UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

	OFFICE OF PREVENTION, PESTICIDE

	AND TOXIC SUBSTANCES

  SEQ CHAPTER \h \r 1 MEMORANDUM

	Date:	February 5, 2009

	SUBJECT:	  Chlorimuron-ethyl:  Revised Human Health Risk Assessment for
Proposed Uses

				On Cranberry and Low-growing Berry Subgroup 13-07H, except
Strawberry,

                          PP# 6E7153.

PC Code:  128901	DP Barcode:  361368

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

Petition No.:  6E7153	Regulatory Action:  Section 3, Additional Uses

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

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

Decision No.:  372736	40 CFR 180.429

	FROM:	Karlyn Middleton, M.S., Toxicologist

		S. Oonnithan, Biologist

		Anant Parmar, Biologist

		Dennis McNeilly, Risk Assessor

		Risk Assessment Branch II (RAB2)

		Health Effects Division (7509P)  SEQ CHAPTER \h \r 1

	THROUGH:	Christina Swartz, Branch Chief

		Risk Assessment Branch II (RAB2)

		Health Effects Division (7509P)

	TO:	Daniel Rosenblatt/Sidney Jackson/Barbra Madden, RIMUERB

		Registration Division (7505P)  SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r
1

This document revises the previous risk assessment for chlorimuron-ethyl
(D357987) regarding susceptibility in a reproduction toxicity study in
rats.  In a 2-generation reproduction study (MRID 00149580), offspring
effects (cellular changes in the cerebellum) observed at 177 mg/kg/day
in the absence of maternal toxicity were misclassified as evidence of
increased qualitative susceptibility.  Qualitative susceptibility is
defined as adverse effects seen at the same dose as maternal animals but
are different or more severe. Quantitative susceptibility is defined as
similar adverse effects seen in offspring animals at doses lower than
maternal animals. Since the offspring effects in the reproduction study
are seen in the absence of maternal effects (and thus, at a lower dose),
this is evidence of quantitative susceptibility.  No other changes have
been made to the risk assessment.

    Table of Contents

  TOC \f \h \z    HYPERLINK \l "_Toc219618801"  1.0  Executive Summary
PAGEREF _Toc219618801 \h  4

  HYPERLINK \l "_Toc219618802"  2.0 Physical/Chemical Properties
Characterization	  PAGEREF _Toc219618802 \h  7

  HYPERLINK \l "_Toc219618803"  3.0  Hazard Characterization/Assessment
 PAGEREF _Toc219618803 \h  8

  HYPERLINK \l "_Toc219618804"  3.1  Hazard and Dose-Response
Characterization	  PAGEREF _Toc219618804 \h  8

  HYPERLINK \l "_Toc219618805"  3.1.1  Database Summary	  PAGEREF
_Toc219618805 \h  8

  HYPERLINK \l "_Toc219618806"  <IP_ADDRESS>  Sufficiency of studies/data
PAGEREF _Toc219618806 \h  8

  HYPERLINK \l "_Toc219618807"  <IP_ADDRESS>  Mode of action, metabolism,
toxicokinetic data	  PAGEREF _Toc219618807 \h  9

  HYPERLINK \l "_Toc219618808"  3.1.2  Toxicological Effects	  PAGEREF
_Toc219618808 \h  9

  HYPERLINK \l "_Toc219618809"  3.1.3  Dose-response	  PAGEREF
_Toc219618809 \h  10

  HYPERLINK \l "_Toc219618810"  3.1.4  FQPA	  PAGEREF _Toc219618810 \h
10

  HYPERLINK \l "_Toc219618811"  3.2  Absorption, Distribution,
Metabolism, Excretion (ADME)	  PAGEREF _Toc219618811 \h  11

  HYPERLINK \l "_Toc219618812"  3.3  FQPA Considerations	  PAGEREF
_Toc219618812 \h  11

  HYPERLINK \l "_Toc219618813"  3.3.1  Adequacy of the Toxicity Database
  PAGEREF _Toc219618813 \h  11

  HYPERLINK \l "_Toc219618814"  3.3.2  Evidence of Neurotoxicity
PAGEREF _Toc219618814 \h  11

