Document ID: EPA-HQ-OPP-2009-0009-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-12-18T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460      

	OFFICE OF PREVENTION, PESTICIDE

	AND TOXIC SUBSTANCES

	

  SEQ CHAPTER \h \r 1 MEMORANDUM

	Date:	9/14/09

	SUBJECT:	  Chlorimuron ethyl.  Human Health Risk Assessment for
Proposed Uses 

				on Field Corn and Soybean.

                          

PC Code:  128901	DP Num.:  358796

MRID No.:  None	Registration No.:  352-436

Petition No.:  8F7430 & 8F7439	Regulatory Action:  Section 3

Assessment Type:  Single Chemical, Aggregate	Registration Case No.:  Not
Applicable

TXR No.:  None	CAS No.:   90982-32-4 

Decision No.:  400389	40 CFR 180.429 

	       FROM:	W. Cutchin, Acting Senior Branch Scientist 

			Alternative Risk Integration and Assessment (ARIA)

				Risk Integration, Minor Use, and Emergency Response Branch (RIMUERB)

				Registration Division (RD; 7505P)

	THRU:	D. McNeilly, Chemist 

		C. Swartz, Branch Chief

		Risk Assessment Branch II (RABII)

		Health Effects Division (HED; 7509P)

	TO:	D. Rosenblatt/S. Jackson/B. Madden

		RIMUERB/RD (7505P)  SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1 

ARIA/RIMUERB of RD of the Office of Pesticide Programs (OPP) is charged
with estimating the risk to human health from exposure to pesticides. 
RD of OPP has requested that ARIA evaluate hazard and exposure data and
conduct dietary, occupational, residential and aggregate exposure
assessments, as needed, to estimate the risk to human health that will
result from proposed and currently registered uses of the active
ingredient chlorimuron ethyl. 

E.I. du Pont de Nemours and Co. (DuPont) has submitted petitions to
establish tolerances as a result of the uses of chlorimuron ethyl on
herbicide resistant field corn and soybean for control of annual grass
and broadleaf weeds.  In this document, ARIA has conducted an assessment
of the human exposure and health risks resulting from these proposed
uses and all currently registered uses.  The overall risk assessment,
dietary risk assessment, and residue chemistry assessment were provided
by W. Cutchin (ARIA), the water exposure assessment by W. Shaughnessy
(Environmental Fate and Effects Division (EFED)) and the occupational
exposure assessments by M. Dow (ARIA).  

    Table of Contents

  TOC \f \h \z    HYPERLINK \l "_Toc240690201"  1.0  Executive Summary	 
PAGEREF _Toc240690201 \h  5  

  HYPERLINK \l "_Toc240690202"  2.0 Physical/Chemical Properties
Characterization	  PAGEREF _Toc240690202 \h  12  

  HYPERLINK \l "_Toc240690203"  3.0  Hazard Characterization/Assessment	
 PAGEREF _Toc240690203 \h  13  

  HYPERLINK \l "_Toc240690204"  3.1  Hazard and Dose-Response
Characterization	  PAGEREF _Toc240690204 \h  13  

  HYPERLINK \l "_Toc240690205"  3.1.1  Database Summary	  PAGEREF
_Toc240690205 \h  13  

  HYPERLINK \l "_Toc240690206"  3.1.1.1  Sufficiency of studies/data	 
PAGEREF _Toc240690206 \h  13  

  HYPERLINK \l "_Toc240690207"  3.1.1.2  Mode of action, metabolism,
toxicokinetic data	  PAGEREF _Toc240690207 \h  13  

  HYPERLINK \l "_Toc240690208"  3.1.2  Toxicological Effects	  PAGEREF
_Toc240690208 \h  13  

  HYPERLINK \l "_Toc240690209"  3.1.3  Dose-response	  PAGEREF
_Toc240690209 \h  14  

  HYPERLINK \l "_Toc240690210"  3.1.4  FQPA	  PAGEREF _Toc240690210 \h 
15  

  HYPERLINK \l "_Toc240690211"  3.2  Absorption, Distribution,
Metabolism, Excretion (ADME)	  PAGEREF _Toc240690211 \h  15  

  HYPERLINK \l "_Toc240690212"  3.3  FQPA Considerations	  PAGEREF
_Toc240690212 \h  15  

  HYPERLINK \l "_Toc240690213"  3.3.1  Adequacy of the Toxicity Database
  PAGEREF _Toc240690213 \h  15  

  HYPERLINK \l "_Toc240690214"  3.3.2  Evidence of Neurotoxicity	 
PAGEREF _Toc240690214 \h  15  

  HYPERLINK \l "_Toc240690215"  3.3.3  Developmental Toxicity Studies	 
PAGEREF _Toc240690215 \h  16  

  HYPERLINK \l "_Toc240690216"  3.3.4  Reproductive Toxicity Study	 
PAGEREF _Toc240690216 \h  16  

  HYPERLINK \l "_Toc240690217"  3.3.5  Additional Information from
Literature Sources	  PAGEREF _Toc240690217 \h  16  

  HYPERLINK \l "_Toc240690218"  3.3.6  Pre-and/or Postnatal Toxicity	 
PAGEREF _Toc240690218 \h  16  

  HYPERLINK \l "_Toc240690219"  3.3.6.1  Determination of Susceptibility
  PAGEREF _Toc240690219 \h  16  

  HYPERLINK \l "_Toc240690220"  3.3.6.2  Degree of Concern Analysis and
Residual Uncertainties for Pre- and/or Postnatal Susceptibility	 
PAGEREF _Toc240690220 \h  16  

  HYPERLINK \l "_Toc240690221"  3.3.7  Recommendation for not requiring
a Developmental Neurotoxicity Study	  PAGEREF _Toc240690221 \h  17  

  HYPERLINK \l "_Toc240690222"  3.4  FQPA Safety Factor for Infants and
Children	  PAGEREF _Toc240690222 \h  17  

  HYPERLINK \l "_Toc240690223"  3.5  Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc240690223 \h  18  

  HYPERLINK \l "_Toc240690224"  3.5.1  Acute Reference Dose (aRfD) –
General Population	  PAGEREF _Toc240690224 \h  18  

  HYPERLINK \l "_Toc240690225"  3.5.2  Acute Reference Dose (aRfD) -
Females age 13-49	  PAGEREF _Toc240690225 \h  18  

  HYPERLINK \l "_Toc240690226"  3.5.3  Chronic Reference Dose (cRfD)	 
PAGEREF _Toc240690226 \h  18  

  HYPERLINK \l "_Toc240690227"  3.5.4  Incidental Oral Exposure	 
PAGEREF _Toc240690227 \h  18  

  HYPERLINK \l "_Toc240690228"  3.5.5  Dermal Absorption	  PAGEREF
_Toc240690228 \h  18  

  HYPERLINK \l "_Toc240690229"  3.5.6  Short- and Intermediate-term
Occupational Dermal and Inhalation Exposure	  PAGEREF _Toc240690229 \h 
19  

  HYPERLINK \l "_Toc240690230"  3.5.7  Level of Concern for Margin of
Exposure	  PAGEREF _Toc240690230 \h  19  

  HYPERLINK \l "_Toc240690231"  3.5.8  Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc240690231 \h  19  

  HYPERLINK \l "_Toc240690232"  3.5.9  Classification of Carcinogenic
Potential	  PAGEREF _Toc240690232 \h  19  

  HYPERLINK \l "_Toc240690233"  3.5.10  Summary of Toxicological Doses
and Endpoints for Trifloxysulfuron for Use in Human Risk Assessments	 
PAGEREF _Toc240690233 \h  20  

  HYPERLINK \l "_Toc240690234"  3.6  Endocrine disruption	  PAGEREF
_Toc240690234 \h  21  

  HYPERLINK \l "_Toc240690235"  4.0  Public Health and Pesticide
Epidemiological Data	  PAGEREF _Toc240690235 \h  21  

  HYPERLINK \l "_Toc240690236"  5.0  Exposure Assessment	  PAGEREF
_Toc240690236 \h  22  

  HYPERLINK \l "_Toc240690237"  5.1  Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc240690237 \h  22  

  HYPERLINK \l "_Toc240690238"  5.1.1  Metabolism in Primary Crops	 
PAGEREF _Toc240690238 \h  22  

  HYPERLINK \l "_Toc240690239"  5.1.2  Metabolism in Rotational Crops	 
PAGEREF _Toc240690239 \h  23  

  HYPERLINK \l "_Toc240690240"  5.1.3  Metabolism in Livestock	  PAGEREF
_Toc240690240 \h  24  

  HYPERLINK \l "_Toc240690241"  5.1.4  Analytical Methodology	  PAGEREF
_Toc240690241 \h  27  

  HYPERLINK \l "_Toc240690242"  5.1.5  Environmental Degradation	 
PAGEREF _Toc240690242 \h  28  

  HYPERLINK \l "_Toc240690243"  5.1.6  Comparative Metabolic Profile	 
PAGEREF _Toc240690243 \h  29  

  HYPERLINK \l "_Toc240690244"  5.1.7  Toxicity Profile of Major
Metabolites and Degradates	  PAGEREF _Toc240690244 \h  30  

  HYPERLINK \l "_Toc240690245"  5.1.8  Pesticide Metabolites and
Degradates of Concern	  PAGEREF _Toc240690245 \h  30  

  HYPERLINK \l "_Toc240690246"  5.1.9  Drinking Water Residue Profile	 
PAGEREF _Toc240690246 \h  31  

  HYPERLINK \l "_Toc240690247"  5.1.10  Food Residue Profile	  PAGEREF
_Toc240690247 \h  33  

  HYPERLINK \l "_Toc240690248"  5.1.11  International Residue Limits	 
PAGEREF _Toc240690248 \h  35  

  HYPERLINK \l "_Toc240690249"  5.2  Dietary Exposure/Risk Pathway	 
PAGEREF _Toc240690249 \h  35  

  HYPERLINK \l "_Toc240690250"  5.2.1  Residue Profile	  PAGEREF
_Toc240690250 \h  35  

  HYPERLINK \l "_Toc240690251"  5.2.2  Water Exposure/Risk Pathway	 
PAGEREF _Toc240690251 \h  35  

  HYPERLINK \l "_Toc240690252"  5.2.3  Acute and Chronic Dietary
Exposure and Risk	  PAGEREF _Toc240690252 \h  36  

  HYPERLINK \l "_Toc240690253"  6.0  Residential Exposure/Risk Pathway	 
PAGEREF _Toc240690253 \h  36  

  HYPERLINK \l "_Toc240690254"  6.1  Other (Spray Drift, etc.)	  PAGEREF
_Toc240690254 \h  36  

  HYPERLINK \l "_Toc240690255"  7.0  Aggregate Risk Assessments	 
PAGEREF _Toc240690255 \h  36  

  HYPERLINK \l "_Toc240690256"  8.0  Cumulative Risk	  PAGEREF
_Toc240690256 \h  37  

  HYPERLINK \l "_Toc240690257"  9.0  Occupational Exposure	  PAGEREF
_Toc240690257 \h  37  

  HYPERLINK \l "_Toc240690258"  10.0  Data Needs and Label Requirements	
 PAGEREF _Toc240690258 \h  41  

  HYPERLINK \l "_Toc240690259"  10.1  Toxicology	  PAGEREF _Toc240690259
\h  41  

  HYPERLINK \l "_Toc240690260"  10.2  Residue Chemistry	  PAGEREF
_Toc240690260 \h  41  

  HYPERLINK \l "_Toc240690261"  10.3  Occupational and Residential
Exposure	  PAGEREF _Toc240690261 \h  42  

  HYPERLINK \l "_Toc240690262"  A.1	Toxicology Data Requirements	 
PAGEREF _Toc240690262 \h  44  

  HYPERLINK \l "_Toc240690263"  A.2	Toxicity Profile Tables for
Chlorimuron-ethyl.	  PAGEREF _Toc240690263 \h  45  

  HYPERLINK \l "_Toc240690264"  A.3	Rationale for Toxicology Data
Requirements	  PAGEREF _Toc240690264 \h  48  

  HYPERLINK \l "_Toc240690265"  A.4	Tolerance Summary for
Chlorimuron-ethyl.	  PAGEREF _Toc240690265 \h  50  

 

1.0  Executive Summary  TC "1.0  Executive Summary" \f C \l "1"  

Chlorimuron ethyl [ethyl
2-(4-chloro-6-methoxypyrimidin-2-ylcarbamoylsulfamoyl) benzoate] is a
sulfonylurea class herbicide with a mode of action of inhibiting
acetolactate synthase.  In the current petition, Dupont is proposing use
of a 25% WDG formulation of chlorimuron ethyl (DuPont Classic®
Herbicide; EPA Reg. No. 352-436) on herbicide resistant field corn and
soybean for control of annual grass and broadleaf weeds.  The proposed
use is for a single application at up to 0.0625 lb ai/A either
preemergence or postemergence.  The use directions require the use of an
adjuvant: either a crop oil concentrate at up to 1.0% of the spray
volume or non-ionic surfactant (NIS) at up to 0.25% of the spray volume.
 The proposed preharvest interval (PHI) is 7 days for corn. 
Applications may be made no later than flowering (R2 growth stage) to
soybeans.  In conjunction with this use, Dupont is proposing permanent
tolerances for chlorimuron ethyl on the following:

Corn, field, forage	0.5 ppm

Corn, field, grain	0.01 ppm

Corn, field, stover	2.0 ppm

Corn, field, meal	0.014 ppm

Corn, field, flour	0.015 ppm

Corn, aspirated grain fractions	1.28 ppm

Soybean, hay	1.8 ppm

Soybean, forage	0.45 ppm

Soybean, seed	0.01 ppm

Soybean, hulls	0.04 ppm

Soybean, aspirated grain fraction	2.79 ppm

Chlorimuron ethyl has low or minimal acute toxicity via the oral
(category IV), dermal (category III), and inhalation routes of exposure
(category IV).  It is mildly irritating to the eye (category III) and
non-irritating to the skin (category IV); it is not a skin sensitizer. 
In subchronic toxicity studies, no adverse effects were observed up to
the limit dose tested (1030 mg/kg/day) in mice.  In rats, decreased body
weight gain and liver pathology (margination of hepatocyte cytoplasmic
content in the centrilobular areas) were observed in males only at 173
mg/kg/day.  Mild hemolytic anemia, atrophy of the thymus and prostate
and increased liver weights were seen in dogs at 42.7 mg/kg/day. 
Chronic exposure to chlorimuron ethyl also led to mild anemia (decreased
erythrocyte count, hematocrit, and hemoglobin concentration) in dogs,
but atrophy of the thymus and prostate were not seen.  In rats, observed
treatment-related effects were limited to decreased body weight and body
weight gain in both sexes after long-term exposure.  Prostatitis
(males), and fatty replacement in the pancreas (both sexes) were also
observed but considered incidental occurrences; biliary hyperplasia/
fibrosis (females) was also seen and attributed to aging.  In mice,
there were no treatment-related effects observed up to 216 mg/kg/day. 
There was no evidence of carcinogenicity observed in the mouse or rat
carcinogenicity studies.  In addition, there was no indication of
mutagenicity in the battery of available studies.

In the developmental toxicity studies, decreases in maternal body weight
gain and delayed ossification in fetuses were observed in rats at 150
mg/kg/day.  In rabbits, decreases in maternal body weight gain were seen
at 300 mg/kg/day, while delayed ossification was seen in fetuses at a
lower dose of 48 mg/kg/day, indicating increased quantitative
susceptibility.  In a guideline 2-generation reproduction study in rats,
decreased body weight and histopathology in the cerebellum (cellular
changes in the internal granular and external germinal layers) were seen
in pups at 177 mg/kg/day.  These effects were seen in the absence of
maternal toxicity indicating increased quantitative susceptibility of
the pups to chlorimuron ethyl.  However, these effects were not
associated with any neurotoxicity or neurobehavioral changes, and not
observed in other reproduction studies in rats.  In a non-guideline
reproduction toxicity study (1-generation) in rats, decreased body
weight (females) and liver histopathology (males) were seen in parental
animals at 173 mg/kg/day, along with decreases in litter weights.  In
another reproduction study (1-year interim sacrifice) in rats, decreases
in maternal and pup body weights were observed at 195 mg/kg/day.

In the available toxicity studies, there was no evidence of estrogen-,
androgen-, and/or thyroid-mediated toxicity.

Metabolism data showed that chlorimuron ethyl is absorbed from the
gastrointestinal tract and is eliminated equally in urine and feces with
a biological half-life of about 50 hours.  Chlorimuron ethyl is
distributed throughout the body, with the largest portions found in the
liver.  

