  Summary of Endpoints Selected for Risk Assessment

	

Table 3.6.a. Summary of Toxicological Endpoints for S-metolachlor for
Use in Dietary Human Health Risk Assessments

Exposure/Scenario	Point of Departure	Uncertainty/FQPA Safety Factors
RfD, PAD, LOC for Risk Assessment	Study and Toxicological Effects

Acute Dietary

(General Population)	NOAEL = 300 mg/kg/day	UFA= 10x

UFH=10x

FQPA SF= 1x	Acute RfD = 3.0 mg/kg/day

aPAD = 3.0 mg/kg/day	Developmental Toxicity Study - Rat 

LOAEL = 1000 mg/kg/day based increased incidence of death, clinical
signs (clonic and/or tonic convulsions, excessive salivation,
urine-stained abdominal fur and/or excessive lacrimation) and decreased
body weight gain.  

Chronic Dietary 

(All Populations)	NOAEL = 9.7

mg/kg/day	UFA= 10x

UFH=10x

FQPA SF= 1x	Chronic RfD = 0.097

mg/kg/day

cPAD = 0.97mg/kg/day	Chronic Toxicity – Dog;

LOAEL = 33 mg/kg/day based decreased body weight gain in females  

Cancer (all routes)	Metolachlor has been classified as a Group C
carcinogen with risk quantitated using a non-linear (Margin of Exposure)
approach.  

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and  used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  

NOAEL = no observed adverse effect level.  LOAEL = lowest observed
adverse effect level.  

UF = uncertainty factor.  UFA = extrapolation from animal to human
(interspecies).  UFH = potential variation in sensitivity among members
of the human population (intraspecies).  

FQPA SF = FQPA Safety Factor.  

PAD = population adjusted dose (a = acute, c = chronic). 

RfD = reference dose.  

MOE = margin of exposure.  

LOC = level of concern.  

Table 3.6.b.  Summary of Toxicological Doses and Endpoints for
S-METOLACHLOR for Use in Residential and Occupational Human Health Risk
Assessments

Exposure/

Scenario	Point of Departure	Uncertainty Factors	Level of Concern for
Risk Assessment	Study and Toxicological Effects

Incidental Oral Short-term (1-30 days)

	NOAEL= 

50 mg/kg/day	UFA= 10x

UFH=10x

	Residential LOC for MOE = 100	Developmental Toxicity Study - Rat 

LOAEL = 500 mg/kg/day based on increased incidence of clinical signs,
decreased body weight/body weight gain, food consumption and food
efficiency seen at the LOAEL  in maternal animals. 

Inhalation Short-Term (1-30 days)	NOAEL= 

50 mg/kg/day	UFA= 10x

UFH=10x

	Occupational LOC for MOE = 100	Developmental Toxicity Study - Rat 

LOAEL = 500 mg/kg/day based on increased incidence of clinical signs,
decreased body weight/body weight gain, food consumption and food
efficiency seen at the LOAEL  in maternal animals.

Inhalation Short-Term (1-30 days)	NOAEL= 

8.8 mg/kg/day	UFA= 10x

UFH=10x

	Occupational LOC for MOE = 100	Subchronic Toxicity Study - Dog 

LOAEL = 29.4 mg/kg/day based on decreased body weight gain

Cancer (all routes)	Metolachlor has been classified as a Group C
carcinogen with risk quantitated using a non-linear (Margin of Exposure)
approach.  

3.7  Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess
potential adverse outcomes from exposure to chemicals.  Collectively,
these studies include acute, subchronic and chronic toxicity, including
assessments of carcinogenicity, neurotoxicity, developmental,
reproductive, and general or systemic toxicity.  These studies include
endpoints which may be susceptible to endocrine influence, including
effects on endocrine target organ histopathology, organ weights, estrus
cyclicity, sexual maturation, fertility, pregnancy rates, reproductive
loss, and sex ratios in offspring.  For ecological hazard assessments,
EPA evaluates acute tests and chronic studies that assess growth,
developmental and reproductive effects in different taxonomic groups. 
As part of its most recent registration decision, EPA reviewed these
data and selected the most sensitive endpoints for relevant risk
assessment scenarios from the existing hazard database.  However, as
required by FFDCA section 408(p), S-metolachlor, as an enriched isomer
of metolachlor, is subject to the endocrine screening part of the
Endocrine Disruptor Screening Program (EDSP). 

EPA has developed the EDSP to determine whether certain substances
(including pesticide active and other ingredients) may have an effect in
humans or wildlife similar to an effect produced by a “naturally
occurring estrogen, or other such endocrine effects as the Administrator
may designate.”  The EDSP employs a two-tiered approach to making the
statutorily required determinations. Tier 1 consists of a battery of 11
screening assays to identify the potential of a chemical substance to
interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal
systems.  Chemicals that go through Tier 1 screening and are found to
have the potential to interact with E, A, or T hormonal systems will
proceed to the next stage of the EDSP where EPA will determine which, if
any, of the Tier 2 tests are necessary based on the available data. Tier
2 testing is designed to identify any adverse endocrine-related effects
caused by the substance, and establish a dose-response relationship
between the dose and the E, A, or T effect. 