  HYPERLINK \l "_Toc219618815"  3.3.3  Developmental Toxicity Studies
PAGEREF _Toc219618815 \h  11

  HYPERLINK \l "_Toc219618816"  3.3.4  Reproductive Toxicity Study
PAGEREF _Toc219618816 \h  11

  HYPERLINK \l "_Toc219618817"  3.3.5  Additional Information from
Literature Sources	  PAGEREF _Toc219618817 \h  12

  HYPERLINK \l "_Toc219618818"  3.3.6  Pre-and/or Postnatal Toxicity
PAGEREF _Toc219618818 \h  12

  HYPERLINK \l "_Toc219618819"  <IP_ADDRESS>  Determination of Susceptibility
  PAGEREF _Toc219618819 \h  12

  HYPERLINK \l "_Toc219618820"  <IP_ADDRESS>  Degree of Concern Analysis and
Residual Uncertainties for Pre- and/or Postnatal Susceptibility
PAGEREF _Toc219618820 \h  12

  HYPERLINK \l "_Toc219618821"  3.3.7  Recommendation for not requiring
a Developmental Neurotoxicity Study	  PAGEREF _Toc219618821 \h  13

  HYPERLINK \l "_Toc219618822"  3.4  FQPA Safety Factor for Infants and
Children	  PAGEREF _Toc219618822 \h  13

  HYPERLINK \l "_Toc219618823"  3.5  Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc219618823 \h  13

  HYPERLINK \l "_Toc219618824"  3.5.1  Acute Reference Dose (aRfD) –
General Population	  PAGEREF _Toc219618824 \h  13

  HYPERLINK \l "_Toc219618825"  3.5.2  Acute Reference Dose (aRfD) -
Females age 13-49	  PAGEREF _Toc219618825 \h  13

  HYPERLINK \l "_Toc219618826"  3.5.3  Chronic Reference Dose (cRfD)
PAGEREF _Toc219618826 \h  14

  HYPERLINK \l "_Toc219618827"  3.5.4  Incidental Oral Exposure
PAGEREF _Toc219618827 \h  14

  HYPERLINK \l "_Toc219618828"  3.5.5  Dermal Absorption	  PAGEREF
_Toc219618828 \h  14

  HYPERLINK \l "_Toc219618829"  3.5.6  Occupational Short-and
Intermediate-Term Dermal and Inhalation Exposure	  PAGEREF _Toc219618829
\h  14

  HYPERLINK \l "_Toc219618831"  3.5.7  Level of Concern for Margin of
Exposure	  PAGEREF _Toc219618831 \h  15

  HYPERLINK \l "_Toc219618832"  3.5.8  Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc219618832 \h  15

  HYPERLINK \l "_Toc219618834"  3.5.9  Classification of Carcinogenic
Potential	  PAGEREF _Toc219618834 \h  15

  HYPERLINK \l "_Toc219618835"  3.5.10  Summary of Toxicological Doses
and Endpoints for Trifloxysulfuron for Use in Human Risk Assessments
PAGEREF _Toc219618835 \h  16

  HYPERLINK \l "_Toc219618838"  3.6  Endocrine disruption	  PAGEREF
_Toc219618838 \h  17

  HYPERLINK \l "_Toc219618839"  4.0  Public Health and Pesticide
Epidemiological Data	  PAGEREF _Toc219618839 \h  18

  HYPERLINK \l "_Toc219618840"  5.0  Exposure Assessment	  PAGEREF
_Toc219618840 \h  18

  HYPERLINK \l "_Toc219618841"  5.1	Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc219618841 \h  18

  HYPERLINK \l "_Toc219618842"  5.1.1	Metabolism in Primary Crops
PAGEREF _Toc219618842 \h  18

  HYPERLINK \l "_Toc219618843"  5.1.2	Metabolism in Rotational Crops
PAGEREF _Toc219618843 \h  20

  HYPERLINK \l "_Toc219618844"  5.1.3	Metabolism in Livestock	  PAGEREF
_Toc219618844 \h  20

  HYPERLINK \l "_Toc219618845"  5.1.4	Analytical Methodology	  PAGEREF
_Toc219618845 \h  20

  HYPERLINK \l "_Toc219618846"  5.1.5	Environmental Degradation
PAGEREF _Toc219618846 \h  22