No toxicological endpoint attributable to a single dose of chlorimuron
ethyl has been identified.  For chronic dietary exposure, the chronic
toxicity study, along with the subchronic toxicity study in dogs were
used as co-critical studies to calculate the chronic reference dose
(cRfD) of 0.09 mg/kg/day.  The no observed adverse effect level (NOAEL)
of 9 mg/kg/day from the chronic study and the lowest observed adverse
effect level (LOAEL) of 42.7 mg/kg/day from the subchronic study were
used for risk assessment (see section 3.1.3); acute dietary endpoints
(general population and females age 13-49) were not selected.  The
co-critical dog studies were also used to select the dose and endpoint
for occupational short- and intermediate-term dermal and inhalation
exposures.  Based on hazard and exposure data, HED recommends the
special FQPA Safety Factor be reduced to1x because there are low
concerns, no residual uncertainties with regard to pre- and/or postnatal
toxicity, and high confidence that exposure estimates have not been
underestimated.  

Based on hazard and exposure data, HED had previously recommended the
special FQPA Safety Factor be reduced to 1x because there are low
concerns, no residential uncertainties with regard to pre- and/or
postnatal toxicity, a DNT study is not required, and because the doses
and endpoints selected for risk assessment are protective of the effects
observed in pre- and postnatal toxicity studies.  Furthermore, there is
high confidence that evposure estimates have not been underestimated. 
HED reconsidered these conclusions in light of the required
immunotoxicity and neurotoxicty studies. Hematological changes
(indicative of mild anemia) and atrophy of the thymus was not associated
with any histopathology and not seen after chronic exposure.  No other
potential immunotoxic effects were observed in the toxicology database.
Addtionally, no evidence of neurotoxicity was observed and HED continues
to conclude a developmental neurotoxicity study is not needed. 
Therefore, an additional 10x database uncertainty factor to account for
the lack of the required studies is not needed; the previous decision to
reduce the FQPA Safety Factor to 1x has been confirmed. 

The toxicity database for chlorimuron ethyl is adequate for purposes of
evaluating the requested uses.  Although there are several toxicology
data gaps under the current (revised) 40 CFR Part 158 toxicology data
requirements (immunotoxicity, rat acute and subchronic neurotoxicity,
and rat 28-day inhalation and 21-day dermal toxicity studies), due to
the lack of evidence of immunotoxicity or neurotoxicity in available
studies, it is unlikely that these studies will identify a NOAEL below
the dose currently selected for exposure assessments.  Therefore, ARIA
does not believe that a database uncertainty factor is warranted at this
time.

Nature of the residue studies are available for chlorimuron ethyl on
peanuts, soybeans, and corn.  For peanuts, the data indicated a lack of
significant translocation of the active ingredient in nutmeats or hulls.
 For the soybean study which was conducted using an herbicide tolerant
variety, only parent chlorimuron ethyl was observed.  For corn, the data
indicated a lack of significant translocation of the active ingredient
in grain.  The deficiencies in the corn metabolism study cited in the
last risk assessment remain outstanding.  However, since the metabolism
data for soybean, peanut, and corn are similar, for the purposes of
these petitions, ARIA will consider the residue of concern to be
chlorimuron ethyl for purposes of risk assessment and tolerance
enforcement.  Resolution of the deficiencies of the corn metabolism
study is a condition of registration for these petitions.

Ruminant and poultry metabolism studies were submitted with this
petition.  For ruminants, the data from urine and feces and the milk and
tissue data indicate that chlorimuron ethyl is absorbed and rapidly
excreted by goats primarily as parent via the urine.  In addition,
chlorimuron ethyl is also metabolized by oxidative dechlorination of
parent or metabolites, cleavage of the ethyl ester, and hydrolytic
cleavage of the amide linkage.  The presence of chlorimuron ethyl thiol
in urine also suggests that parent may undergo conjugation with
glutathione, with subsequent degradation of the glutathione moiety.  For
poultry, parent was identified as a major residue in eggs and all
tissues, and the pyrimidine amine and sulphonamide metabolites were
detected in eggs.  Sulphonamide was also detected in skin and muscle.
The available data suggest that the primary route of metabolism for
chlorimuron ethyl in poultry involves cleavage of the sulfonylurea
bridge to yield the pyrimidine amine and sulphonamide metabolites. 
Since very low residues are expected in livestock, exaggerated doses
were used in the metabolism studies, and considering the low toxicity of
the parent and by analogy the metabolites, ARIA and HED will consider
chlorimuron ethyl as the residue of concern (ROC) in livestock. 
Resolution of the deficiencies of the ruminant and poultry metabolism
studies is a condition of registration for these petitions. 

Adequate methods are available for tolerance enforcement.  The
enforcement method for soybeans (AMR-459-85) is found in Pesticide
Analytical Manual (PAM) Volume II.  Residues are determined by high
performance liquid chromatography (HPLC) using a photoconductivity
detector with a method limit of quantitation (LOQ) of 0.01 ppm.  An HPLC
with ultraviolet detector (HPLC/UV) method is also available for peanuts
(AMR-990-87).  Corn and soybean samples in the submitted residue field
trials and processing studies were analyzed for chlorimuron ethyl using
a liquid chromatography method with tandem mass spectroscopy/ mass
spectroscopy (LC/MS/MS) method, DuPont-13412, Revision No. 1.  This
method has been proposed as a new tolerance enforcement method for
residues of sulfonylureas, and has an independent laboratory validation
(ILV) trial.  The method is adequate for data collection.  At this time,
no detectable residues are expected in livestock commodities; therefore,
an enforcement method for residues of chlorimuron ethyl in livestock
commodities is not required.

The registrant submitted adequate field trial data supporting the use of
chlorimuron ethyl on field corn that is tolerant to sulfonylurea
herbicides.  Chlorimuron ethyl was applied to field corn as a single
broadcast foliar application at 0.06 lb ai/A.  ARIA recommends for the
requested tolerances of 0.01 ppm in/on field corn grain, 0.5 ppm in/on
field corn forage, and 2.0 ppm in/on field corn stover.

The registrant submitted adequate field trial data supporting the use of
chlorimuron ethyl on soybeans that are tolerant to sulfonylurea
herbicides.  Chlorimuron ethyl was applied to soybeans as a single
broadcast foliar application at 0.06 lb ai/A.  For both forage and hay,
chlorimuron ethyl residues declined rapidly within the first week after
application and then declined more slowly thereafter.  The existing
soybean tolerance that harmonizes with the current Canadian MRL for
soybeans at 0.05 ppm will cover the proposed use; a revised Section F
should be submitted removing the requested change in the soybean seed
tolerance.  Rather than a 0-day PHI as supported by the submitted data,
the registrant is requesting a 14-day PHI for forage and hay.  Based on
the data from the residue decline studies, ARIA recommends for the
requested tolerances of 0.45 ppm in/on soybean forage and 1.8 ppm in/on
soybean hay.  

There are livestock feed items of regulable interest associated with
these petitions.  At the feeding levels calculated for cattle and
poultry, and using the reasonably balance dietary burdens (RBD) and the
highest total radioactive residues (TRR) from the metabolism studies, no
detectable residues of chlorimuron ethyl are expected in livestock
commodities; therefore, tolerances and feeding studies are not required
for livestock at this time.  

The available corn and soybean processing data for chlorimuron ethyl are
adequate.  As residues did not concentrate in corn grits, starch or
refined oil, separate tolerances are not required for these corn
commodities.  Since the tolerance on the raw agricultural commodity
(RAC), field corn grain, is set at the method limit of quantitation
(LOQ; 0.01 ppm) and the suggested tolerances on corn meal and flour are
less than 2x the LOQ, tolerances on those processed commodities are not
required.  A revised Section F should be submitted removing the
requested tolerances on field corn meal and flour.  Residues did not
concentrate in soybean meal or refined oil; therefore separate
tolerances are not required for these processed fractions.  As the level
of residues for soybean hulls is expected to be below the current
tolerance for soybean seeds, a separate tolerance is also not required. 
A revised Section F should be submitted removing the requested tolerance
on soybean hulls.  Chlorimuron ethyl residues were shown to concentrate
in aspirated grain fractions (AGF) from both corn and soybean seeds.  As
residues in soybean AGF are expected to be higher than from corn, the
tolerance for AGF should be set at 3.0 ppm based on the soybean residue
data.  The requests for separate soybean and corn AGF should be removed
from the revised Section F.  A revised Section F for the residues of
chlorimuron ethyl in aspirated grain fractions at 3.0 ppm is required.  

Due to the insignificant residues (<0.01 ppm) detected in the confined
rotational crop study, trials for field accumulation in rotational crops
are not required.  The rotational crop restrictions on the product label
are adequate.

An updated drinking water assessment was conducted for the proposed uses
on herbicide tolerant field corn and soybeans.  To account for exposure
to residues in water under the most conservative scenario, the value of
6.99 ppb (one-in-10-year mean) was used in the chronic dietary exposure
assessment.  Water residues were incorporated in the DEEM-FCID into the
food categories “water, direct, all sources” and “water, indirect,
all sources.”   

ARIA has conducted a new dietary exposure assessment.  No toxicological
endpoint attributable to a single dose of chlorimuron ethyl has been
identified; therefore, an acute dietary exposure assessment was not
conducted.  The new assessment incorporated exposure via residues in
drinking water directly into the dietary exposure model.  The resulting
dietary risk estimates are 1% or less of the chronic population-adjusted
dose (cPAD) for all population subgroups and exposure durations; this is
below ARIA’s level of concern, which is typically 100% of the PAD. 
The risk estimates are based on tolerance-level residues and an
assumption of 100% crop treatment for the food uses, and “Tier 1”
estimates for the drinking water contamination that may be associated
with the crop use.

There are no residential uses proposed for chlorimuron ethyl; therefore,
incidental oral and residential dermal and inhalation risk assessments
were not conducted.  Aggregate risk is based on tolerance-level residues
and an assumption of 100% crop treatment for the food uses, and on
“Tier 1” estimates for the drinking water contamination that may be
associated with crop use.  The upper-bound cPAD risk estimates for the
general U.S. and specific population subgroups are 1% or less of the
cPAD, which is below ARIA’s level of concern.

ARIA has completed occupational exposure assessments to evaluate the
requested uses.  For occupational pesticide handlers, the dermal and
inhalation toxicological endpoints are appropriate for short- and
intermediate-term duration exposures.  Thus, the estimates of risk are
appropriate to address both short- and intermediate exposures.  Based
upon the proposed use pattern, ARIA believes exposures are most likely
to be short-term (1-30 days).  The most exposed occupational population,
mixer/loaders using open-pour loading of water dispersible granules, has
an MOE at 125.  MOEs are acceptable for post-application activities
except for detasseling treated corn grown for seed.  Since the
detasseling estimates are based upon the default assumption of 100 %
dermal absorption, the MOE of 33 should not be taken at face value. 
Actual exposure is believed to be less but lacking dermal absorption
data, the estimate is not refined.  The actual MOE is expected to be
larger than 33.  Occupational risk estimates associated with application
as well as post-application activities are below ARIA’s level of
concern.

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 chlorimuron ethyl and any
other substances.  Also, chlorimuron ethyl does not appear to produce a
toxic metabolite produced by other substances.  For the purposes of this
tolerance action, therefore, EPA has not assumed that chlorimuron ethyl
has a common mechanism of toxicity with other substances.  

Environmental Justice Considerations

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 ).

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures. 
In line with OPP policy, ARIA estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup’s
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting.  Extensive data on food
consumption patterns are compiled by the USDA under the Continuing
Survey of Food Intakes by Individuals (CSFII) and are used in pesticide
risk assessments for all registered food uses of a pesticide.  These
data are analyzed and categorized by subgroups based on age, season of
the year, ethnic group, and region of the country.  Whenever
appropriate, nondietary exposures based on home use of pesticide
products and associated risks for adult applicators and for toddlers,
youths, and adults entering or playing on treated areas postapplication
are evaluated.  Further considerations are currently in development as
OPP has committed resources and expertise to the development of
specialized software and models that consider exposure to bystanders and
farm workers as well as lifestyle and traditional dietary patterns among
specific subgroups.

Review of Human Research

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, which comprise the Pesticide Handlers Exposure
Database (PHED), have been determined to require a review of their
ethical conduct, and have received that review.  The studies in PHED
were considered appropriate (ethically conducted) for use in risk
assessments.  

CONCLUSIONS/RECOMMENDATIONS

Provided the data needs described in Section 10 below are addressed,
there are no human health considerations that would preclude granting
the requested uses of chlorimuron ethyl on field corn and soybean.  ARIA
recommends for establishing a permanent tolerance for residues of
chlorimuron ethyl on the following:

Corn, field, forage	0.5 ppm

Corn, field, grain	0.01 ppm

Corn, field, stover	2.0 ppm

Soybean, hay	1.8 ppm

Soybean, forage	0.45 ppm

Soybean, seed	0.05 ppm

Grain, aspirated fractions	3.0 ppm

Tolerances for residues of chlorimuron ethyl are currently expressed in
terms of chlorimuron ethyl per se.  However, the tolerance expression
for established and proposed tolerances should be corrected in 40 CFR
§180.429(a) to adhere to HED policy (S. Knizner, 5/27/09):
“Tolerances are established for residues of chlorimuron ethyl,
including its metabolites and degradates, in or on the commodities in
the table below.  Compliance with the tolerance levels specified below
is to be determined by measuring only chlorimuron ethyl [ethyl
2-(4-chloro-6-methoxypyrimidin-2-ylcarbamoylsulfamoyl) benzoate], in or
on the commodity.”   

2.0  Ingredient Profile

Chlorimuron ethyl is a dispersible granule formulation to be mixed with
water and sprayed for selective post emergence weed control of many
broadleaf weeds and yellow nutsedge.  According to the proposed
supplemental labeling prepared by DuPont, the maximum amount of active
ingredient that can be applied is 1 oz. or 0.016 lb/A which can be
applied once during the growing season.  A late spring application is
recommended but not later than 60 days before harvest.  Applications of
the herbicide may include a crop oil concentrate or nonionic surfactant
as specified in the label at the rate of 0.25% (1 quart/100 gallons of
spray solution).

2.1  Summary of Proposed Uses

TABLE 2.1  Summary of Proposed Directions for Use of Chlorimuron ethyl.

Applic. Timing, Type, and Equip.	Formulation

[EPA Reg. No.]	Applic. Rate 

(lb ai/A)	Max. No. Applic. per Season	Max. Seasonal Applic. Rate

(lb ai/A)	PHI

(days)	Use Directions and Limitations

Field Corn (OPTIMUM® GAT® herbicide tolerant)

Broadcast foliar application pre- or post-emergence or burndown	25% WDG

[352-436]	0.0045-0.06	1	0.06	7	Include a crop oil concentrate or NIS.

Apply in a minimum of 10 gal/A by ground, 3 gal/A by air

Soybean (OPTIMUM® GAT® herbicide tolerant)

Broadcast foliar application pre- or post-emergence or burndown	25% WDG

[352-436]	0.0045-0.06	1	0.06	NA	Include a crop oil concentrate or NIS.