Under FFDCA section 408(p), the Agency must screen all pesticide
chemicals. Between October 2009 and February 2010, EPA issued test
orders/data call-ins for the first group of 67 chemicals, which contains
58 pesticide active ingredients and 9 inert ingredients.  Metolachlor
was included on that list and has been issued an order to conduct the
Tier 1 testing.  Once all required Tier 1 and Tier 2 data have been
received and reviewed, the endpoints and safety factors used for risk
assessment purposes will be examined and a new risk assessment performed
for S-metolachlor if necessary.  For further information on the status
of the EDSP, the policies and procedures, the list of 67 chemicals,
future lists, the test guidelines and the Tier 1 screening battery,
please visit our website:    HYPERLINK "http://www.epa.gov/endo/" 
http://www.epa.gov/endo/ . 

4.0  RESIDUE CHEMISTRY CONSIDERATIONS

4.1  Metabolism in Plants/Livestock

The qualitative nature of metolachlor residues in plants is adequately
understood based upon the adequate corn, potato, and soybean metabolism
studies.  The metabolism of metolachlor involves conjugation with
glutathione, breakage of this bond to form the mercaptan, conjugation of
the mercaptan with glucuronic acid, O-demethylation of the methyl ether,
and conjugation of the resultant alcohol with a neutral sugar.  A minor
pathway may involve sugar conjugation of metolachlor directly to the
corresponding oxo-compounds.  Residues of concern in plants include
metolachlor and its metabolites, determined as the derivatives CGA-37913
and CGA-49751.  The Agency previously concluded that the residues of
concern for S-metolachlor are the same as for metolachlor.

Adequate studies are available depicting the metabolism of metolachlor
in ruminants and poultry.  Metolachlor is rapidly metabolized and almost
totally eliminated in the urine and feces of ruminants (goats),
non-ruminants (rats), and poultry.  Metolachlor per se was not detected
in any of the excreta or tissues.  As in plants, metolachlor residues of
concern in livestock commodities include metolachlor and its
metabolites, determined as the derivatives CGA-37913 and CGA-49751.  The
residues of concern for S-metolachlor in livestock are the same as those
for metolachlor.  

The residues of concern for S-metolachlor in drinking water include the
parent, CGA-354743 (metolachlor ethanesulfonic acid (ESA)) and CGA-51202
(metolachlor oxanilic acid (OA)).

4.2  Metabolism in Rotational Crops 

Based on the available data, HED concluded that the metabolism of
[14C]S-metolachlor in rotational crops is similar to the metabolism
observed in the primary crops.  Metabolism in rotational crops primarily
involves two pathways: (i) conjugation of the parent molecule with
glutathione by substitution of the chlorine, followed by the degradation
of the glutathione moiety to form a variety of sulfur containing
metabolites; and (ii) direct oxidation of parent or secondary
metabolites, primarily on the chloroacetyl side chain.  Complete
degradation of secondary metabolites either in the soil and/or plants
also resulted in the incorporation of molecule fragments into natural
plant constituents.  The residues of concern for both metolachlor and
S-metolachlor in rotational crops are the same as for primary crops,
metolachlor and its metabolites, determined as the derivatives CGA-37913
and CGA-49751.  

Table 4.2  Summary of Metabolites and Degradates to be included in the
Risk Assessment and Tolerance Expression

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Plants

	Primary Crop	Parent & metabolites convertible to CGA-37913, CGA-49751
Parent & metabolites convertible to CGA-37913, CGA-49751

	Rotational Crop	Parent, CGA-37913 & metabolites convertible to
CGA-49751	Parent & metabolites convertible to CGA-37913, CGA-49751

Livestock

	Ruminant	Parent & metabolites convertible to CGA-37913, CGA-49751
Parent & metabolites convertible to CGA-37913, CGA-49751

	Poultry	Parent & metabolites convertible to CGA-37913, CGA-49751	Parent
& metabolites convertible to CGA-37913, CGA-49751

Drinking Water

	Parent & metabolites convertible to CGA-354743 (metolachlor
ethanesulfonic acid (ESA)) and CGA-51202 (metolachlor oxanilic acid
(OA))	Not Applicable

4.3  Residue Analytical Methods

4.3.1  Enforcement Methods

Adequate methodology is available for enforcing the established and
recommended tolerances.  PAM Vol. II, Pesticide Regulation Section
180.368, lists a GC/NPD method (Method I) for determining residues in/on
crop commodities and a GC/MSD method (Method II) for determining
residues in livestock commodities.  These methods determine residues of
metolachlor and its metabolites as either CGA-37913 or CGA-49751
following acid hydrolysis.  