Apply no later than R2 growth stage.  Allow 14 days after application
before grazing or feeding forage or hay. Apply in a minimum of 10 gal/A
by ground, 3 gal/A by air

  SEQ CHAPTER \h \r 1 2.2 Physical/Chemical Properties Characterization 
TC "2.0 Physical/Chemical Properties Characterization" \f C \l "1"  

TABLE 2.2.a  Chlorimuron ethyl Nomenclature

Compound

Chlorimuron ethyl 

	

Common name	

Chlorimuron ethyl 

Company experimental name	

N/A

IUPAC name	

ethyl 2-(4-chloro-6-methoxypyrimidin-2-ylcarbamoylsulfamoyl)benzoate

CAS name	

ethyl
2-[[[[(4-chloro-6-methoxy-2-pyrimidinyl)amino]carbonyl]amino]sulfonyl]be
nzoate

CAS #	

90982-32-4

TABLE 2.2.b  Physicochemical Properties of the Technical Grade
Chlorimuron ethyl 

Parameter	

Value	

Reference

Melting point/range	

181(C	

PP#3G2959; 1/10/84; S. Creeger

pH	

4.4	

PP#3G2959; 1/10/84; S. Creeger

Density	

1.51 g/cc	

PP#3G2959; 1/10/84; S. Creeger

Water solubility (mg/L)	

pH 1.3 = 1.5

pH 1.9 = 1.5

pH 2.5 = 1.5

pH 4.2 = 4.1

pH 5.0 = 9.0

pH 5.8 = 99

pH 6.5 = 450

pH 7.0 = 1200	

PP#3G2959; 1/10/84; S. Creeger 

Solvent solubility 

(mg/100 mL at 25(C)	

Acetone = 7.05

Acetonitrile = 3.10

Benzene = 0.815

Ethyl Acetate = 2.36

Ethyl Alcohol = 0.392

n-Hexane = 0.006

Methyl Alcohol = 0.740

Methylene Chloride = 15.3

Xylene = 0.283	

PP#3G2959; 1/10/84; S. Creeger

Vapor pressure at 25(C	

1.5 x 10-5 mm Hg	

PP#3G2959; 1/10/84; S. Creeger

Dissociation constant (pKa) at 25(C	

4.2	

PP#3G2959; 1/10/84; S. Creeger

Octanol/water partition coefficient Log(KOW)	

1.3	

PP#3G2959; 1/10/84; S. Creeger

UV/visible absorption spectrum	

Not Available	

3.0  Hazard Characterization/Assessment  TC "3.0  Hazard
Characterization/Assessment" \f C \l "1"  

3.1  Hazard and Dose-Response Characterization  TC "3.1  Hazard and
Dose-Response Characterization" \f C \l "2"  

3.1.1  Database Summary  TC "3.1.1  Database Summary" \f C \l "3"  

3.1.1.1  Sufficiency of Studies/Data  TC "3.1.1.1  Sufficiency of
studies/data" \f C \l "4"  

Based on the proposed use pattern, the toxicology database for
chlorimuron ethyl is adequate for risk assessment.  There are acceptable
studies available for endpoint selection that include: 1) subchronic
oral toxicity studies in rats, mice, and dogs; 2) a chronic oral
toxicity study in dogs and carcinogenicity studies in rats and mice; and
3) developmental and reproduction studies in rats and a developmental
study in rabbits.  There is also a complete mutagenicity battery, as
well as a metabolism study in the rat.  As part of the new EPA 158
guideline requirements, a 21/28 day dermal study, acute and subchronic
neurotoxicity studies, as well as an immunotoxicity study in rats and/or
mice (see appendix III) are now required for chlorimuron ethyl.  

Hematological changes (indicative of mild anemia) and atrophy of the
thymus were observed in dogs after subchronic exposure. However, atrophy
of the thymus was not associated with any histopathology and not seen
after chronic exposure.  No other potential immunotoxic effects were
observed in the toxicology database.  Additionally, no evidence of
neurotoxicity was observed and a developmental neurotoxicity study is
not warranted at this time.  Therefore, an additional 10x database
uncertainty factor is not needed.

3.1.1.2  Mode of Action, Metabolism, Toxicokinetic Data  TC "3.1.1.2 
Mode of action, metabolism, toxicokinetic data" \f C \l "4"  

Chlorimuron ethyl is an herbicide belonging to the sulfonylurea class of
chemicals.  The pesticidal mode of action for chlorimuron ethyl is
through inhibition of the plant enzyme acetolactate synthase. 
Inhibition of this enzyme blocks branch-chain amino acid biosynthesis
involved in plant growth processes which leads to death of the plant. 
Acetolactate synthase is not found in humans or other mammals.

 

3.1.2  Toxicological Effects  TC "3.1.2  Toxicological Effects" \f C \l
"3"  

Chlorimuron ethyl has low or minimal acute toxicity via the oral
(category IV), dermal (category III), and inhalation routes of exposure
(category IV).  It is mildly irritating to the eye (category III) and
non-irritating to the skin (category IV); it is not a skin sensitizer.

In subchronic toxicity studies, no adverse effects were observed up to
the limit dose tested (1030 mg/kg/day) in mice.  In rats, decreased body
weight gain and liver pathology (margination of hepatocyte cytoplasmic
content in the centrilobular areas) were observed in males only at 173
mg/kg/day.  Mild hemolytic anemia, atrophy of the thymus and prostate
and increased liver weights were seen in dogs at 42.7 mg/kg/day. 
Chronic exposure to chlorimuron ethyl also led to mild anemia (decreased
erythrocyte count, hematocrit, and hemoglobin concentration) in dogs,
but atrophy of the thymus and prostate were not seen. In rats,
treatment-related effects observed were limited to decreased body weight
and body weight gain in both sexes after long-term exposure. 
Prostatitis (males), and fatty replacement in the pancreas (both sexes)
were also observed but considered incidental occurrences; biliary
hyperplasia/ fibrosis (females) was also seen and attributed to aging. 
In mice, there were no treatment-related effects observed up to 216
mg/kg/day.  There was no evidence of carcinogenicity observed in the
mouse or rat carcinogenicity studies.  In addition, there was no
indication of mutagenicity in the battery of available studies.

In the developmental toxicity studies, decreases in maternal body weight
gain and delayed ossification in fetuses were observed in rats at 150
mg/kg/day.  In rabbits, decreases in maternal body weight gain were seen
at 300 mg/kg/day, while delayed ossification was seen in fetuses at a
lower dose of 48 mg/kg/day, indicating increased quantitative
susceptibility.  In a guideline 2-generation reproduction study in rats,
decreased body weight and histopathology in the cerebellum (cellular
changes in the internal granular and external germinal layers) were seen
in pups at 177 mg/kg/day.  These effects were seen in the absence of
maternal toxicity indicating increased quantitative susceptibility of
the pups to chlorimuron ethyl.  However, these effects were not
associated with any neurotoxicity or neurobehavioral changes, and not
observed in other reproduction studies in rats.  In a non-guideline
reproduction toxicity study (1-generation) in rats, decreased body
weight (females) and liver histopathology (males) were seen in parental
animals at 173 mg/kg/day, along with decreases in litter weights.  In
another reproduction study (1-year interim sacrifice) in rats, decreases
in maternal and pup body weights were observed at 195 mg/kg/day. 

Based on the hazard and exposure data available for chlorimuron ethyl,
there are low concerns and no residual uncertainties with regard to pre
and/or postnatal toxicity.  Therefore, HED recommends the FQPA Safety
Factor be reduced to1x. 

In the available toxicity studies, there was no evidence of estrogen-,
androgen-, and/or thyroid-mediated toxicity.

3.1.3  Dose-response  TC "3.1.3  Dose-response" \f C \l "3"  

For chronic dietary exposure, the chronic toxicity study, along with the
subchronic toxicity study in dogs were used as co-critical studies to
calculate the cRfD of 0.09 mg/kg/day.  In the chronic study, the NOAEL
of 9 mg/kg/day was based on mild anemia observed at the LOAEL of 51
mg/kg/day.  In the subchronic study, the NOAEL of 2.8 mg/kg/day was
based on hematological changes (increased hematocrit, hemoglobin, and
erythrocyte counts), atrophy of the thymus and prostate and increased
absolute and relative liver weights observed at the LOAEL of 42.7
mg/kg/day.  Although the LOAELS in both the subchronic and chronic dog
studies are similar, the NOAELs established in the studies are
different.  In the subchronic study, a NOAEL of 2.8 mg/kg/day was
established while a NOAEL of 9.0 mg/kg/day was determined in the chronic
study.  However, the lower NOAEL of 2.8 mg/kg/day seen in the subchronic
study is considered an artifact of the dose selection process and
attributed to the dose spacing.  Therefore, the NOAEL of 9 mg/kg/day
from the chronic study and the LOAEL of 42.7 mg/kg/day from the
subchronic study were used for the chronic dietary risk assessment. 
Acute dietary endpoints (general population and females age 13-49) were
not selected due to the absence of effects that can be attributed to a
single dose exposure.  The co-critical dog studies were also used to
select the dose and endpoint for occupational short- and
intermediate-term dermal and inhalation exposures.  There are no
residential uses proposed for chlorimuron ethyl; therefore, incidental
oral and residential dermal and inhalation risk assessments were not
conducted. 

3.1.4  FQPA  TC "3.1.4  FQPA" \f C \l "3"  

HED recommends the FQPA SF be reduced to 1X because there are no/low
concerns and no residual uncertainties with regard to pre- and/or
postnatal toxicity, and the toxicological database is essentially
complete (see section 3.4).  Although histopathological alterations were
seen in the cerebellum of pups in the 2-generation reproduction study,
the findings were not associated with any neurobehavioral changes or any
indications of neurotoxicity.  Furthermore, the histopathological
alterations were not observed in two other rat reproduction studies and
there was no evidence of neurotoxicity observed in other rat toxicity
studies or toxicity studies in other species (rabbits, mice, or dogs).

3.2  Absorption, Distribution, Metabolism, Excretion (ADME)  TC "3.2 
Absorption, Distribution, Metabolism, Excretion (ADME)" \f C \l "2"   

Several deficiencies were noted for the chlorimuron ethyl metabolism
studies.  However, the data did show that chlorimuron ethyl is absorbed
from the gastrointestinal tract and is eliminated equally in urine and
feces with a biological half-life of about 50 hours.  Chlorimuron ethyl
is distributed throughout the body, with the largest portions found in
the liver.  Ten identified and several unidentified metabolites were
isolated from the tissues and excreta; however, conclusions concerning
the distribution of metabolites within the tissue, urine, or feces, or
effects of sex or dosing regimen on metabolism can not be made due to
the deficiencies in the reported data and/or study design.

3.3  FQPA Considerations  TC "3.3  FQPA Considerations" \f C \l "2"  

3.3.1  Adequacy of the Toxicity Database  TC "3.3.1  Adequacy of the
Toxicity Database" \f C \l "3"  

The database is adequate to characterize potential pre- and/or
post-natal risk for infants and children.  Acceptable/guideline studies
for developmental toxicity in rats and rabbits, and reproduction in rats
are available for FQPA assessment.

3.3.2  Evidence of Neurotoxicity  TC "3.3.2  Evidence of Neurotoxicity"
\f C \l "3"  

In a 2-generation reproduction study in rats, histopathological
alterations were seen in the cerebellum (cellular changes in the
internal granular and external germinal layers) of F2 pups at 177
mg/kg/day.  These findings were not associated with any neurobehavioral
changes or any indications of neurotoxicity.  In addition, these
histopathological alterations were not observed in two other
reproduction studies.  Furthermore, there was no evidence of
neurotoxicity observed in other rat toxicity studies or toxicity studies
in other species (rabbits, mice, or dogs).

3.3.3  Developmental Toxicity Studies  TC "3.3.3  Developmental Toxicity
Studies" \f C \l "3"  

In a developmental toxicity study in rats, slight decreases (5%) in body
weight were observed in maternal animals and delayed ossification was
seen in fetuses at 150 mg/kg/day (NOAEL= 30 mg/kg/day).  In a
developmental toxicity study in rabbits, maternal effects included
decreased body weight gain at 300 mg/kg/day (NOAEL= 48 mg/kg/day) and
delayed ossification in fetuses at 48 mg/kg/day (NOAEL=13 mg/kg/day).

3.3.4  Reproductive Toxicity Study  TC "3.3.4  Reproductive Toxicity
Study" \f C \l "3"  

In a reproduction study in rats after a 1-year interim sacrifice (MRID #
00143128), there were decreases in body weight (12%) observed in
parental females at 195/227 mg/kg/day (NOAEL = 19/23 mg/kg/day).  In
pups at 195/227 mg/kg/day, there were also decreases in body weights in
F1a males and females (20/19%) and F1b females (12%).  In a 1-generation
reproduction study in rats, decreased body weight in females (12%) and
liver histopathology in males were observed at 173/209 mg/kg/day (M/F). 
Additionally, decreased litter weights were observed in pups at 173/209
mg/kg/day.  In a 2-generation reproduction study in rats, decreases in
body weight [(F1a -20/19%), F1b  (7/12%), F2a (13%)] and
histopathological findings in the cerebellum (cellular changes in the
internal granular and external germinal layers) were seen in pups at 177
mg/kg/day.  These effects were observed in the absence of maternal
toxicity.

3.3.5  Additional Information from Literature Sources  TC "3.3.5 
Additional Information from Literature Sources" \f C \l "3"  

A literature search did not reveal information that would impact the
risk assessment.

3.3.6  Pre-and/or Postnatal Toxicity  TC "3.3.6  Pre-and/or Postnatal
Toxicity" \f C \l "3"  

3.3.6.1  Determination of Susceptibility  TC "3.3.6.1  Determination of
Susceptibility" \f C \l "4"  

Increased quantitative susceptibility was observed in a developmental
toxicity study in rabbits.  In the study, delayed ossification was
observed in fetuses at 48 mg/kg/day, while maternal effects (decreased
body weight gain) were seen at 300 mg/kg/day.  No evidence of
susceptibility was seen in a developmental toxicity study in rats. 
Increased quantitative susceptibility was also seen in a 2-generation
reproduction study in rats.  Decreased body weight and histopathology
findings in the cerebellum were observed in pups at 177/214 mg/kg/day
(male/female) in the absence of maternal toxicity.

3.3.6.2  Degree of Concern Analysis and Residual Uncertainties for Pre-
and/or Postnatal Susceptibility  TC "3.3.6.2  Degree of Concern Analysis
and Residual Uncertainties for Pre- and/or Postnatal Susceptibility" \f
C \l "4"  

The purposes of the Degree of Concern analysis are: (1) to determine the
level of concern for the effects observed when considered in the context
of all available toxicity data; and (2) to identify any residual
uncertainties after establishing toxicity endpoints and traditional
uncertainty factors to be used in the risk assessment.  If residual
uncertainties are identified, then HED determines whether these residual
uncertainties can be addressed by an FQPA safety factor and, if so, the
size of the factor needed.

Although the data suggests increased quantitative susceptibility in the
developmental rabbit study and the rat reproduction study, there are no
residual uncertainties with regard to prenatal toxicity following in
utero exposure to rats or rabbits and pre and/or post-natal exposures to
rats.  The fetal effect seen in rabbits was limited to delayed
ossification and although effects (histopathology in the cerebellum)
were seen in a rat reproduction study, there was no evidence of
increased susceptibility observed in two additional reproduction studies
in rats.  Additionally, there are clear NOAELs for the offspring effects
seen in rabbits (NOAEL=13 mg/kg/day) and rats (17 mg/kg/day). 
Furthermore, the NOAEL (9 mg/kg/day) used to establish the cRfD of 0.09
mg/kg/day is considered protective of potential developmental effects
observed at the higher doses.  Considering the overall toxicity database
and doses selected for risk assessment, the degree of concern for the
effects observed in the studies is low.  Therefore, it is recommended
that the FQPA safety factor be reduced to 1X and no additional safety
factors are needed (Section 3.4).

3.3.7  Recommendation for Not Requiring a Developmental Neurotoxicity
Study  TC "3.3.7  Recommendation for not requiring a Developmental
Neurotoxicity Study" \f C \l "3"  

Although histopathological alterations were seen in the cerebellum
(cellular changes in the internal granular and external germinal layers)
of F2 pups in the 2-generation reproduction study, these findings were
not associated with any neurobehavioral changes or any indications of
neurotoxicity.  In addition, there was no evidence of neurotoxicity
observed in two other reproduction studies in rats at similar doses,
developmental studies in rats or rabbits, or any other toxicity study in
rats, rabbits, mice, or dogs.  In addition, there are no residual
uncertainties regarding pre- and/or postnatal toxicity following
chlorimuron ethyl exposure (see 3.3.6.2).  Therefore, a developmental
neurotoxicity study is not warranted at this time.

3.4  FQPA Safety Factor for Infants and Children  TC "3.4  FQPA Safety
Factor for Infants and Children" \f C \l "2"  

HED recommends that the FQPA SF be reduced to 1x based on the following:

The toxicity database for chlorimuron ethyl is complete in regards to
pre- and postnatal toxicity.  There are acceptable developmental
toxicity studies in rats and rabbits and reproduction studies in rats. 
There are low concerns and no residual uncertainties with regard to pre-
and postnatal toxicity.

Although histopathological alterations were seen in the cerebellum of
pups in the 2-generation reproduction study, the findings were not
associated with any neurobehavioral changes or any indications of
neurotoxicity.  Furthermore, the histopathological alterations were not
observed in two other rat reproduction studies and there was no evidence
of neurotoxicity observed in other rat toxicity studies or toxicity
studies in other species (rabbits, mice, or dogs).  A developmental
neurotoxicity toxicity study is not warranted at this time.

The dietary (food + water) exposure assessment is based on
health-protective assumptions that are designed to ensure actual
exposures are not underestimated.