4.3.2  Multiresidue Methods

Adequate data are available on the recovery of metolachlor through
Multiresidue Method Testing Protocols.  The FDA PESTDATA database
indicates that metolachlor is completely recovered through Method 302,
PAM Vol. I (3rd ed., revised 10/97).

4.3.3  Residues in Crops

Coriander (Cilantro)

The submitted study is adequate in number and geographic location of
residue field trials.  Five field trials were conducted in EPA Regions 2
(2), 6, 9, and 10.  At all sites, two plots received a single broadcast
application of S-metolachlor at the approximate rate of 0.64 lb ai/A or
0.96 lb ai/A.  Coriander (cilantro) fresh leaf and stem samples were
harvested approximately 30 (27-34) days pre-harvest interval (PHI),
after the application and placed into frozen storage shortly after
harvest.  At one site, additional treated plots received a single
broadcast application of S-metolachlor at the approximate rate of 0.64
lb ai/A or 0.96 lb ai/A, where coriander (cilantro) seed were collected.
 At another site, additional treated plots received a single broadcast
application of S-metolachlor at the approximate rate of 0.64 lb ai/A or
0.96 lb ai/A, and coriander (cilantro) leaves and stems were collected
at 27 days and dried in an oven.  No spray adjuvant was used at the
trials.  No residue decline studies were submitted.

Coriander (cilantro) fresh, dried and seed samples were analyzed for
residues of S-metolachor using the “Working Method for PR 09595:
Analysis of s-Metolachlor in Cilantro as Metabolites s-CGA-37913
(SYN-506357) and s-CGA-49751 (SYN-508500),” a modification of Syngenta
Method No. 1848-01, dated June 26, 2003 entitled “Analytical Method
for the Enantioselective Determination of Residues of s-Metolachlor as
Metabolites SYN-506357 and SYN-508500 in Agricultural Commodities by
Chiral High Performance Liquid Chromatograph with Mass Spectrometric
Detection.”  

The residue analytical method for S-metolachlor residues in/on coriander
(cilantro) samples was validated both prior to and concurrently with
field samples. Based on recoveries at the LLMV, the LOD (std. dev. x
one-tailed t-statistic) were calculated.  The LOQ (3 x LOD) were also
calculated.  The LLMV, LOD and LOQ for SYN-506357 and SYN-508500 in/on
the three matrices are listed below:

Table 4.4.3.  Summary of  S-Metolachlor Analytical Method Limits

Commodity	Analyte	Calculated LOD

(ppm)	Calculated LOQ

(ppm)	LLMV

(ppm)

Coriander (cilantro) Fresh Samples	SYN-506357

SYN-508500	0.0145

0.0132	0.0436

0.0396	0.05

0.05

Coriander (cilantro) Dried Samples	SYN-506357

SYN-508500	0.0160

0.0175	0.0480

0.0526	0.05

0.05

Coriander (cilantro) Seed Samples	SYN-506357

SYN-508500	0.0154

0.0120	0.0463

0.0359	0.05

0.05

The data collection method was adequate for the determination of
S-metolachlor residues in coriander (cilantro) commodities. 

The analytical results show that after a single foliar broadcast
application of S-metolachlor at the approximate rate of 0.64 lb ai/A and
0.96 lb ai/A with a 27 to 34-days PHI, the maximum total S-metolachlor
residues as parent equivalents were approximately 3.7 ppm and 4.1 ppm in
coriander (cilantro) fresh leaves and stems, respectively.  The maximum
total S-metolachlor residues as parent equivalents were increased from
approximately <0.131 ppm (fresh samples) to 0.834 ppm (dried samples) in
the 0.64 lb ai/A treated plot.  The maximum total S-metolachlor residues
as parent equivalents were increased from approximately 0.170 ppm (fresh
samples) to 2.031 ppm (dried samples) in the 0.96 lb ai/A treated plot. 
The maximum total S-metolachlor residues as parent equivalents were
<0.131 ppm in coriander (cilantro) seed at both application rates.  

Based on the results of these trials, the appropriate tolerance for
residues of S-metolachlor in/on coriander (cilantro) leaves is 8.0 ppm. 
However, the Agency uses the preferred name coriander not cilantro for
this raw agricultural commodity and, in addition, does not differentiate
between dry and fresh leaves for coriander (cilantro).  Therefore, a
revised Section F should be submitted to indicate a request for
coriander, leaves at 8.0 ppm and the cilantro dried and fresh leaves
should be removed.  The study data indicates that the requested
tolerance on coriander, seed at 0.13 ppm is adequate.  

Beet, Garden, Leaves

No new data have been submitted in support of the requested tolerance on
beet, garden, leaves.  The request is based on the currently established
tolerance for residues of S-metolachlor on Brassica leafy vegetables
(Sub-group 5B), of 1.8 ppm.  The Chemistry Science Advisory Council
(ChemSAC) has considered the issue and determined that since the use
pattern for beet greens is the same as that for leafy Brassica (sub
group 5B), and beet greens are similar to the commodities in the leafy
Brassica subgroup 5B, it is appropriate to translate this tolerance of
1.8 ppm to beet greens.  