The dietary drinking water assessment is based on values generated by
model and associated modeling parameters which are designed to provide
conservative, health protective, high-end estimates of water
concentrations.

3.5  Hazard Identification and Toxicity Endpoint Selection  TC "3.5 
Hazard Identification and Toxicity Endpoint Selection" \f C \l "2"  

3.5.1  Acute Reference Dose (aRfD) – General Population  TC "3.5.1 
Acute Reference Dose (aRfD) – General Population" \f C \l "3"  

No appropriate endpoint attributable to a single dose was identified in
the toxicity database.

3.5.2  Acute Reference Dose (aRfD) - Females age 13-49  TC "3.5.2  Acute
Reference Dose (aRfD) - Females age 13-49" \f C \l "3"  

No appropriate endpoint attributable to a single dose was identified in
the toxicity database.  

3.5.3  Chronic Reference Dose (cRfD)  TC "3.5.3  Chronic Reference Dose
(cRfD)" \f C \l "3"   

Studies Selected:  Subchronic and Chronic Toxicity-Dog (Co-critical)

MRID No:  00132745 and 00149579		

Dose and Endpoint for Risk Assessment: NOAEL= 9 mg/kg/day 

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x
intraspecies variability)

  = 0.09 mg/kg/day

Comments about Study/Endpoint/Uncertainty Factors:  

Subchronic toxicity and chronic toxicity studies in dogs were used to
select the dose and endpoint for short- and intermediate-term dermal and
inhalation exposure. The NOAEL of 9 mg/kg/day was selected from the
chronic study, based on mild anemia at the LOAEL of 50 mg/kg/day (see
section 3.1.3).  The LOAEL of 42.7 mg/kg/day was selected from the
subchronic study, based on hematological changes (increased hematocrit,
hemoglobin, erythrocyte counts), atrophy of the thymus and prostate as
well as increased absolute and relative liver weights; the subchronic
NOAEL is 2.8 mg/kg/day.  Although a lower NOAEL of 2.8 mg/kg/day was
established in the subchronic dog study, it is considered an artifact of
the dose selection process and attributed to the dose spacing. 
Uncertainty factors (100x) include: 10x for interspecies extrapolation,
and 10x for intraspecies variability.

3.5.4  Incidental Oral Exposure  TC "3.5.4  Incidental Oral Exposure" \f
C \l "3"  

There are no residential uses proposed or registered; therefore
exposures and risks via this route are not of concern and points of
departure have not been selected at this time.

3.5.5  Dermal Absorption  TC "3.5.5  Dermal Absorption" \f C \l "3"  

There are no dermal toxicity or dermal absorption studies available for
chlorimuron ethyl.  Therefore, a default dermal absorption factor of
100% is assumed for risk assessment.

3.5.6  Short-and Intermediate-Term Occupational Dermal and Inhalation
Exposure  TC "3.5.6  Short- and Intermediate-term Occupational Dermal
and Inhalation Exposure" \f C \l "3"  

Studies Selected:  Subchronic and Chronic Toxicity-Dog (Co-critical)

MRID No:  00132745 and 00149579		

Dose and Endpoint for Risk Assessment: NOAEL= 9.0 mg/kg/day 

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x
intraspecies variability)

Comments about Study/Endpoint/Uncertainty Factors:  

Subchronic toxicity and chronic toxicity studies in dogs were used to
select the dose and endpoints for short- and intermediate-term dermal
and inhalation exposure. The NOAEL of 9 mg/kg/day was selected from the
chronic study, based on mild anemia at the LOAEL of 50 mg/kg/day (see
section 3.1.3).  The LOAEL of 42.7 mg/kg/day was selected from the
subchronic study, based on hematological changes (increased hematocrit,
hemoglobin, erythrocyte counts), atrophy of the thymus and prostate as
well as increased absolute and relative liver weights; the subchronic
NOAEL is 2.8 mg/kg/day.  Although a lower NOAEL of 2.8 mg/kg/day was
established in the subchronic dog study, it is considered an artifact of
the dose selection process and attributed to the dose spacing. 
Uncertainty factors (100x) include: 10x for interspecies extrapolation,
and 10x for intraspecies variability.

3.5.7  Level of Concern for Margin of Exposure  TC "3.5.7  Level of
Concern for Margin of Exposure" \f C \l "3"  

TABLE 3.5.7   Summary of Levels of Concern for Risk Assessment.

Route	Short-Term

(1 - 30 Days)	Intermediate-Term

(1 - 6 Months)	Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal	100	100	N/A

Inhalation	100	100	N/A

3.5.8  Recommendation for Aggregate Exposure Risk Assessments  TC "3.5.8
 Recommendation for Aggregate Exposure Risk Assessments" \f C \l "3"  

As per FQPA, 1996, when there are potential residential exposures to a
pesticide, aggregate risk assessment must consider exposures from three
major sources: oral, dermal and inhalation exposures.  However, an
aggregate risk assessment across the three routes of exposure is not
required for chlorimuron ethyl since there are no registered or proposed
residential uses.  For occupational risk assessments the dermal and
inhalation exposures should be combined since the same endpoint and
NOAEL have been selected for these exposure routes.

3.5.9  Classification of Carcinogenic Potential  TC "3.5.9 
Classification of Carcinogenic Potential" \f C \l "3"  

There were no treatment-related increases in tumors in rat and mouse
carcinogenicity studies after exposure to chlorimuron ethyl. 
Chlorimuron ethyl is classified as “Not likely to be Carcinogenic to
humans.”

  SEQ CHAPTER \h \r 1 3.5.10  Summary of Toxicological Doses and
Endpoints for Chlorimuron ethyl for Use in Human Risk Assessments  TC
"3.5.10  Summary of Toxicological Doses and Endpoints for
Trifloxysulfuron for Use in Human Risk Assessments" \f C \l "3"  

TABLE 3.5.10a  Toxicological Doses and Endpoints for Chlorimuron ethyl
for Use in Dietary and Non-Occupational Human Health Risk Assessments.

Exposure/

Scenario	Point of Departure	Uncertainty/

FQPA Safety Factors	RfD, PAD, Level of Concern for Risk Assessment	Study
and Toxicological Effects

Acute Dietary (All populations)	N/A

	N/A

	N/A

	No appropriate endpoint identified.

Chronic Dietary (All Populations)	NOAEL = 9 mg/kg/day	UFA = 10X

UFH = 10X

FQPA SF = 1X	Chronic RfD = 0.09 mg/kg/day

cPAD = 0.09 mg/kg/day	Co-critical studies

90-day oral toxicity – dogs

LOAEL = 42.7 mg/kg/day, based on hematological changes (increased
hematocrit, hemoglobin, erythrocyte counts) atrophy of the thymus and
prostate, increased absolute and relative liver weights.

Chronic toxicity – dogs

LOAEL = 50 mg/kg/day, based on mild anemia.

Cancer (oral, dermal, inhalation)	“Not Likely to be Carcinogenic to
Humans.”

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).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use
of a short-term study for long-term risk assessment.  UFDB = to account
for the absence of key data (i.e., lack of a critical study).  FQPA SF =
FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c =
chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level
of concern.  N/A = not applicable. 

TABLE 3.5.10b  Summary of Toxicological Doses and Endpoints for
Chlorimuron ethyl for Use in    Occupational Human Health Risk
Assessments.

Exposure/

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

Dermal (1-30 days) and Intermediate-term (1-6 months)	NOAEL = 9.0
mg/kg/day

DAF=100%	UFA = 10X

UFH = 10X

FQPA SF = 1X 	Residential LOC for MOE = 100	Co-critical studies

90-day oral toxicity – dogs

LOAEL = 42.7 mg/kg/day, based on hematological changes (increased
hematocrit, hemoglobin, erythrocyte counts) atrophy of the thymus and
prostate, increased absolute and relative liver weights.

Chronic toxicity – dogs

LOAEL = 50 mg/kg/day, based on mild anemia.  

Inhalation Short-(1-30 days) and Intermediate-term (1-6 months)	NOAEL =
9.0 mg/kg/day

IAF=100%	UFA = 10X

UFH = 10X

FQPA SF = 1X	Residential LOC for MOE = 100	Co-critical studies

90-day oral toxicity – dogs

LOAEL = 42.7 mg/kg/day, based on hematological changes (increased
hematocrit, hemoglobin, erythrocyte counts) atrophy of the thymus and
prostate, increased absolute and relative liver weights.

Chronic toxicity – dogs

LOAEL = 50 mg/kg/day, based on mild anemia.

Cancer (oral, dermal, inhalation)	“Not Likely to be Carcinogenic to
Humans.”

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).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use
of a short-term study for long-term risk assessment.  UFDB = to account
for the absence of key data (i.e., lack of a critical study).  FQPA SF =
FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c =
chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level
of concern.  N/A = not applicable.

3.6  Endocrine disruption  TC "3.6  Endocrine disruption" \f C \l "2"  

EPA is required under the FFDCA, as amended by FQPA, to develop a
screening program to determine whether certain substances (including all
pesticide active and other ingredients) “may have an effect in humans
that is similar to an effect produced by a naturally occurring estrogen,
or other such endocrine effects as the Administrator may designate.” 
Following recommendations of its Endocrine Disruptor Screening and
Testing Advisory Committee (EDSTAC), EPA determined that there was a
scientific basis for including, as part of the program, the androgen and
thyroid hormone systems, in addition to the estrogen hormone system. 
EPA also adopted EDSTAC’s recommendation that the Program include
evaluations of potential effects in wildlife.  For pesticide chemicals,
EPA will use FIFRA and, to the extent that effects in wildlife may help
determine whether a substance may have an effect in humans, FFDCA
authority to require the wildlife evaluations.  As the science develops
and resources allow, screening of additional hormone systems may be
added to the Endocrine Disruptor Screening Program (EDSP).

When additional appropriate screening and/or testing protocols being
considered under the Agency’s EDSP have been developed, chlorimuron
ethyl may be subjected to further screening and/or testing to better
characterize effects related to endocrine disruption.  In the available
toxicity studies, there was no evidence of estrogen-, androgen-, and/or
thyroid-mediated toxicity.

4.0  Public Health and Pesticide Epidemiological Data  TC "4.0  Public
Health and Pesticide Epidemiological Data" \f C \l "1"  

None.

  SEQ CHAPTER \h \r 1 5.0  Dietary Exposure Risk Characterization  TC
"5.0  Exposure Assessment" \f C \l "1"  

5.1	Pesticide Metabolism and Environmental Degradation  TC \l2 "5.1 
Pesticide Metabolism and Environmental Degradation 

5.1.1	Metabolism in Primary Crops  TC \l3 "5.1.1  Metabolism in Primary
Crops 

Plant metabolism studies on soybeans and peanuts were summarized in a
previous risk assessment (DP# 301317, R. Griffin, 8/31/04).  Soybean
plants in the first to third trifoliate leaf stage were sprayed with
[14C-phenyl] or [14C-pyrimidine-2]chlorimuron-ethyl at a rate of 0.031
lbs ai/A.  Plants were sampled on 0, 19, and 35 days after treatment
(DAT) and mature beans were harvested at 103 DAT.  Only parent compound
chlorimuron-ethyl was observed in the plant wash (94-100%).  Growth
chamber studies were also submitted in which cut soybean plants were
immersed in solutions of [14C]chlorimuron-ethyl for several hours to 2
days.  These studies resulted in the identification of the following
metabolites: chlorimuron-ethyl homoglutathione conjugate,
chlorimuron-ethyl acid, pyrimidine amine, desmethyl pyrimidine amine,
and saccharin.  Considering the low level of residues in/on mature
soybeans expected from the use on soybeans (6-7 metabolites equivalent
to a total of <0.02 ppm chlorimuron-ethyl), HED did not require further
work to identify the metabolites comprising the terminal radioactive
residues.

In a greenhouse metabolism study, peanuts were treated with [14C-phenyl]
and [2-14C-pyrimidine]chlorimuron-ethyl at 0.031 lb ai/A, 60 days prior
to harvest. The data indicated a lack of significant translocation of
the active ingredient.  Less than 1% of the total radioactive residues
(extractable and unextractable) were found in either nutmeats or hulls,
and over 99% of the radioactivity was present in vines at harvest.  The
total radioactive residues were found to be about 0.02 and 0.05 ppm in
nutmeat and hulls, respectively.  The extractable residues in nut meats
are between 51-63% of the TRR, whereas those in the corresponding hulls
are 54-75%. The identified metabolites constitute <15-28% and 29-33% of
the total radioactive residues in peanut nutmeats and hulls,
respectively.  

A previously submitted corn metabolism study was reviewed in conjunction
with a petition for uses on cranberry and low-growing berry (PP# 6E7153,
DP# 361368, K. Middleton, 2/5/09).  The variety used in the corn
metabolism study, Pioneer 3377IR (43483707, A. Parmar, 1/6/08), is
identified as being resistant to acetolactate synthase (ALS) inhibitors
which includes sulfonylureas (Weed Technology, 1995, 9:696-702).  Based
on the corn metabolism study, the overall metabolic pathway involves
cleavage of the sulfonylurea linkage to yield the corresponding
sulfonamide and pyrimidine amine, and hydroxylation of the parent to
yield 4-hydroxy-chlorimuron-ethyl.  The fate of chlorimuron-ethyl was
consistent in both pre- and postemergence treatments.  The results were
similar to those of the peanut and soybean metabolism studies which were
previously reviewed (PP#8F3694, DEB# 4691, H. Fonouni, 2/7/89 and
PP#5F3186, C. Deyrup, 12/16/85).

There were deficiencies cited in the last risk assessment which remain
outstanding: (1) for the corn metabolism study the petitioner should
provide the dates of sample extraction and analysis to confirm that the
majority of the immature samples were initially analyzed within ~6
months of harvest; and (2) confirmatory data should be submitted to
validate that these samples were analyzed within ~6 months of harvest. 
This information has not as yet been submitted.

The proposed metabolic pathway for chlorimuron ethyl in corn is
presented in Figure 1, which was copied without alteration from MRID
43483707.

	

FIGURE 1. 	Proposed Metabolic Profile of Chlorimuron ethyl in Corn.

Conclusions:  Based on the similar metabolism in corn (herbicide
tolerant variety) and soybeans and peanuts (likely not done with
tolerant varieties), for the purposes of these petitions, ARIA and HED
will consider chlorimuron ethyl as the residue of concern (ROC) in
plants (email, R. Loranger, 7/15/09).  Resolution of the deficiencies of
the corn metabolism study is a condition of registration for these
petitions.

5.1.2	Metabolism in Rotational Crops  TC \l3 "5.1.2  Metabolism in
Rotational Crops 

A sandy loam soil was treated with [14C-phenyl(U)]chlorimuron ethyl at
the rate of 0.0375 lbs ai/A and aged for 120 days in a greenhouse. 
Barley, beets, cotton and peanuts were planted after the 120-day aging
period and grown to maturity.  Crop samples were harvested and analyzed
at various stages of growth and at maturity. At final harvest barley
straw, peanuts, and cotton foliage contained total 14C residues of
0.025, 0.016, and 0.016 ppm, respectively, but contained very low
concentrations (<0.005 ppm) of chlorimuron ethyl and its major
metabolites.  Total 14C-residue concentrations in each of the other
mature crop fractions were insignificant (<0.01 ppm).  14C-Residues in
the soil samples declined from 0.019 ppm at treatment to 0.0022 ppm at
the final harvest.  Field accumulation in rotational crops studies have
not been requested, due to the insignificant residues (<0.01 ppm)
detected in the confined rotational crop study.

5.1.3	Metabolism in Livestock  TC \l3 "5.1.3  Metabolism in Livestock 

Ruminants

In a ruminant metabolism study, two British Saanen goats were dosed
orally via capsule twice a day for three consecutive days with either
[14C-2-pyrimidinyl] (PYR) or [14C-U-phenyl] (PH) chlorimuron-ethyl at a
dose of 20 mg ai/goat/day.  This dose level was equivalent to 0.30 and
0.36 mg ai/kg body weight/day for the 14C-PYR and 14C-PH labels,
respectively, or 9.99 and 10.02 ppm of chlorimuron ethyl in the diet. 
The data from the two 14C-labels were similar and indicate that the
primarily route of excretion and metabolism of chlorimuron ethyl in
goats appears to involve the direct excretion of parent compound via the
urine.  The identification of chlorimuron acid and dechloro chlorimuron
ethyl in kidneys and urine also indicates that parent can undergo
cleavage of the ethyl ester and oxidative dechlorination.  Chlorimuron
ethyl also may undergo hydrolytic cleavage of the amide linkage to form
the sulphonamide and pyrimidine amine metabolites, which can be either
excreted directly or further degraded to more polar metabolites, such as
dechloro-pyrimidine amine and demethoxy pyrimidine amine.  The
identification of chlorimuron ethyl thiol in urine also suggests that
parent may undergo conjugation with glutathione, with subsequent
degradation of the glutathione moiety. 