Based on the CHEMSAC determination and that the proposed use pattern for
beet, garden, leaves is the same as leafy Brassica greens, subgroup 5B,
ARIA recommends for the proposed tolerance of 1.8 ppm on beet, garden,
leaves.

4.4  Residues in Livestock

The proposed use for S-metolachlor will have no significant impact on
the dietary burden of metolachlor to livestock.  As a result, no changes
are required in the current tolerances for metolachlor residues in
livestock commodities.

4.5  Residues in Processed Commodities

The proposed use for S-metolachlor on coriander (cilantro) and beet,
garden, leaves will result in no processed commodities of regulatory
interest.  A discussion of processed commodities is not germane to this
action

4.6  Residues in Rotational Crops

Field rotational crop data have been submitted previously which are
adequate to support the existing rotational crop restrictions.  Do not
rotate to food or feed crops other than those listed in the Dual
Magnum® label.  For all crops not listed, wait at least 12 months
following the last application of Dual Magnum® before planting. 

4.7  Drinking Water Profile

4.7.1  Environmental Fate and Transport

Environmental fate data indicate that parent metolachlor/S-metolachlor
is moderately persistent to persistent.  It is mobile to highly mobile
in different soils and has been detected extensively in surface water
and groundwater.  Metolachlor/S-metolachlor degradation appears to be
dependent on microbially mediated and abiotic processes.  Major
degradates identified in groundwater include metolachlor ESA and
metolachlor OA in both groundwater and surface water.  Depending on the
soil (i.e. organic matter content), metolachlor/S-metolachlor has the
potential to range from a moderately mobile to a highly mobile material.
 The Environmental Fate and Effects Division (EFED) concluded there is
no difference in soil sorption affinity between metolachlor and
S-metolachlor.  Available data suggest that metolachlor and
S-metolachlor are expected to be highly mobile to mobile in soil and
water environments.  

4.7.2  Estimated Drinking Water Concentrations

EFED calculated conservative, Tier I EDWCs of metolachlor and
S-metolachlor in ground water and surface water for use in the last
human health risk assessment.  Since there are existing uses of
S-metolachlor with higher application rates than the proposed Section 3
uses, those EDWCs will not increase.  EDWCs for metolachlor and
S-metolachlor were calculated for both the parent compound and the
metolachlor ethanesulfonic acid (ESA) and metolachlor oxanilic acid (OA)
degradates (see metabolites table, Appendix 1).  Although it was
determined by HED’s Metabolism Assessment Review Committee (MARC) that
the ESA and OA metabolites appear to be less toxic than parent
metolachlor, they are included in the risk assessment since they were
found in greater abundance than the parent in water monitoring studies. 

EDWCs were calculated using drinking water models PRZM/EXAMS and FIRST
for surface water and SCIGROW for ground water.  Current NAWQA
monitoring data was also used to determine EDWCs.  Based on a review of
the current monitoring data, concentrations of parent S-metolachlor and
its degradates were less than values reported from the previous
monitoring data (US EPA, 2002).  Based on monitoring and modeling data,
total EDWCs for peak and average surface water respectively are 219 ppb
(78 ppb parent + 48 ppb metolachlor ESA+ 94 ppb metolachlor OA) and 119
ppb (18 ppb parent + 34 ppb metolachlor ESA+ 34 ppb metolachlor OA). 
Recommended groundwater EDWCs (peak and average) are 126 ppb (33 ppb
parent + 64 ppb metolachlor ESA+ 30 ppb metolachlor OA).

4.8  Dietary Exposure Analysis and Risk Estimates

Following recommendations made in the revised Tolerance Reassessment
Eligibility Decision (TRED) for Metolachlor and S-Metolachlor (DP#
292881, S. Kinard, 8/15/03), tolerances for metolachlor and
S-metolachlor have been separated into different subsections of 40 CFR
§180.368.  

The acute and chronic dietary exposure assessments were conducted using
the Dietary Exposure Evaluation Model software with the Food Commodity
Intake Database (DEEM-FCID™, Version 1.3), which incorporates
consumption data from USDA’s Continuing Surveys of Food Intakes by
Individuals (CSFII), 1994-1996 and 1998.  The dietary risk assessment
incorporates both exposure and toxicity of S-metolachlor and
metolachlor.  For acute and chronic assessments, the risk is expressed
as a percentage of a maximum acceptable dose (i.e., the dose which HED
has concluded will result in no unreasonable adverse health effects). 
This dose is referred to as the population adjusted dose (PAD).  The PAD
is equivalent to the Reference Dose (RfD) divided by the special FQPA
Safety Factor.  HED is concerned when estimated dietary risk exceeds
100% of the PAD.  