The proposed metabolic pathway for chlorimuron ethyl in the dairy goat
is shown below in Figure 2.  The high level of parent compound detected
in the urine indicates that chlorimuron ethyl is readily absorbed and
excreted without additional modification.  The identification of
chlorimuron acid and dechloro chlorimuron ethyl in kidneys and urine
indicates that parent can also undergo cleavage of the ethyl ester and
oxidative dechlorination.  The data from kidneys and feces also indicate
that parent may undergo hydrolytic cleavage of the amide linkage to form
the sulphonamide and pyrimidine amine metabolites, which can be either
excreted directly or further degraded to more polar metabolites, such as
dechloro-pyrimidine amine and demethoxy pyrimidine amine, which were
tentatively identified in milk.  The presence of chlorimuron ethyl thiol
in urine also suggests that parent may undergo conjugation with
glutathione with subsequent degradation of the glutathione moiety.

Figure 2.  Proposed Metabolic Profile of Chlorimuron Ethyl in Lactating
Goats

Ruminant Conclusions:   Although identification of 14C-residues in milk
and tissues was limited due to the low levels of TRR (<0.07 ppm), the
additional analyses of urine and feces provided sufficient information
to adequately characterize the metabolism of [14C] chlorimuron ethyl in
goats.  However, before the goat metabolism study can be deemed
adequate, additional information is required on the duration of sample
storage prior to extraction and analysis, along with any data supporting
the stability of 14C-residues in milk and tissues during frozen storage.

In conjunction with the data from urine and feces, the milk and tissue
data from both 14C-labels indicate that chlorimuron ethyl is absorbed
and rapidly excreted by goats primarily as parent via the urine.  In
addition, chlorimuron ethyl is also metabolized by oxidative
dechlorination of parent or metabolites, cleavage of the ethyl ester,
and hydrolytic cleavage of the amide linkage.  The presence of
chlorimuron ethyl thiol in urine also suggests that the parent may
undergo conjugation with glutathione, with subsequent degradation of the
glutathione moiety.

Poultry

In a poultry metabolism study, two groups of Hisex laying hens (5
hens/group) were dosed orally for seven consecutive days with either
[14C-2-pyrimidinyl] (PYR) or [14C-U-phenyl] (PH) chlorimuron ethyl at a
dose of 1.46 and 1.32 mg ai/hen/day, respectively.  The data from the
two 14C-labels were similar and indicate that the primarily route of
metabolism for chlorimuron ethyl in hens appears to involve cleavage of
the sulfonylurea bridge to yield the pyrimidine amine and sulphonamide
metabolites, which are then further degraded to more polar metabolites. 
The parent can also undergo cleavage of the ethyl ester to form
chlorimuron acid and oxidative dechlorination to form
dechloro-chlorimuron ethyl.  There was also some evidence for direct
hydroxylation of the parent compound. The proposed metabolic pathway for
chlorimuron ethyl in the poultry is shown below in Figure 3.  Based on
the major metabolites identified in eggs, tissues and excreta, the
metabolism of chlorimuron ethyl in poultry primarily involves cleavage
of the sulfonylurea bridge to yield the pyrimidine amine and
sulphonamide metabolites, which are further degraded to more polar
metabolites.  Parent also can undergo cleavage of the ethyl ester to
form chlorimuron acid and oxidative dechlorination to form
dechloro-chlorimuron ethyl. 

 

Figure 3.  Proposed Metabolic Profile of Chlorimuron Ethyl in Laying
Hens.

Poultry Conclusions:   The poultry metabolism study is not adequate. 
There was a general lack of supporting raw data related to the
extraction and analysis of samples, and the following specific
deficiencies were noted in the study: 

Due to the small size of the fat and skin subsamples (~0.1 g) used for
radioassay, the LOD for fat and skin samples were too high (0.02-0.03
ppm).

The dates of sample extraction and analysis were not reported.

No supporting storage stability data were provided although samples may
have been stored frozen for up to 8 months prior to analysis. 

Details were not provided on the recovery of radioactivity through the
various extraction procedures.

Only the identities of parent and sulphonamide were confirmed by LC-MS.

A major unknown in egg yolks (34-48% TRR; 0.011-0.023 ppm) and liver
(40-69% TRR; 0.040-0.204 ppm) was not adequately identified.  The
unknown was organosoluble and contained an intact sulfonylurea bridge.

Although the study is inadequate, the available data suggest that the
primary route of metabolism for chlorimuron ethyl in poultry involves
cleavage of the sulfonylurea bridge to yield the pyrimidine amine and
sulphonamide metabolites.

Nature of the Residue - Livestock Conclusions:  Since very low residues
are expected in livestock, exaggerated doses were used in the metabolism
studies, and considering the low toxicity of the parent and by analogy
the metabolites, ARIA and HED will consider chlorimuron ethyl as the
residue of concern in livestock (email, R. Loranger, 7/15/09). 
Resolution of the deficiencies of the ruminant and poultry metabolism
studies is a condition of registration for these petitions. 

Analytical Methodology  TC \l3 "5.1.4  Analytical Methodology 

Plants

Current Enforcement Methods

Two HPLC methods are available for enforcing tolerances of chlorimuron
ethyl. The original enforcement method for soybeans (AMR-459-85) is
found in PAM Volume II.  For this method, residues are extracted with
dichloromethane, filtered, diluted with water, and concentrated to an
aqueous remainder.  The aqueous fraction is partitioned against hexane,
discarding the hexane phase, and residues are then partitioned into
dichloromethane and cleaned up using a silica gel cartridge.  Residues
are concentrated to dryness and redissolved in HPLC mobile phase
(hexane/isopropanol/methanol /glacial acetic acid/water;
750:125:125:2:1).  Residues are then determined by HPLC using a
photoconductivity detector.  The method LOQ is 0.01 ppm.

An HPLC/UV method is also available for peanuts (AMR-990-87).  This
method differs slightly from the above method primarily in the use of
different solvents for the sample preparation step.  The method LOQ is
0.02 ppm for peanut nutmeat and 0.05 ppm for peanut hulls.

Data Collection Method Review

Corn and soybean samples were analyzed for chlorimuron ethyl using an
LC/MS/MS method, DuPont-13412, Revision No. 1, “Analytical Method for
the Determination of Nicosulfuron, Thifensulfuron Methyl,
Ethametsulfuron Methyl, Rimsulfuron, Tribenuron Methyl, and Chlorimuron
ethyl in Oil Crop Matrices Using SPE Purification and LC/MS/MS
Detection.”  This method has been proposed as a new tolerance
enforcement method for residues of sulfonylureas, and an independent
laboratory validation trial for this method has been previously reviewed
(DP# 330813, S. Hummel, 8/8/06).

 

For this method, samples were initially hydrated with 20 mM potassium
phosphate buffer.  Residues were then extracted from each matrix twice
with ACN/K2HPO4 (75:25 v:v, pH 7) followed by centrifugation.  The
combined extracts were partitioned against hexane, and the remaining
aqueous phase was concentrated and then diluted with 0.01% acetic acid. 
Residues were then cleaned up using an ENV SPE cartridge eluted with 25
mM NaOH in methanol.  The residues were concentrated and then diluted
with 50 mM ammonium acetate/ACN (9:1 v:v) and analyzed by LC/MS/MS using
external standards.  Residues of chlorimuron ethyl in corn and soybean
matrices were detected and quantified using the ion transition m/z
415→186.  The LOQ for each corn and soybean commodity is 0.01 ppm and
the LOD is 0.003 ppm.

The method was validated in conjunction with the analysis of the field
corn trial samples using control samples fortified with chlorimuron
ethyl at 0.01-2.0 ppm for forage and fodder (whole plants), 0.01-3.0 ppm
for stover, and 0.01-0.10 ppm for grain. The method was validated in
conjunction with the analysis of the soybean field trial samples using
control samples fortified with chlorimuron ethyl at 0.01-15 ppm for
forage, 0.01-30 ppm for hay, 0.01-0.4 ppm for seeds.

Conclusions:  There are adequate methods available for tolerance
enforcement for corn and soybean.  The method used for data collection
for corn and soybean commodities is adequate.   

Livestock

At this time, no detectable residues (<0.01 ppm) are expected in
livestock commodities; therefore, an enforcement method for residues of
chlorimuron ethyl in livestock commodities is not required.

5.1.5	Environmental Degradation TC \l3 "5.1.5  Environmental Degradation

The expected major route of degradation is by metabolism in soil, with
disappearance half-lives (for parent plus demethylated parent) of 75 to
112 days measured in sandy loam (Woodstown) and silt loam (Flanagan)
soils.  Terrestrial field dissipation studies in Delaware and North
Carolina yielded soil half-lives of 6.4 to 27 days for the disappearance
of the parent.  Abiotic hydrolysis is as fast as soil metabolism at pH 5
(half-lives 17 to 27 days) but is slow at pH 7 and 9.  Aqueous and soil
photolysis were found not to be significant processes.  Aerobic aquatic
metabolism was not tested; anaerobic aquatic metabolism yielded
half-lives of 2-3 weeks in a Florida sediment-water system, and 5-6
weeks in a Pennsylvania sediment-water system.

Chlorimuron ethyl has 6 major degradates, and no minor degradates. 
These include de-methylated parent, a “sulfonamide,” a
“pyrimidine-amine,” saccharin, dechlorinated pyrimidine-amine, and
demethylated pyrimidine-amine.  The demethylated parent, saccharin,
sulfonamide and pyrimidine-amine each remained at greater than 10% of
applied radioactivity at the end of some of the aerobic soil metabolism
studies (one year), and were major degradates in the field dissipation
studies at some time.  The sulfonamide and pyrimidine-amine were also
major products at the end of the pH 5 hydrolysis studies (30 days).  

5.1.6	Comparative Metabolic Profile TC \l3 "5.1.6  Comparative Metabolic
Profile 

Chlorimuron ethyl was seen to be extensively metabolized by both male
and female rats at the low and high dose.  Excretion was monitored up to
168 hrs and the elimination of radioactivity was equal approximately via
the urine and feces.  The retention of only small amounts of the
administered doses at 168 hours postdosing indicates that excretion is
the primary route of elimination in rats (ca. 98%).  The half-life is 50
hrs.  The major metabolites are (see Appendix V for structures):

1)  HOPY-DPX-F6025       {ethyl
2-[[[[(4-hydroxy-6-methoxy-2-pyrimidin-2-                

                                             
yl)amino]carbonyl]amino]sulfonyl]benzoate}

2)  ODM-DPX-F6025         {ethyl 2-[[[[(4-chloro-6-hydroxy-pyrimidin-2-

                                              
yl)amino]carbonyl]amino]sulfonyl]benzoate}

3)  HPY-DPX-F6025          {ethyl
2-[[[[(4-chloro-5-hydroxy-6-methoxy-pyrimidin-2-

                                              
yl)amino]carbonyl]amino]sulfonyl]benzoate}

4)  DI-HOPY-DPX-F6025  {ethyl
2-[[[[(4-6-dihydroxy-pyrimidin-2-yl)amino]carbonyl]

                                               amino]sulfonyl]benzoate}

5)  DPX-F6025                    {ethyl
2-[[[[(4-chloro-6-methoxy-2-pyrimidin-2-

                                              
yl)amino]carbonyl]amino]sulfonyl]benzoate}

6)  FA-Sulfonamide	          {2-[(amino)sulfonyl]benzoic acid}

In plants, the overall metabolic pathway involves cleavage of the
sulfonylurea linkage to yield the corresponding sulfonamide and
pyrimidine amine, and hydroxylation of the parent to yield
4-hydroxy-chlorimuron ethyl.  The fate of chlorimuron ethyl was
consistent in both pre- and postemergence treatments.  The plant
metabolism studies also resulted in the identification of the following
metabolites:  chlorimuron ethyl homoglutathione conjugate, chlorimuron
ethyl acid, pyrimidine amine, desmethyl pyrimidine amine, and saccharin.
 In general, the data indicated a lack of significant translocation of
the active ingredient in plants.

Chlorimuron ethyl is absorbed and rapidly excreted by goats primarily as
parent via the urine.  In addition, chlorimuron ethyl is also
metabolized by oxidative dechlorination of parent or metabolites,
cleavage of the ethyl ester, and hydrolytic cleavage of the amide
linkage.  The presence of chlorimuron ethyl thiol in urine also suggests
that the parent may undergo conjugation with glutathione, with
subsequent degradation of the glutathione moiety.  The primary route of
metabolism for chlorimuron ethyl in poultry involves cleavage of the
sulfonylurea bridge to yield the pyrimidine amine and sulphonamide
metabolites.

With respect to environmental fate, the expected major route of
degradation is by metabolism in soil, with disappearance half-lives (for
parent plus demethylated parent) of 75 to 112 days measured in sandy
loam (Woodstown) and silt loam (Flanagan) soils.  Terrestrial field
dissipation studies in Delaware and North Carolina yielded soil
half-lives of 6.4 to 27 days for the disappearance of the parent. 
Abiotic hydrolysis is as fast as soil metabolism at pH 5 (half-lives 17
to 27 days) but is slow at pH 7 and 9.  Aqueous and soil photolysis were
found not to be significant processes.  Aerobic aquatic metabolism was
not tested; anaerobic aquatic metabolism yielded half-lives of 2-3 weeks
in a Florida sediment-water system, and 5-6 weeks in a Pennsylvania
sediment-water system.

Chlorimuron ethyl has 6 major degradates.  These include demethylated
parent, a “sulfonamide,” a “pyrimidine-amine,” saccharin,
dechlorinated pyrimidine-amine, and demethylated pyrimidine-amine.  The
demethylated parent, saccharin, sulfonamide and pyrimidine-amine each
remained at greater than 10% of applied radioactivity at the end of some
of the aerobic soil metabolism studies (one year), and were major
degradates in the field dissipation studies at some time.  The
sulfonamide and pyrimidine-amine were also major products at the end of
the pH 5 hydrolysis studies (30 days).

In general, the overall metabolic pathway in all studied matrices
involves cleavage of the sulfonylurea linkage to yield the corresponding
sulfonamide and pyrimidine amine.  Demethylation is a significant
pathway in rats and the environment.  In plants, hydroxylation of the
phenyl ring of the parent occurs which yields 4-hydroxy-chlorimuron
ethyl.  The hydroxylation of the intact parent molecule appears to be a
minor pathway, and would likely increase its excretion.  HED and ARIA
consider the residue of concern to be parent in livestock. EFED has
included in the residue of concern for risk assessment purposes for
drinking water both chlorimuron ethyl and a major metabolite,
demethylated parent (12/17/08 email from EFED’s W. Shaughnessy).

5.1.7	Toxicity Profile of Major Metabolites and Degradates TC \l3 "5.1.7
 Toxicity Profile of Major Metabolites and Degradates 

The metabolism, or degradation of chlorimuron ethyl, has been studied in
the rat, in plants, and in the environment.  Although field corn,
soybean and peanut commodities may be feed items, finite residues of
chlorimuron ethyl are not expected in livestock commodities.  Based on
an analysis of the structural relationship of metabolites to parent
chlorimuron ethyl, the toxicity of metabolites is not expected to exceed
the parent compound.

5.1.8	Pesticide Metabolites and Degradates of Concern TC \l3 "5.1.8 
Pesticide Metabolites and Degradates of Concern 

Based on an analysis of the structural relationship of metabolites to
parent chlorimuron ethyl, the toxicity of metabolites is not expected to
exceed the parent compound.

Given the low total radioactivity in the RACs of treated plants and the
low absolute residue levels of the various plant metabolites, the parent
compound can serve as the residue of concern for both risk assessment
and tolerance enforcement purposes. 

Since very low residues are expected in livestock, exaggerated doses
were used in the metabolism studies, and considering the low toxicity of
the parent and by analogy the metabolites, ARIA and HED will consider
chlorimuron ethyl as the residue of concern in livestock.

Although chlorimuron ethyl has six major environmental degradates, due
to the demethylated parent likely having the most similar toxicity to
the parent, the residues of concern for risk assessment in drinking
water are chlorimuron ethyl and demethylated parent.  This decision also
takes into account the extremely low application rates and very low
absolute residue levels expected for the degradates in water.