The acute and chronic dietary exposure/risk analyses for all supported
S-metolachlor/metolachlor food uses were conducted using conservative,
unrefined exposure assessments.  The unrefined analyses assume tolerance
level residues for all registered uses, 100% crop treated for all
commodities with existing tolerances, and default processing factors. 
In cases where separate tolerance listings occur for both metolachlor
and S-metolachlor on the same commodity, the higher value of the two is
used in the analyses.  Acute and chronic dietary S-metolachlor exposure
and risk estimates resulting from food intake were determined for the
general U.S. population and various population subgroups.  

Based on analyses of estimated dietary risks for the general U.S.
population and various population subgroups, the acute and chronic
dietary exposure estimates for S-metolachlor are significantly below
HED’s level of concern for all supported commodities (The 95th
percentile acute dietary exposure estimate for the highest exposed
population subgroup, all infants < 1 year old, is 0.05 mg/kg/day or 1.5%
of the aPAD.  The chronic dietary exposure estimate for the highest
exposed population subgroup, all infants < 1 year old, is 0.012
mg/kg/day or 11.6% of the cPAD.  

Table 4.8.a.  Summary of Acute Dietary Exposure and Risk for
S-metolachlor and Metolachlor

Population Subgroup	aPAD (mg/kg/day)	Acute (95th Percentile)

Exposure (mg/kg/day)	%aPAD

General U.S. Population	3.0	0.014688	<1.0

All Infants (< 1 year old)

0.046244	1.5

Children 1-2 years old

0.025061	<1.0

Children 3-5 years old

0.022362	<1.0

Children 6-12 years old

0.015532	<1.0

Youth 13-19 years old

0.011553	<1.0

Adults 20-49 years old

0.012690	<1.0

Adults 50+ years old

0.011471	<1.0

Females 13-49 years old

0.012602	<1.0

Table 4.8.b.  Summary of Chronic Dietary Exposure and Risk for
S-metolachlor and Metolachlor

Population Subgroup	cPAD (mg/kg/day)	Chronic

Exposure (mg/kg/day)	%cPAD

General U.S. Population	0.1	0.004550	4.5

All Infants (< 1 year old)

0.011574	11.6

Children 1-2 years old

0.008666	8.7

Children 3-5 years old

0.007852	7.9

Children 6-12 years old

0.005372	5.4

Youth 13-19 years old

0.003698	3.7

Adults 20-49 years old

0.003994	4.0

Adults 50+ years old

0.004017	4.0

Females 13-49 years old

0.003929	3.9

5.0  NON-DIETARY, NON-OCCUPATIONAL EXPOSURE

There are no residential exposures for the proposed new use of
S-metolachlor for this Section 3 assessment.  However, there is
potential for residential exposure to S-metolachlor from use of other
registered products which are applied to residential lawns or turf by
professional applicators.  Pennant MAGNUMTM (EPA Reg. No. 100-950) is
labeled for use on commercial (sod farm) and residential warm-season
turf grasses and other non-crop land including golf courses, sports
fields, and ornamental gardens.  Since Pennant MAGNUMTM is not intended
for homeowner purchase or use (i.e., used by professional/commercial
applicators), the only potential short-term residential risk scenario
anticipated is post-application hand-to-mouth exposure of children
playing on treated lawns.  S-metolachlor incidental oral exposure is
assumed to include hand-to-mouth exposure, object-to-mouth exposure and
exposure through incidental ingestion of soil.  Residential post
application exposure to S-metolachlor for this scenario has been
assessed in a separate document (D274331, R. Griffin, 2/20/02).  The
residential exposure to toddlers for this scenario was calculated to be
0.046 mg/kg/day resulting in an MOE of 1100.  The MOE from the
residential risk scenario for exposure to S-metolachlor does not exceed
the Agency’s level of concern. Results from that assessment have been
used to assess aggregate risk from exposure to food, drinking water, and
residential lawns for this Section 3 analysis.  Based on this analysis,
short-term oral MOEs are not of concern.

6.0  AGGREGATE RISK

In accordance with the FQPA, HED must consider and aggregate pesticide
exposures and risks from three major sources: food, drinking water, and
residential exposures.  In an aggregate assessment, exposures from
relevant sources are added together and compared to quantitative
estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can
be aggregated.  When aggregating exposures and risks from various
sources, HED considers both the route and duration of exposure.

Based on the proposed and existing Section 3 uses, acute, short-term,
intermediate-term and chronic aggregate exposures are anticipated. 
Aggregate exposure assessments were performed for acute aggregate
dietary exposure (food + drinking water), chronic aggregate dietary
exposure (food + drinking water), and residential short-term exposure to
children from incidental oral exposures.  A cancer aggregate risk
assessment was not performed because for S-metolachlor the chronic
reference dose is considered protective of cancer effects.  All
potential exposure pathways were assessed in the aggregate risk
assessment.  