TABLE 5.1.8 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	Chlorimuron ethyl 	Chlorimuron ethyl 

	Rotational Crop	Chlorimuron ethyl 	N/A

Livestock*

	Ruminant	Chlorimuron ethyl	Chlorimuron ethyl

	Poultry	Chlorimuron ethyl	Chlorimuron ethyl

Drinking Water

	Chlorimuron ethyl and demethylated parent	Not Applicable

* Negligible residues of the parent compound in peanut nutmeats and
soybean commodities are not expected to result in detectable secondary
residues in livestock commodities.

5.1.9	Drinking Water Residue Profile TC \l3 "5.1.9  Drinking Water
Residue Profile 

An updated drinking water assessment was conducted for the proposed uses
on herbicide tolerant field corn and soybeans (D358804, W. Shaughnessy,
6/15/09).  To account for exposure to residues in water under the most
conservative scenario, the value of 6.99 ppb (one-in-10-year mean) was
used in the dietary exposure assessment.  Water residues were
incorporated in the DEEM-FCID into the food categories “water, direct,
all sources” and “water, indirect, all sources.”   

The expected major route of degradation for chlorimuron-ethyl is by
metabolism in soil, with disappearance half-lives (for parent plus
demethylated parent) of 75 to 112 days measured in sandy loam
(Woodstown) and silt loam (Flanagan) soils.  Terrestrial field
dissipation studies in Delaware and North Caroline yielded soil
half-lives of 6.4 to 27 days for the disappearance of the parent. 
Abiotic hydrolysis is as fast as soil metabolism at pH 5 (half-lives 17
to 27 days) but is slow at pH 7 and 9.  Aqueous and soil photolysis were
found not to be significant processes.  Aerobic aquatic metabolism was
not tested; anaerobic aquatic metabolism yielded half-lives of 2-3 weeks
in a Florida sediment-water system, and 5-6 weeks in a Pennsylvania
sediment-water system.

Chlorimuron-ethyl has 6 major degradates, and no minor degradates.  The
major degradates include demethylated parent, a “sulfonamide,” and
“pyrimidine-amine,” saccharin, dechlorinated pyrimidine-amine, and
demethylated pyrimidine-amine.  The demethylated parent, saccharin,
sulfonamide and pyrimidine-amine each remained at greater than 10% of
applied radioactivity at the end of some of the aerobic soil metabolism
studies (one year), and were major degradates in the field dissipation
studies.

In the environment, parent chlorimuron-ethyl is very mobile in soil,
with Kd values of <0.03 (sandy loam), 0.28 (silt loam), and >1.6 (silt
loam).  The parent is not expected to be volatile, with a reported vapor
pressure of 4E-12 atm.  In soil column leaching studies using
phenyl-ring labeled parent, saccharin and the sulfonamide were observed
at up to 28% and 4.3%, respectively, of the applied radiation in the
leachate.  Saccharin has Koc values of 4.6 to 15.5, indicating that it
is mobile (MRID 45012638).  Overall, chlorimuron-ethyl is expected to
dissipate by metabolism in soil and transport in water by run-off, or
leaching.

FIRST (Version 1.1.0) and SCI-GROW (Version 2.3) models were used to
predict the estimated environmental concentrations (EECs) of
chlorimuron-ethyl in surface and groundwater, respectively.  The acute
EECs as predicted by the FIRST model ranged from 10.67 (soybeans) –
11.98 (corn) ppb.  The chronic EECs ranged from 4.47 (soybeans) – 5.02
(corn) ppb.  The SCI-GROW model was used by EFED to estimate ground
water concentrations from use of the herbicide.  The groundwater EEC as
predicted by the SCI-GROW model was 6.99 ppb.  Modeling results are
presented in Table 5.1.9.a.

TABLE 5.1.9.a.  Summary of Estimated Surface Water and Groundwater
Concentrations for Chlorimuron ethyl (and demethylated parent).

	Chlorimuron ethyl 

	Surface Water Conc., ppb a	Groundwater Conc., ppb b

Acute	11.98	6.99

Chronic (non-cancer)	5.02	6.99

Chronic (cancer)	5.02	6.99

a From the FIRST model assuming a maximum seasonal use rate of 0.25 lb
ai/A.

b From the SCI-GROW model assuming a maximum seasonal use rate of 0.25
lb ai/A.

Monitoring Data 

The US Geological Survey (USGS) reports that chlorimuron ethyl has been
detected in the drinking water facilities as presented in Table 5.1.9.b.
 The data show the percent of the total number of samples in which the
herbicide was detected and the maximum concentration observed at that
location.  The reported concentrations are less than those predicted by
the FIRST model.

TABLE 5.1.9.b.  Detection Frequency and Maximum Concentration at Four
Drinking  

                             Water Facilities 

Reservoir Location	Concentration at Water-supply Intake	Concentration at
Reservoir Outflow Site	Concentration of Treated Effluent

	Detection %	Max Conc. (ppb)	Detection %	Max Conc. (ppb)	Detection %	Max
Conc. (ppb)

Indianapolis Water Co., IN	-	-	-	-	5	0.04

Higginsville Reservoir, MO	11	0.018	10	0.026	-	-

East Fork Lake, OH	47	0.05	36	0.021	-	-

Lake Mitchell, SD	5	0.021	11	0.023	9	0.026

Source: USGS Open file report 01-456 (Pesticides in Selected
Water-Supply Reservoirs and Finished Drinking Water, 1999-2000: Summary
of results from a Pilot Monitoring Program)

OPP has no information on the effect of drinking water treatment on
chlorimuron ethyl.  From the laboratory fate studies, it can be
concluded that alkaline hydrolysis is slow (as during water softening). 
Low Kd values indicate that precipitation of the parent (as during
flocculation and coagulation) may be difficult.

Surface raw drinking water concentrations estimated by the FIRST model
are 5.7 ppb and 2.4 ppb for acute and chronic exposures, respectively. 
These modeled concentrations are between 48 and 285 times greater than
concentrations measured in the drinking water facilities surveyed by the
USGS.

5.1.10	Food Residue Profile  TC \l3 "5.1.10  Food Residue Profile 

The registrant submitted field trial data supporting the use of
chlorimuron ethyl on field corn that is tolerant to sulfonylurea
herbicides.  In a total of 23 field trials, chlorimuron ethyl was
applied to field corn as a single broadcast foliar application at 0.06
lb ai/A at either 7 days prior to normal forage harvest , 7 days prior
to grain harvest, or at growth stage R1-R2.  All applications were made
using ground equipment and included the use of a non-ionic surfactant. 
In residue decline trials, chlorimuron ethyl residues in/on forage from
showed a rapid decline in residues within the first 7 days after
treatment.  Thereafter, residues in forage declined more slowly and were
generally <0.02 ppm within 21 days of treatment.  ARIA recommends for
the requested tolerances of 0.01 ppm in/on field corn grain, 0.5 ppm
in/on field corn forage, and 2.0 ppm in/on field corn stover.

The registrant submitted field trial data supporting the use of
chlorimuron ethyl on soybeans that are tolerant to sulfonylurea
herbicides.  In a total of 23 field trials, chlorimuron ethyl was
applied to soybeans as a single broadcast foliar application at 0.06 lb
ai/A at growth stage R1-R2 (the proposed use) or approximately 7 days
prior to normal seed harvest.  All applications were made using ground
equipment, and included the use of a non-ionic surfactant.  In the
majority of trials, samples of forage and hay were harvested on the day
of application followed by seed harvest at normal maturity.  In the
remainder of the field trials, seeds were harvested 5-8 day PHI.  For
both forage and hay, chlorimuron ethyl residues declined rapidly within
the first week after application and then declined more slowly
thereafter.  The residue field trial data support the requested 0.01 ppm
tolerance for soybean seeds.  However, there is an existing 0.05 ppm
tolerance for chlorimuron ethyl on soybeans which was previously
established in order to harmonize with the current Canadian MRL for
soybeans.  Since the existing soybean tolerance will cover the proposed
use and continue to harmonize with the Canadian MRL, ARIA recommends
that it should be retained.  A revised Section F should be submitted
removing the requested change in the soybean seed tolerance.

Rather than a 0-day PHI as supported by the submitted data, the
registrant is requesting a 14-day PHI for forage and hay. Based on the
data from the residue decline studies, the rate constant from the
decline curve with the longest rate of decline was used to extrapolate
possible residue values for soybean forage and hay at the proposed
14-day PHI.  The extrapolated 14-day residue values for forage and hay
support the requested tolerances.  ARIA recommends for the requested
tolerances of 0.45 ppm in/on soybean forage and 1.8 ppm in/on soybean
hay.  

There are livestock feed items of regulable interest associated with
these petitions.  For cattle, using the RBD and the highest TRR from the
ruminant metabolism study, the highest residues expected in cattle would
be 0.002 ppm in liver and 0.004 ppm in milk. For poultry, using the RBD
and the highest TRR, the highest residues expected in poultry would be
0.002 ppm in eggs.  At the levels calculated for cattle and poultry
above, there would be no detectable residues of chlorimuron ethyl
expected in livestock commodities.  Detectable residues of chlorimuron
ethyl are also not expected in hogs; therefore, tolerances and feeding
studies are not required for livestock at this time.  

The available corn and soybean processing data for chlorimuron ethyl are
adequate.  As residues did not concentrate in corn grits, starch or
refined oil, separate tolerances are not required for these corn
commodities.  Based on the highest average field trial (HAFT) residues
for corn grain and the processing factors for meal and flour from the
exaggerated rate processing study, the maximum expected residues in corn
meal and flour would be less than 0.02 ppm.  Since the tolerance on the
RAC, field corn grain, is set at the method LOQ (0.01 ppm) and the
suggested tolerances on corn meal and flour are less than 2x the LOQ,
tolerances on those processed commodities are not required.  A revised
Section F should be submitted removing the requested tolerances on field
corn meal and flour.  

For soybeans, residues did not concentrate in meal or refined oil;
therefore separate tolerances are not required for these processed
fractions.  Based on the HAFT residues for soybeans (0.01 ppm) and the
processing factor for hulls, the maximum expected residues in hulls are
0.035 ppm.  As this level of residues is below the current 0.05 ppm
tolerance for soybean seeds, a separate tolerance is also not required
for soybean hulls.  A revised Section F should be submitted removing the
requested tolerance on soybean hulls.

 

Chlorimuron ethyl residues were shown to concentrate in aspirated grain
fractions (AGF) from both corn grain (120x) and soybean seeds (279x). 
Based on the HAFT residues of field corn grain (0.01 ppm) and soybean
seeds (0.01 ppm), the maximum expected residues in AGF would be 1.2 ppm
for corn grain and 2.79 ppm for soybean seeds.  As residues in soybean
AGF are higher than for corn grain, the tolerance for AGF should be set
at 3.0 ppm based on the soybean residue data.  A revised Section F for
the residues of chlorimuron ethyl in aspirated grain fractions at 3.0
ppm is required.  The requests for separate soybean and corn AGF should
be removed from the revised Section F.

Due to the insignificant residues (<0.01 ppm) detected in the confined
rotational crop study, trials for field accumulation in rotational crops
are not required.  All crops maybe rotated after a 30-day plant back
interval.  The rotational crop restrictions on the product label are
adequate.

5.1.11	International Residue Limits TC \l3 "5.1.11  International
Residue Limits 

There are no established or proposed Codex or Mexican maximum residue
limits (MRLs) for residues of chlorimuron ethyl (Appendix II); however,
there is a Canadian MRL for soybeans (0.05 mg/kg), which harmonizes with
the current U.S. tolerance on soybeans.

5.2  Dietary Exposure/Risk Pathway  TC "5.2  Dietary Exposure/Risk
Pathway" \f C \l "2"  

5.2.1  Acute Dietary Exposure/Risk  TC "5.2.1  Residue Profile" \f C \l
"3"  

No toxicological endpoint attributable to a single dose of chlorimuron
ethyl has been identified; therefore acute dietary risk is not a concern
for chlorimuron ethyl.

5.2.2  Chronic Dietary Exposure/Risk  TC "5.2.2  Water Exposure/Risk
Pathway" \f C \l "3"    

A chronic dietary risk assessment was conducted using the Dietary
Exposure Evaluation Model (DEEM-FCID(, Version 2.03), which uses food
consumption data from the USDA’s Continuing Surveys of Food Intakes by
Individuals (CSFII) from 1994-1996 and 1998.  The analysis was performed
to support the Section 3 requests to add uses on the field corn and
soybean.

The unrefined chronic dietary analysis for chlorimuron ethyl is a
conservative estimate of dietary exposure with tolerance-level residues
and 100% crop treated.  The risk estimate from chronic dietary exposure
to chlorimuron ethyl as represented by the cPAD is below HED’s level
of concern for the U.S. population and all population subgroups.  The
exposure estimates for U.S. population and all population subgroups are
1% or lower of the cPAD.

TABLE 5.2.2.  Summary of Dietary Exposure and Risk for Chlorimuron
ethyl 

Population Subgroup	Acute Dietary	Chronic Dietary	Cancer

	Dietary Exposure (mg/kg/day)	% aPAD	Dietary Exposure

(mg/kg/day)	% cPAD	Dietary Exposure

(mg/kg/day)	Risk

General U.S. Population	N/A	0.000188	<1	N/A

All Infants (< 1 year old)

0.000570	1

	Children 1-2 years old

0.000310	<1

	Children 3-5 years old

0.000300	<1

	Children 6-12 years old

0.000209	<1

	Youth 13-19 years old

0.000151	<1

	Adults 20-49 years old

0.000170	<1

	Adults 50+ years old

0.000168	<1

	Females 13-49 years old

0.000168	<1

	

5.2.3  Cancer Dietary Exposure and Risk  TC "5.2.3  Acute and Chronic
Dietary Exposure and Risk" \f C \l "3"  

Chlorimuron ethyl is classified as a “Not likely to be Carcinogenic to
Humans.”  Therefore there is no cancer concern for this compound.

6.0  Residential Exposure/Risk Pathway  TC "6.0  Residential
Exposure/Risk Pathway" \f C \l "1"  

Since there are no chlorimuron ethyl containing products registered for
use in residential areas and no new use is being proposed at this time,
a residential exposure assessment is not required.

6.1  Other (Spray Drift, etc.)  TC "6.1  Other (Spray Drift, etc.)" \f C
\l "2"  

Spray drift is always a potential source of exposure to residents living
in close proximity to spraying operations.  This situation is
particularly the case with aerial application.  However, to a lesser
extent, spray drift resulting from the ground application of chlorimuron
ethyl could also be a potential source of exposure.  The Agency has been
working with the Spray Drift Task Force (a membership of U.S. pesticide
registrants), EPA Regional Offices, State Lead Agencies for pesticide
regulation, and other parties to develop the best spray drift management
practices.  The Agency is now requiring interim mitigation measures for
aerial applications that must be placed on product labels/labeling.  The
Agency has completed its evaluation of the new database submitted by the
Spray Drift Task Force, and is developing a policy on how to apply
appropriately the data and the AgDRIFT computer model to its risk
assessments for pesticides applied by air, orchard airblast, and ground
hydraulic methods.  After the policy is in place, the Agency may impose
further refinements in spray drift management practices to reduce
off-target drift risks associated with pesticide application.

7.0  Aggregate Risk Assessments  TC "7.0  Aggregate Risk Assessments" \f
C \l "1"  

In accordance with the FQPA, when there are potential residential
exposures to a pesticide, aggregate risk assessment must consider
exposures from three major routes: oral, dermal, and inhalation.  There
are three sources for these types of exposures:  food, drinking water,
and residential uses.  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, ARIA considers both the route and duration of exposure.  Due to
the absence of residential uses for chlorimuron ethyl, the aggregate
exposure and risk are equivalent to dietary (food and water) exposure
and risk, and these are below ARIA’s level of concern.

8.0  Cumulative Risk  TC "8.0  Cumulative Risk" \f C \l "1"  

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 for chlorimuron ethyl and any other
substances, and chlorimuron ethyl does not appear to produce a toxic
metabolite produced by other substances.  For the purposes of this
tolerance action, therefore, EPA assumed that chlorimuron ethyl does not
have 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  Occupational Exposure  TC "9.0  Occupational Exposure" \f C \l "1" 

Based upon the proposed use pattern, ARIA believes the most highly
exposed occupational pesticide handlers will be 1) mixer/loaders using
open-pour loading of water dispersible granules, 2) applicators using
open-cab, ground-boom sprayers and 3) aerial applicators.  

Private (i.e., grower) applicators may perform all functions, that is,
mix, load and apply the material.  The ExpoSAC standard procedure
directs that although the same individual may perform all those tasks,
they shall be assessed separately.  By separating the job functions,
HED/ARIA determine the most appropriate levels of personal protective
equipment (PPE) for each aspect of the job without requiring an
applicator to wear unnecessary PPE that might be required for a
mixer/loader (e.g., chemical resistant gloves may only be necessary
during the pouring of a liquid formulation).  These exposure scenarios
are outlined in the Pesticide Handler Exposure Database (PHED) Surrogate
Exposure Guide (August 1998).  Most exposure scenarios for hand-held
equipment (such as hand wands, backpack sprayers, and push-type granular
spreaders) are assessed as a combined job function.  With these types of
hand held operations, all handling activities are assumed to be
conducted by the same individual.

No chemical specific data were available with which to assess potential
exposure to pesticide handlers.  The estimates of exposure to pesticide
handlers are based upon surrogate study data available in the PHED (v.
1.1, 1998).  It should be noted that the PHED does not contain data
regarding water dispersible granules per se.  However, there are data
regarding occupational handlers loading dry flowable formulations which
are considered acceptable surrogates.  

The product label directs applicators and other handlers to wear
personal protective equipment (PPE) consisting of long-sleeved shirt,
long pants, shoes plus socks and chemical-resistant gloves made of any
water proof material such as polyethylene or polyvinyl chloride.

The toxicological factors used in this assessment are taken from: Memo,
PP# 6E7153, DP Num: 361368, K. Middleton, 2/5/09; “Chlorimuron-ethyl: 
Revised Human Health Risk Assessment for Proposed Uses on Cranberry and
Low-growing Berry Subgroup 13-07H, except Strawberry.”

The Agency identified dermal and inhalation toxicological endpoints. 
The short-term and intermediate-term duration, dermal NOAEL is 9.0 mg/kg
bw/day and was identified from “co-critical” studies; a 90 day dog
oral toxicity study and a chronic toxicity study in dogs.  In the 90 day
study the effects seen were hematological changes (increased hematocrit,
hemoglobin, erythrocyte counts), atrophy of the thymus and prostate, and
increased absolute liver weights.  The effect in the chronic study was
based on mild anemia.  The Agency assumed 100 % dermal absorption.

The Agency identified the inhalation toxicological endpoint from the
same two studies and cited the same NOAEL and toxicological adverse
effects.  Inhalation absorption was assumed to be 100 %.  See the
ATTACHMENT for a summary of toxicological effects used for risk
assessment.

Since the dermal and inhalation toxicological endpoints are identified
from the same studies and cite the same adverse effects, the dermal and
inhalation exposures are summed prior to calculation of MOE.

For a summary of risks and exposures to occupational pesticide handlers,
see Table 9.0.  The dermal and inhalation toxicological endpoints are
appropriate for short- and intermediate-term duration exposures.  Thus,
the estimates of risk are appropriate to address both short- and
intermediate exposures.  Based upon the proposed use pattern, ARIA
believes exposures are most likely to be short-term (1-30 days).  

The Agency determined that chlorimuron-ethyl is “Not Likely to be
Carcinogenic to Humans” thus an assessment of cancer risk is not
necessary.  

TABLE 9.0     Summary of Exposure & Risk to Occupational Handlers From
Applying                     Chlorimuron ethyl to Corn or Soybeans

Unit Exposure1

mg ai/lb handled	Applic. Rate2

lb ai/unit	Units Treated3	Avg. Daily Exposure4

mg ai/kg bw/day	MOE5

Mixer/Loader - Dry Flowable - Open Pour

Dermal:

SLNoGlove      0.066 SLWithGlove   0.066 

Inhal.            0.00077 	0.0625

lb ai/A	1,200 A/day	Dermal:

SLNoGlove    0.0707

SLWithGlove 0.0707

Inhal.              0.000825	No Glove

125

With Glove

125

Applicator - Ground-boom - Open-cab

Dermal:

SLNoGlove       0.014 

SLWithGlove    0.014 

Inhal.              0.00074 	0.0625

lb ai/A	200 A/day	Dermal:

SLNoGlove    0.0025

SLWithGlove 0.0025

Inhal.              0.000132143	No Glove

3420

With Glove

3420

Aerial Applicator (Pilots not required to wear gloves)

Dermal:

SLNoGlove       0.005

Inhal.               0.000068	0.0625

lb ai/A	1,200 A/day	Dermal:

SLNoGlove    0.00536

Inhal.              0.0000729 	No Glove

1656

1.  Unit Exposures are taken from “PHED SURROGATE EXPOSURE GUIDE”,
Estimates of Worker Exposure from The Pesticide Handler Exposure
Database Version 1.1, August 1998.    Dermal = Single Layer Work
Clothing No Gloves; Single Layer  Work Clothing With Gloves;  Inhal. =
Inhalation.  Units = mg ai/pound of active ingredient handled.  

2.  Applic. Rate. = Taken draft supplemental product labeling.  

3.  Units Treated are taken from “Standard Values for Daily Acres
Treated in Agriculture;” ExpoSAC SOP No. 9.1.   Revised 5 July 2000

4.  Average Daily Dose = Unit Exposure * Applic. Rate * Units Treated (
70 kg Body Weight

5.  MOE = Margin of Exposure = NOAEL  ( ADD.   ADD = dermal +
inhalation.  NOAEL = 9.0 mg/kg bw/day

A MOE of 100 is adequate to protect occupational pesticide handlers from
exposures to chlorimuron-ethyl.  The estimated MOEs are all > 100. 
Therefore the proposed new uses do not exceed ARIA’s level of concern.

Post-Application

It is possible for agricultural workers to have post-application
exposure to pesticide residues during the course of typical agricultural
activities.  HED in conjunction with the Agricultural Re-entry Task
Force (ARTF) has identified a number of post-application agricultural
activities that may occur and which may result in post-application
exposures to pesticide residues.  HED has also identified transfer
coefficients (TC) (cm²/hr) relative to the various activities which
express the amount of foliar contact over time, during each of the
activities identified.   

The post-emergence uses of Classic® may occur later in the crop season
i.e., 14 day pregrazing interval for treated soybean hay or a 7-day PHI
for corn.   As such, the highest typical (i.e., most conservative) TC
for the proposed new uses is 1,500 cm2/hr for scouting late season
soybeans.  ARIA herein uses the TC of 1,500 cm2/hr for scouting
soybeans.

Due to the labeled possibility of late season applications to corn, if
that corn is grown for seed it could result in post-application
exposures to workers detasseling the corn.  Detasseling corn has a TC of
17,000 µg/cm2.  Most post-application exposures are not expected to
involve detasseling.  

The TCs used in this assessment are from an interim TC SOP developed by
HED’s ExpoSAC using proprietary data from the ARTF database (SOP #
3.1).  It is the intention of HED’s ExpoSAC that this SOP will be
periodically updated to incorporate additional information about
agricultural practices in crops and new data on transfer coefficients. 
Much of this information will originate from exposure studies currently
being conducted by the ARTF, from further analysis of studies already
submitted to the Agency, and from studies in the published scientific
literature.

Lacking compound specific dislodgeable foliar residue (DFR) data, HED
assumes 20% of the application rate is available as dislodgeable foliar
residue on day zero after application.  This is adapted from the ExpoSAC
SOP No. 003 (7 May 1998 - Revised 7 August 2000).  

The following convention may be used to estimate post-application
exposure.  

Average Daily Dose (ADD) (mg ai/kg bw/day) = DFR µg/cm2 * TC cm2/hr *
hr/day * 0.001 mg/µg * 1/70 kg bw 

 and where:

Surrogate Dislodgeable Foliar Residue (DFR) = application rate * 20%
available as dislodgeable residue * (1-D)t * 4.54 x 108 µg/lb * 2.47 x
10-8 A/cm2 .  

0.0625 lb ai/A * 0.20 * (1-0)0 * 4.54 x 108 µg/lb *  2.47 x10-8 A/cm²
= 0.14 µg/cm2 , therefore,

0.14 µg/cm2 * 1,500 cm2/hr  (for scouting) * 8 hr/day * 0.001 mg/µg (
70 kg bw = 0.024 mg/kg bw/day.

MOE = NOAEL ( ADD then 9.0 mg/kg bw/day ( 0.024 mg/kg bw/day = 375.

As noted earlier, detasseling treated corn is a possibility.  Therefore
it is also assessed.

0.14 µg/cm2 * 17,000 cm2/hr (for detasseling) * 8 hr/day * 0.001 mg/µg
( 70 kg bw = 0.272 mg/kg bw/day.

MOE = NOAEL ( ADD then 9.0 mg/kg bw/day ( 0.272 mg/kg bw/day = 33. 

A MOE of 100 is adequate to protect agricultural workers from
post-application exposures.  For post-application activities other than
detasseling, MOEs are >100.  The MOE for detasseling is 33.  Ordinarily
this would exceed ARIA’s level of concern.  For regulatory purposes,
due to circumstances involved in this assessment, the MOE for
detasseling should be viewed advisedly.  First, while it might be
“possible,” ARIA believes it is not probable that workers would be
exposed for 30 or more consecutive days to the levels of  dislodgeable
foliar residues that result from the day “0” i.e., the day of,
application as has been assessed by standard procedure.  Second, due to
a lack of dermal absorption data, the default of 100% dermal absorption
was used.  ARIA is not aware of any case where there is 100% dermal
absorption.  

If the MOE of 33, based upon default assumptions, is considered in a
regulatory sense, then a different restricted entry interval (REI) would
be necessary for the detasseling activity in corn grown for seed. 
Lacking compound specific data, HED believes dislodgeable foliar
residues decline by 10% each day.  As such, it is Day After Treatment 10
before an MOE of 95 is achieved (DAT 11 = MOE of 110).  

In summary, MOEs are acceptable for post-application activities except
for detasseling treated corn grown for seed.  Since the estimates are
based upon the default assumption of 100 % dermal absorption, the MOE of
33 should not be taken at face value.  Actual exposure is believed to be
less but lacking dermal absorption data, the estimate is not refined. 
The actual MOE is expected to be larger than 33.

Restricted Entry Interval

Chlorimuron ethyl is classified in Acute Toxicity Category III for Acute
Dermal toxicity and Primary Eye Irritation.  It is classified in Acute
Toxicity Category IV for Acute Inhalation toxicity and Primary Dermal
Irritation.  It is not a dermal sensitizer.  Therefore, except for
workers involved in detasseling treated corn grown for seed, the interim
worker protection standard (WPS) restricted entry interval of 12 hours
is adequate to protect agricultural workers from post-application
exposures to chlorimuron-ethyl.  The “Classic®” label lists a REI
of 12 hours.  

For regulatory purposes, the estimated MOEs for detasseling treated corn
should be viewed advisedly.  A REI of 11 days for that activity is based
upon the assumption that dermal absorption is 100%.  It is certainly not
100% but ARIA is not aware of information that would allow refinement of
the estimate.  As noted earlier, chlorimuron is classified in acute
dermal toxicity category III with a dermal LD50 of >2000 mg/kg.

10.0  Data Needs and Label Requirements  TC "10.0  Data Needs and Label
Requirements" \f C \l "1"  

10.1  Toxicology  TC "10.1  Toxicology" \f C \l "2"  

As part of the revised 40 CFR Part 158, these additional studies are
required for registration of a pesticide:

 *  OPPTS 870.7800 – Immunotoxicity.

 *  OPPTS Guideline 870-6200 - Acute and subchronic neurotoxicity
studies. 

 *  OPPTS Guideline 870.3200  -  21/28 Day Dermal Study  (Note:  This
study is now required

    for food use chemicals under the updated 40CFR §158 data
requirements.  The route specific

   study eliminates the uncertainties associated with the use of an oral
study and dermal

   absorption factors.)

10.2  Residue Chemistry      TC "10.2  Residue Chemistry" \f C \l "2"  

The petitioner should provide confirmatory data for the corn metabolism
study verifying that    the majority of the immature samples were
initially analyzed within ~6 months of harvest.  

The goat metabolism study is not adequate and additional information is
required on the duration of sample storage prior to extraction and
analysis, along with any data supporting the stability of 14C-residues
in milk and tissues during frozen storage. 

The poultry metabolism study is not adequate and the following specific
deficiencies were noted in the study: 

Due to the small size of the fat and skin subsamples (~0.1 g) used for
radioassay, the LODs for fat and skin samples were too high (0.02-0.03
ppm).

The dates of sample extraction and analysis were not reported.

No supporting storage stability data were provided although samples may
have been stored frozen for up to 8 months prior to analysis. 

Details were not provided on the recovery of radioactivity through the
various extraction procedures.

Only the identities of parent and sulphonamide were confirmed by LC-MS.

A major unknown in egg yolks (34-48% TRR; 0.011-0.023 ppm) and liver
(40-69% TRR; 0.040-0.204 ppm) was not adequately identified.  The
unknown was organosoluble and contained an intact sulfonylurea bridge.

A revised Section F should be submitted removing the requested change in
the soybean seed tolerance.

A revised Section F should be submitted removing the requested
tolerances on field corn meal and flour.  

A revised Section F should be submitted removing the requested tolerance
on soybean hulls.

 

A revised Section F for the residues of chlorimuron ethyl in aspirated
grain fractions at 3.0 ppm should be submitted.  The requests for
separate soybean and corn AGF should be removed from the revised Section
F.

10.3  Occupational and Residential Exposure

  TC "10.3  Occupational and Residential Exposure" \f C \l "2"  None.

References:

PP# 8F7430 & 8F7439, D360845, W. Cutchin, 8/18/09. Chlorimuron Ethyl. 
Petition for Tolerances on Field Corn and Soybean with Metabolism
Studies on Ruminant and Poultry.  Summary of Analytical Chemistry and
Residue Data.  

D365816, M. Dow, 6/24/09.  CHLORIMURON-ETHYL – Human Occupational
Exposure/Risk

	Assessment for the Proposed Use of Chlorimuron-ethyl on Corn and
Soybeans.

PP# 8F7430 & 8F7439, D365815, W. Cutchin, 8/18/09. Chlorimuron ethyl. 
Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk
Assessment for the Section 3 Registration Action on Field Corn and
Soybean.  

D358804, W. Shaughnessy, 6/15/09.  Tier 1 Drinking Water Assessment for
the DuPont CLASSIC® Herbicide Containing the Active Ingredient
Chlorimuron-ethyl for use on OPTIMUM® GAT® Herbicide Tolerant Corn and
Soybeans.

PP# 6E7153, D361368, K. Middleton, 2/5/09.  Chlorimuron-ethyl:  Revised
Human Health Risk Assessment for Proposed Uses On Cranberry and
Low-growing Berry Subgroup 13-07H, except Strawberry.

			PP# 6E7153, D335807, A. Parmar, 1/6/09.  Chlorimuron ethyl.  Petition
for Tolerances on Cranberry, Bearberry, Bilberry, Lowbush Blueberry,
Cloudberry, Lingonberry, Muntries and Partridgeberry (Lowgrowing Berry
Subgroup 13-07-H, Except Strawberry).  Summary of Analytical Chemistry
and Residue Data.  

	D340291, A. Parmar, 1/6/09.  Chlorimuron ethyl.  Chronic Aggregate
Dietary (Food and Drinking Water) Exposure and Risk Assessment for the
Section 3 Registration Action on the Lowgrowing Berry Subgroup 13-07H,
except strawberry.

	D341849, S. Oonnithan, 12/12/08.  Chlorimuron ethyl:  An Assessment of
Occupational and Residential Risks Resulting from the Proposed New Uses
on Cranberry and Related Berries (Berries Subgroup 13-H).

A.1	Toxicology Data Requirements TC "A.1	Toxicology Data Requirements 

The requirements (40 CFR 158.340) for food uses of chlorimuron ethyl are
in Table 1. Use of the new guideline numbers does not imply that the new
guideline protocols were used.