6.1  Acute Aggregate Risk

The aggregate acute risk estimates include exposure to residues of
S-metolachlor in food and drinking water, and does not include dermal,
inhalation or incidental oral exposure.  Since the acute dietary
exposure assessment already includes the highest acute exposure from the
drinking water modeling data, no further calculations are necessary. 
The acute risk estimate for all populations, resulting from aggregate
exposure to S-metolachlor in food and drinking water is below ARIA’s
level of concern.  The food and drinking water exposure estimates for
the most highly exposed subgroup, all infants (< 1 year old), is 1.5% of
the aPAD.

6.2  Short- & Intermediate-Term Aggregate Risk

There are no residential user exposures for the proposed new use of
S-metolachlor for this Section 3 assessment.  However, there is
potential for residential exposure to S-metolachlor from use of other
registered products which are applied to residential lawns or turf by
professional applicators.  No intermediate-term risk scenarios are
anticipated for the existing and proposed uses of S-metolachlor.  The
only potential short-term residential risk scenario anticipated is
post-application exposure of children playing on treated lawns. 
S-metolachlor incidental oral exposure is assumed to include
hand-to-mouth exposure, object-to-mouth exposure and exposure through
incidental ingestion of soil.  Results from that assessment have been
used to assess aggregate risk from exposure to food, drinking water, and
residential lawns for this Section 3 analysis.  Based on this analysis,
short-term aggregate MOEs are not of concern.

Table 6.2  Short-Term Aggregate Risk Calculations for S-metolachlor

Population	NOAEL 1

mg/kg/day	LOC 2	Average

Food & Water

Exposure mg/kg/day	Residential Exposure 3

mg/kg/day	Aggregate MOE

(food/water and

residential) 4

Toddlers	50	100	0.012	0.046	860

1 NOAEL for incidental oral exposure.  

2 The level of concern (LOC) MOE is 100, based on inter- and
intra-species safety factors totaling 100.

3 Residential Exposure = [Incidental Oral exposure from all possible
sources -combined hand-to-mouth, object-to-mouth, and soil ingestion
oral exposure].  No residential oral exposure is expected for adults

3 Aggregate MOE = [NOAEL ÷ (Avg Food & Water Exposure + Residential
Exposure)]

6.3  Chronic Aggregate Risk

The aggregate chronic risk estimates include exposure to residues of
S-metolachlor in food and drinking water, and does not include dermal,
inhalation or incidental oral exposure.  Since the chronic dietary
exposure assessment already includes the highest chronic exposure from
the drinking water modeling data, no further calculations are necessary.
 The chronic risk estimate for all populations, resulting from aggregate
exposure to S-metolachlor in food and drinking water is below ARIA’s
level of concern.  The food and drinking water exposure estimates for
the most highly exposed subgroup, all infants (< 1 year old), is 11.6%
of the cPAD.

6.4  Cancer Aggregate Risk

As risks are calculated based on the chronic reference dose are
protective of cancer effects, no separate cancer risk assessment is
necessary.  The chronic aggregate risk assessment is below the
Agency’s level of concern.

7.0  OCCUPATIONAL EXPOSURE AND RISK 

7.1  Exposure Scenarios

HED assessed the occupational exposure scenario of mixing, loading, and
applying S-metolachlor (Dual Magnum® Herbicide (EPA Reg. No. 100-816)
and Dual II Magnum® (EPA Reg. No. 100-818)) EC formulations as an
herbicide on crops.  The proposed uses may result in
short-/intermediate-term (i.e., 1-30 days or up to 6 months) dermal and
inhalation exposures during mixing, loading, applying, and
postapplication activities.  Long-term exposures (i.e., 6 months of
continuous exposure) are not expected to occur based on the proposed use
pattern.  Dermal toxicological endpoints of concern were not identified
(i.e., no systemic toxicity was seen following dermal exposure at the
limit dose) therefore, no dermal exposures were calculated.  Short- and
intermediate-term exposures from inhalation exposure routes were
assessed for all exposure scenarios.  Occupational and residential
exposure and risk estimates were conducted using maximum application
rates and surrogate exposure data from the Pesticide Handlers Exposure
Database and the Residential Exposure Assessment SOPs.  

7.1.1	Handler Exposure Scenarios

The term “handler” applies to individuals who mix, load, and apply
the pesticide product.  Based on the use pattern, two occupational
exposure scenarios were identified for S-metolachlor.  

	1)   mixing/loading liquid formulation for groundboom application;	

	2)   applying spray with groundboom equipment.  

7.1.2 	Post-Application Exposure Scenarios

Since there are no dermal endpoints of concern, post-application dermal
exposure was not examined for occupational uses.  Based on the Agency's
current practices, a quantitative postapplication inhalation exposure
was also not assessed.  However, volatilization of pesticides may be a
potential source of postapplication inhalation exposure to individuals
nearby to pesticide applications.  A study published in the Journal of
Environmental Quality, Volume 38, September-October 2009, pages,
1785-1795, “Soil Moisture and Metolachlor Volatilization Observations
over Three Years” demonstrated that metolachlor can see its
volatilization properties significantly increase with increasing surface
soil water content.  Furthermore, OPP recently sought and received
expert advice on pesticide volatilization from the Agency’s Scientific
Advisory Panel (SAP).  The Agency is in the process of evaluating the
SAP’s final report (  HYPERLINK
"http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html" 
http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ) and
may develop policies and procedures to identify the when and how
postapplication inhalation exposure should be incorporated into the
Agency's risk assessments.  Consequently, the Agency may revisit the
need for a quantitative postapplication inhalation exposure assessment
for S-metolachlor as appropriate based on new policies that may result
from this effort.

7.2  Occupational Exposure Data and Assumptions

7.2.1..Exposure Data

	7.2.1.1  Application Parameters 

The maximum application rate for each crop that was listed on the label
ranges from 1.21 to 3.80 lb ai/A.

7.2.1.2  Occupational Exposure Data

Data from Occupational Pesticide Handler Unit Exposure Surrogate
Reference Table, which summarizes data from PHED was used to assess
handler and post-application exposures in the absence of
chemical-specific data.  PHED was designed by a task force of
representatives from the U.S. EPA, Health Canada, the California
Department of Pesticide Regulation, and member companies of the American
Crop Protection Association.  It consists of a database of measured
exposures for workers involved in the handling of pesticides under
actual field conditions and a set of computer algorithms used to subset
and statistically summarize the selected data.  

7.2.2  Exposure Assumptions

The following standard exposure assumptions were used in estimating
risks to handlers from exposure to S-metolachlor:

	•	60 kg, the average body weight of an adult female handler was used
to complete the short-term inhalation risk assessment based on an oral
study where the effects were observed in females

	•	70 kg, the average body weight of an adult handler was used to
complete the intermediate-term non-cancer risk assessment based on an
oral study where the effects were observed in males and females

	•	Exposure duration is short-term and intermediate-term for all
workers assessed.  

	•	Maximum application rates as determined by proposed label
requirements review were used for all types and methods of application.

	•	The area treated for each crop was based on HED’s Exposure
Science Advisory Council Policy Number 9.1.  For groundboom
applications, a default area of 80 acres was used.

7.3  Occupational Exposure and Risk Estimates

7.3.1  Handler Exposure

Assumptions and calculations of the risks for handlers are presented in
Table 7.3.1.  At the baseline level, all inhalation MOEs are above the
target MOE of 100, thus, risks are not of concern.  The handler exposure
estimates in this assessment are based on a central tendency estimate of
unit exposure and an upper-percentile assumption for the application
rate, and thus assumed to represent high-end exposures.  The
uncertainties associated with this assessment stem from the use of
surrogate exposure data (e.g., differences in use scenario and data
confidence), and assumptions regarding the amount of chemical handled. 
The estimated exposures are believed to be reasonable high-end estimates
based on observations from field studies and professional judgment.  In
order to refine this occupational risk assessment, data on actual use
patterns including rates, timing, and areas treated would better
characterize S-metolachlor risks.  

Table 7.3.1 S-metolachlor Short-term and Intermediate-term Inhalation
Risks

Exposure Scenario	Crop 	Applic Ratea 

(lbs ai/A)	Area Treated b (A/day)	Unit Exposures (µg/lb ai) c
Short-termd

(No respirator)	Intermediate-terme

(No respirator)

	Dose (mg/kg/day)	MOE	Dose (mg/kg/day)	MOE

Mixing/Loading Emulsifiable Concentrates (Liquids)

Groundboom	Sesame	1.9	80	1.2	0.003	16,000	0.003	3,400

	Melon	1.21	80	1.2	0.002	26,000	0.002	5,300

	Bushberry and Lowbush Blueberry	1.27	80	1.2	0.002	25,000	0.002	5,100

	Caneberry	3.81	80	1.2	0.006	8,000	0.005	1,700

	Sweet Sorghum	1.67	80	1.2	0.003	19,000	0.002	3,800

	Leafy Brassica Mustard Greens	1.27	80	1.2	0.002	25,000	0.002	5,100

	Carrot	1.9	80	1.2	0.003	16,000	0.003	3,400

	Cucumber	1.27	80	1.2	0.002	25,000	0.002	5,100

	Okra	1.9	80	1.2	0.003	16,000	0.003	3,400

	Bulb Onion	1.27	80	1.2	0.002	25,000	0.002	5,100

	Green Onion	1.27	80	1.2	0.002	25,000	0.002	5,100

Applying Liquid Sprays

Groundboom	Sesame	1.9	80

	0.74	0.002	27,000	0.002	5,500

	Melon	1.21	80	0.74	0.001	42,000	0.001	8,600

	Bushberry and Lowbush Blueberry	1.27	80	0.74	0.001	40,000	0.001	8,200

	Caneberry	3.81	80	0.74	0.004	13,000	0.003	2,700

	Sweet Sorghum	1.67	80	0.74	0.002	30,000	0.001	6,200

	Leafy Brassica Mustard Greens	1.27	80	0.74	0.001	40,000	0.001	8,200

	Carrot	1.9	80	0.74	0.002	27,000	0.002	5,500

	Cucumber	1.27	80	0.74	0.001	40,000	0.001	8,200

	Okra	1.9	80	0.74	0.002	27,000	0.002	5,500

	Bulb Onion	1.27	80	0.74	0.001	40,000	0.001	8,200

	Green Onion	1.27	80	0.74	0.001	40,000	0.001	8,200

a  Application rates are the maximum application rates determined
Section B of the tolerance petition for Dual Magnum® Herbicide.