Test 

	Technical

	Required	Satisfied

870.1100    Acute Oral Toxicity	

870.1200    Acute Dermal Toxicity	

870.1300    Acute Inhalation Toxicity	

870.2400    Primary Eye Irritation	

870.2500    Primary Dermal Irritation	

870.2600    Dermal Sensitization		Yes

Yes

Yes

Yes

Yes 

Yes	Yes

Yes

Yes

Yes

Yes

Yes

870.3100    Oral Subchronic (rodent)	

870.3150    Oral Subchronic (nonrodent)	

870.3200    21-Day Dermal	

870.3250    90-Day Dermal	

870.3465    90-Day Inhalation		Yes

Yes

Yes

No

No	Yes

Yes

No

No

No

870.3700a  Developmental Toxicity (rodent)	

870.3700b  Developmental Toxicity (nonrodent)	

870.3800    Reproduction		Yes

Yes

Yes	Yes

Yes

Yes

870.4100a  Chronic Toxicity (rodent)	

870.4100b  Chronic Toxicity (nonrodent)	

870.4200a  Oncogenicity (rat)	

870.4200b  Oncogenicity (mouse)	

870.4300    Chronic/Oncogenicity		Yes

Yes

Yes

Yes

Yes	Yes

Yes

Yes

Yes

Yes

870.5100    Mutagenicity—Gene Mutation - bacterial	

870.5300    Mutagenicity—Gene Mutation - mammalian	

870.5385    Mutagenicity—Mammalian Bone Marrow 

                                          Chromosome Aberration
Aberrations	

870.5550    Mutagenicity—Unscheduled DNA Synthesis		Yes

Yes

Yes

No	Yes

Yes

Yes

No

870.6200a  Acute Neurotoxicity Screening Battery (rat)	

870.6200b  90-Day Neurotoxicity Screening Battery (rat)	

870.6300    Developmental Neurotoxicity		Yes

Yes

No	No

No

No

870.7485    General Metabolism	

870.7600    Dermal Penetration	

870.7800    Immunotoxicity		Yes

No

Yes	Yes

No

No

Special Studies for Ocular Effects

Acute Oral (rat)	

Subchronic Oral (rat)	

Six-month Oral (dog)		

No

No

No	

No

No

No



A.2	Toxicity Profile Tables for Chlorimuron ethyl.  TC "A.2	Toxicity
Profile Tables for Chlorimuron-ethyl." \f C \l "1"   

TABLE I.1.  Acute Toxicity Profile – Chlorimuron ethyl 

Type of Study/Guide line	Study Title	MRID	Results

870.1000	Acute Oral LD50, Rat (75%)	00131566	LD50 (M/F) >5000 mg/kg

Tox Category IV

870.1200	Acute Dermal LD50, Rabbit (75%)	00131567	LD50 (M/F) >2000 mg/kg

Tox Category III

870.1300	Acute Inhalation Toxicity, Rats (96%)	40843203	LC50 (M/F) 5
mg/L

Tox Category IV

870.2400	Primary Eye Irritation, Rabbit

(75%)	00131568	mild irritation @ 26 mg

 Tox Category III

870.2500	Primary Dermal Irritation, Rabbit  (75%)	00131569	mild erythema
and edema @ 0.5 g

Tox Category IV

870.2600	Dermal Sensitization, Guinea Pig  (75%)	00131570	Not a
sensitizer

TABLE I.2.	Subchronic, Chronic and Other Toxicity Profile for
Chlorimuron ethyl 

Type of Study/Guide line	Study Title	MRID	Results

870.3100	90-Day Oral Toxicity, Rat	00131581	Levels tested: 0, 100, 2500,
7500 ppm, equivalent to:

[M]: 0, 7, 173, 551 mg/kg/day

[F]: 0, 8, 209, 672 mg/kg/day

NOAEL (M/F) = 7/8 mg/kg/day (100 ppm)

LOAEL (M/F) = 173/209 mg/kg/day (2500 ppm) based on decreased body
weight gain (14%) in females and liver pathology (margination of
hepatocyte cytoplasmic content in centrilobular areas) in males

870.3100	90-Day Oral Toxicity, Mouse	00143127	Levels tested: 0, 25, 125,
1250, 5000 ppm equivalent to: [M]: 0, 6, 27, 268, 1030 mg/kg/day

[F]: 0, 6, 30, 381, 1151mg/kg/day

NOAEL (M/F) 1030/1151 mg/kg/day

LOAEL not established

870.3150	90-Day Oral Toxicity, Dog	00132745	Levels tested: 0, 100, 1500,
7500 ppm equivalent to:

[M]: 0, 2.8, 45.8, 176.5 mg/kg/day

[F]: 0, 2.9, 42.7, 187.1 mg/kg/day

NOAEL (M/F) = 2.8/2.9 mg/kg/day (100 ppm)

LOAEL (M/F) = 45.8/42.7 mg/kg/day (1500 ppm), based on hematologic
changes (increased hematocrit, hemoglobin, erythrocyte counts in mid and
high dose dogs) atrophy of thymus and prostate, increased absolute and
relative liver weights.

870.3200	21-Day Dermal, Rabbit	

No study available

870.4100b	Chronic Feeding, Dog	00149579	Levels tested: 0, 25, 250, 1500
ppm, equivalent to: [M]: 0, 0.8, 10, 51 mg/kg/day

[F]: 0, 0.8, 9, 55 mg/kg/day

NOAEL = 10/9 mg/kg/day (250 ppm)

LOAEL = 51/55 mg/kg/day (1500 ppm), based on mild decrease in
erythrocyte count, hematocrit, and hemoglobin concentration (mild
anemia)

870.4200a	Carcinogenicity, Rat	 	 No study available; see Guideline
870.4300 (chronic/oncogenicity study)

870.4200b	Carcinogenicity, 18-Month Feeding, Mouse	00145781	Levels
tested: 0, 12.5, 125, 1250 ppm equivalent to:

[M]: 0, 1.6, 16, 160 mg/kg/day,

[F]: 0, 2.1, 21, 216 mg/kg/day

NOAEL (M/F) 160/216 mg/kg/day 

LOAEL not established

No treatment-related neoplasms

870.3700a	Developmental Toxicity, Rat	00131582	Levels tested: 0, 30,
150, 600 mg/kg/day GD 7-16

Maternal NOAEL = 30 mg/kg/day

Maternal LOAEL = 150 mg/kg/day based on decreased weight gain during GD
7-16 (11%)

Developmental NOAEL = 30 mg/kg/day

Developmental LOAEL = 150 mg/kg/day based on growth retardation (delayed
ossification, centra and sternebrae)

870.3700b	Developmental Toxicity, Rabbit	00145782	Levels tested: 0, 13,
48, 300 mg/kg/day GD 7-19

Maternal NOAEL = 48 mg/kg/day

Maternal LOAEL = 300 mg/kg/day based on decreased weight gain during DG
7-19 (5%)

Developmental NOAEL = 13 mg/kg/day

Developmental LOAEL = 48 mg/kg/day based on delayed ossification

870.3800	Reproduction (1- Generation), Rat	00131581	Levels tested: 0,
100, 2500, 7500 ppm equivalent to: [M]: 0, 7, 173, 551mg/kg/day

[F]: 0, 8, 209, 672 mg/kg/day

Reproductive NOAEL (M/F) = >551/672 mg/kg/day

Reproductive LOAEL (M/F) =  not established

Offspring NOAEL = 7/8 mg/kg/day

Offspring LOAEL = 173/209 mg/kg/day based on decreased litter weights

Parental NOAEL (M/F) =  7/8 mg/kg/day

Parental LOAEL (M/F) =173/209( mg/kg/day) based on decreased body weight
in females (12%) and liver pathology in males

870.3800	Reproduction (1-year interim sacrifice), Rat	00143128	Levels
tested: 0, 25, 250, 2500 ppm equivalent to:

[M]: 0, ?, 19, 195 mg/kg/day

[F]: 0, ?, 23, 227 mg/kg/day

195/227 mg/kg/day

Reproductive LOAEL not established

Offspring NOAEL = 19/23 mg/kg/day

Offspring LOAEL = 195/227 mg/kg/day based on decreased pup weight (20%
and 19% in F1a M and F, respectively; 12% in F1b F)

Parental NOAEL = 19/23 mg/kg/day

Parental LOAEL = 195/227 mg/kg/day based on decreased body weight (12%
F)

870.3800	Reproduction (2- Generation), Rat	00149580	Levels tested: 0,
25, 250, 2500 ppm equivalent to: 

[M]: 0, 1.7, 17, 177 mg/kg/day

[F]: 0, 2.2, 21, 214 mg/kg/day

Reproductive NOAEL 177/214 mg/kg/day

Reproductive LOAEL = not established

Offspring NOAEL = 17/21mg/kg/day

 177/214 mg/kg/day

Parental LOAEL not established

870.4300	Chronic/Oncogenicity, 2- Year-Rat	00149580	Levels tested: 0,
25, 250, 2500 ppm equivalent to: 

[M&F]: 0, 1.25, 12.5, 125 mg/kg/day

NOAEL = 12.5 mg/kg/daya (250 ppm)

LOAEL= 125 mg/kg/day)a (2500 ppm) based on decreased body weight in both
sexes (8/24% [M/F], respectively)

No treatment-related neoplasms

870.5100	Ames Bacterial Mutagenicity Test	00131571	Negative at 0.001
through 0.5 ·g/ml in presence of rat liver S-9 activation.

870.5300	In Vitro Mammalian Gene Mutation - Chinese Hamster Ovary BH4
Cells	00131572	Not mutagenic in the presence or absence of S-9
activation

870.5385	Mammalian Bone Marrow Chromosome Aberration Assay - Rat
00131573	This study was negative for induction of chromosome aberrations
in the bone marrow cells of male or female Sprague-Dawley rats 6-, 12-, 
24-, and 48- hr time points after gavage administration of 500-1500
mg/kg of test material 

870.5550	Unscheduled DNA Synthesis	00132577

00155156	Additional data supporting a justification for the selection of
the highest dose level was submitted and accepted.  Based on these
findings, it was concluded that chlorimuron ethyl showed no evidence of
UDS.

870.6200a

	Acute neurotoxicity screening battery-rats	No study Available

870.6200b

	Subchronic neurotoxicity screening battery	No study Available

870.7485	General Metabolism	00154749

00149578	Doses = 16 and 3000 mg/kg of 14C labeled phenyl or pyrimidinyl
rings of chlorimuron ethyl.  Chlorimuron ethyl extensively metabolized
by both male and female rats at the low and high dose. Excretion was
monitored up to 168 hrs. Elimination of radioactivity was equally via
the urine & feces for low and high dose. Half-life = 50 hrs. Major
metabolites: HOPY-DPX-F6025, ODM-DPX-F6025, HPY-DPX-F6025, DI-HOPY-
DPX-F6025, DPX-F6025 (See Appendix V for structures).

870.7800	Immunotoxicity	No study Available

Appendix III – Rationale for Toxicology Data Requirements.  TC "A.3
Rationale for Toxicology Data Requirements" \f C \l "1"  

Guideline Number:  870.6200

Study Title:  Acute & Subchronic Neurotoxicity

Rationale for Requiring the Data

The acute and subchronic neurotoxicity studies are a new data
requirement under 40 CFR Part 158 as a part of the data requirements for
registration of a pesticide (food and non-food uses). 

The Neurotoxicity Test Guideline (OPPTS 870.6200) prescribes functional
and structural neurotoxicity testing and is designed to evaluate the
potential of a repeated chemical exposure to produce adverse effects on
the nervous system.  Although some information on neurotoxicity may be
obtained from standard guideline toxicity study data, studies not
specifically conducted to assess neurotoxic endpoints may be inadequate
to characterize a pesticide’s potential neurotoxicity.  While data on
clinical signs of toxicity or histopathology in routine chronic or
subchronic toxicity studies may offer useful information on potential
neurotoxic effects, these endpoints alone may be insufficient to detect
more subtle neurological effects.  

Practical Utility of the Data

How will the data be used?

Neurotoxicity studies provide critical scientific information needed to
characterize potential hazard to the human population on the nervous
system from pesticide exposure.  Since epidemiologic data on the effects
of chemical exposures of chlorimuron ethyl on neurologic parameters are
limited and may be inadequate to characterize a pesticide’s potential
neurotoxicity in humans, animal studies are used as the most sensitive
endpoint for risk assessment.  These animal studies can be used to
select endpoints and doses for use in risk assessment of all exposure
scenarios and are considered a primary data source for reliable
reference dose calculation.

How could the data impact the Agency's future decision-making? 

If the neurotoxicity studies show that the test material poses either a
greater or a diminished risk than that given in the interim decision’s
conclusion, the risk assessments for the test material may need to be
revised to reflect the magnitude of potential risk derived from the new
data.

 

If the Agency does not have these data, a 10X database uncertainty
factor may be applied for conducting a risk assessment from the
available studies.

Guideline Number:  870.7800

Study Title:  Immunotoxicity 

Rationale for Requiring the Data

The immunotoxicity study is a new data requirement under 40 CFR Part 158
as a part of the data requirements for registration of a pesticide (food
and non-food uses). 

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional
immunotoxicity testing and is designed to evaluate the potential of a
repeated chemical exposure to produce adverse effects (i.e.,
suppression) on the immune system. Immunosuppression is a deficit in the
ability of the immune system to respond to a challenge of bacterial or
viral infections such as tuberculosis (TB), Severe Acquired Respiratory
Syndrome (SARS), or neoplasia.  Because the immune system is highly
complex, studies not specifically conducted to assess immunotoxic
endpoints are inadequate to characterize a pesticide’s potential
immunotoxicity.  While data from hematology, lymphoid organ weights, and
histopathology in routine chronic or subchronic toxicity studies may
offer useful information on potential immunotoxic effects, these
endpoints alone are insufficient to predict immunotoxicity.  

Practical Utility of the Data

How will the data be used?

Immunotoxicity studies provide critical scientific information needed to
characterize potential hazard to the human population on the immune
system from pesticide exposure. Since epidemiologic data on the effects
of chemical exposures on immune parameters are limited and are
inadequate to characterize a pesticide’s potential immunotoxicity in
humans, animal studies are used as the most sensitive endpoint for risk
assessment.  These animal studies can be used to select endpoints and
doses for use in risk assessment of all exposure scenarios and are
considered a primary data source for reliable reference dose
calculation. For example, animal studies have demonstrated that
immunotoxicity in rodents is one of the more sensitive manifestations of
TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) among developmental,
reproductive, and endocrinologic toxicities.  Additionally, the EPA has
established an oral reference dose (RfD) for tributyltin oxide (TBTO)
based on observed immunotoxicity in animal studies (IRIS, 1997).

How could the data impact the Agency's future decision-making? 

If the immunotoxicity study shows that the test material poses either a
greater or a diminished risk than that given in the interim decision’s
conclusion, the risk assessments for the test material may need to be
revised to reflect the magnitude of potential risk derived from the new
data.

 

If the Agency does not have these data, a 10X database uncertainty
factor may be applied for conducting a risk assessment from the
available studies.



Appendix IV – Recommended Tolerances for Chlorimuron ethyl.  TC "A.4
Tolerance Summary for Chlorimuron-ethyl." \f C \l "1"  

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Corn, field, flour	0.015	None

	Corn, aspirated grain fractions	1.28	None	Adequate residue data are
available indicating that residues concentrate in corn grain AGF by
120x.  Based on a HAFT of 0.01 ppm for corn grain, the maximum expected
residues in corn grain AGF would be 1.2 ppm.

Soybean, hay	1.8	1.8	Adequate residue data are available on soybean
forage and hay harvested at 0 DAT.  These data were extrapolated to
calculate residues at 14 DAT, which is the proposed PHI for forage and
hay.  Tolerances were calculated using the tolerance spreadsheet.

Soybean, forage	0.45	0.45

	Soybean, seed	0.01	0.05 1	Although adequate residue data are available
indicating that residues were <0.01 ppm in/on all seed samples following
an application at the R1-R2 stage, the existing 0.05 ppm tolerance will
cover this use. Note: tolerance is recommended for harmonization
purposes.

Soybean, hulls	0.04	None	Residues in/on hulls will be covered by the
existing 0.05 ppm tolerance on soybean seeds.

Soybean, aspirated grain fractions	2.79	None	Adequate data are available
indicating that residues concentrate in soybean AGF by 279x.  Based on a
HAFT of 0.01 ppm for soybean seeds, the maximum expected residues in
soybean AGF would be 2.79 ppm

Grain, aspirated fractions	None	3.0	A single tolerance should be
established for Grain, aspirated fractions based on the soybean AGF
data.

1	There is an existing tolerance of 0.05 ppm for chlorimuron ethyl
residues in/on soybeans, which is identical to the Canadian MRL on
soybeans (0.05 mg/kg).

Chlorimuron ethyl               	Human Health Risk Assessment           
   	        DP Num:  358796

PC Code 128901

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