b  Amount handled per day values are HED estimates of acres or tons
treated applied based on Exposure SAC SOP #9 “Standard Values for
Daily Acres Treated in Agriculture,” industry sources, and HED
estimates.	

c  Baseline level risk mitigation with no respirator.  When engineering
controls are noted enclosed cockpits are assumed.

d  Short-term inhalation MOE = NOAEL (50 mg/kg/day) / inhalation daily
dose (mg/kg/day), where inhalation dose = daily unit exposure (µg/lb
ai)  x inhalation absorption factor x application rate x amount handled
per day  x conversion factor (1 mg/1,000 µg) / body weight (60 kg adult
female).

e  Intermediate-term inhalation MOE = NOAEL (8.8 mg/kg/day) / inhalation
daily dose (mg/kg/day), where inhalation dose = daily unit exposure
(µg/lb ai)  x inhalation absorption factor x application rate x amount
handled per day  x conversion factor (1 mg/1,000 µg) / body weight (70
kg adult female)

7.3.2  Post Application Exposure

Since there are no dermal endpoints of concern, post-application dermal
exposure was not examined for occupational uses.

8.0  CUMULATIVE RISK

Section 408(b)(2)(D)(v) of FFDCA 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 does not have, at this time, available data to determine whether
S-metolachlor has a common mechanism of toxicity with other substances. 
Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to S-metolachlor and any other
substances and, S-metolachlor does not appear to produce a toxic
metabolite produced by other substances which have tolerances in the U.
S.  For the purposes of this tolerance reassessment action, therefore,
EPA has not assumed that S-metolachlor has a common mechanism of
toxicity with other substances.  For information regarding EPA’s
efforts to determine which chemicals have a common mechanism of toxicity
and to evaluate the cumulative effects of such chemicals, see the policy
statements released by EPA’s OPP concerning common mechanism
determinations and procedures for cumulating effects from substances
found to have a common mechanism on EPA’s website at
http://www.epa.gov/pesticides/cumulative/.

9.0  CONCLUSION

Pending resolution of the data needs described in Section 10 below, ARIA
has no concerns regarding human health exposure and risk from the
proposed Section 3 uses of S-metolachlor on coriander and garden beet
leaves:

Commodity	Recommended Tolerance (ppm)

Coriander, seed	0.13

Coriander, leaves	8.0

Beet, garden, leaves	1.8

.  

10.0  DATA NEEDS

10.1  Toxicology Data Requirements  

	- 	Acute Neurotoxicity (GLN 870. 6200a)

	- 	Subchronic Neurotoxicity (GLN 870.6200b) 

	- 	Immunotoxicity (GLN 870.7800)  

10.2  Residue Chemistry Data Requirements

	-	Section F for coriander, leaves at 8.0 ppm with the cilantro, dried
and fresh leaves removed.

10.3  Occupational/Residential Requirements

	None

References

S-Metolachlor: HED Risk Assessment for Proposed New Use of S-Metolachlor
on Bushberry, Caneberry, Carrot, Cucumber; Leafy Brassica Greens, Melon,
Okra, Bulb and Green Onion, Sesame Seed, Sorghum, and Turnip Greens. 
PP#: 6E7607, DP Barcode: D368726, B. Daiss, 6/30/10

Metolachlor and S-Metolachlor Residue Chemistry Chapter for the
Tolerance Reassessment Eligibility Decision (TRED).  DP Barcode:
D274328, S. Kinard, 2/28/02

Section 18 Exemption for Use of Metolachlor on Spinach.  ID#: 94OK001,
DP Barcode: D196641, J. Stokes, 11/24/93

Metolachlor/S-metolachlor Residential Risk Assessment. DP Barcode:
D274331, R. Griffin, 2/20/02

S-Metolachlor.  Petition for the Use on Coriander (Cilantro) and Garden
Beet Leaves.  Summary of Analytical Chemistry and Residue Data.
PP#1E7898, DP Barcode: D392447, W. Cutchin, 12/6/11

S-metolachlor - Acute and Chronic Dietary and Drinking Water Exposure
and Risk Assessment for Proposed Section 3 Use on Cilantro and Garden
Beet, Leaves. PP#1E7898, DP Barcode: D396451, W. Cutchin, 1/3/12

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(NOAEL) 300 mg/kg =  3.0 mg/kg

                                                                    (UF)
100	

Chronic RfD  (General Population) =  (NOAEL) 9.7 mg/kg =  0.097 mg/kg

                                                                    (UF)
100