  HYPERLINK \l "_Toc219618847"  5.1.6	Comparative Metabolic Profile
PAGEREF _Toc219618847 \h  23

  HYPERLINK \l "_Toc219618848"  5.1.7	Toxicity Profile of Major
Metabolites and Degradates	  PAGEREF _Toc219618848 \h  24

  HYPERLINK \l "_Toc219618849"  5.1.8	Pesticide Metabolites and
Degradates of Concern	  PAGEREF _Toc219618849 \h  24

  HYPERLINK \l "_Toc219618850"  5.1.9	Drinking Water Residue Profile
PAGEREF _Toc219618850 \h  25

  HYPERLINK \l "_Toc219618851"  5.1.10	Food Residue Profile	  PAGEREF
_Toc219618851 \h  27

  HYPERLINK \l "_Toc219618852"  5.1.11	International Residue Limits
PAGEREF _Toc219618852 \h  28

  HYPERLINK \l "_Toc219618853"  5.2  Dietary Exposure/Risk Pathway
PAGEREF _Toc219618853 \h  28

  HYPERLINK \l "_Toc219618854"  5.2.1  Residue Profile	  PAGEREF
_Toc219618854 \h  28

  HYPERLINK \l "_Toc219618855"  5.2.2  Water Exposure/Risk Pathway
PAGEREF _Toc219618855 \h  28

  HYPERLINK \l "_Toc219618856"  5.2.3  Cancer Dietary Exposure and Risk
 PAGEREF _Toc219618856 \h  29

  HYPERLINK \l "_Toc219618857"  6.0  Residential Exposure/Risk Pathway
PAGEREF _Toc219618857 \h  29

  HYPERLINK \l "_Toc219618858"  6.1  Other (Spray Drift, etc.)	  PAGEREF
_Toc219618858 \h  29

  HYPERLINK \l "_Toc219618859"  7.0  Aggregate Risk Assessments
PAGEREF _Toc219618859 \h  30

  HYPERLINK \l "_Toc219618860"  8.0  Cumulative Risk	  PAGEREF
_Toc219618860 \h  30

  HYPERLINK \l "_Toc219618861"  9.0  Occupational Exposure	  PAGEREF
_Toc219618861 \h  30

  HYPERLINK \l "_Toc219618862"  10.0 Data Needs and Label Requirements
PAGEREF _Toc219618862 \h  33

  HYPERLINK \l "_Toc219618863"  10.1 Toxicology	  PAGEREF _Toc219618863
\h  33

  HYPERLINK \l "_Toc219618863"  10.2 Residue Chemistry	  PAGEREF
_Toc219618863 \h  34

  HYPERLINK \l "_Toc219618864"  10.3 Occupational and Residential
Exposure	  PAGEREF _Toc219618864 \h  34

  HYPERLINK \l "_Toc219618865"  A.1      Toxicology Data Requirements
PAGEREF _Toc219618865 \h  35

  HYPERLINK \l "_Toc219618866"  A.2	Toxicity Profile Tables for
Chlorimuron-ethyl.	  PAGEREF _Toc219618866 \h  36

  HYPERLINK \l "_Toc219618867"  A.3	Rationale for Toxicology Data
Requirements	  PAGEREF _Toc219618867 \h  39

  HYPERLINK \l "_Toc219618868"  A.4	Tolerance Summary for
Chlorimuron-ethyl.	  PAGEREF _Toc219618868 \h  41

  HYPERLINK \l "_Toc219618869"  A.5	Rat Metabolites for
Chlorimuron-ethyl	  PAGEREF _Toc219618869 \h  42

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.  Chlorimuron-ethyl is used for the postemergent
control of certain weeds, such as buttercup and yellow nutsedge and for
the suppression of weeds such as purple aster and silverleaf.  This
memorandum presents the results of a assessment on the use of the
herbicide chlorimuron-ethyl, and its Du Pont end-use product Classic®,
on cranberries and  other low-growing berries in subgroup 13H (except
strawberries).  Subgroup 13-07H berries include: bearberry, bilberry,
low-bush blueberry, cloudberry, lingonberry, muntries, and
partridgeberry.  Classic® (EPA Reg. No. 352-436) was previously
approved for use on soybeans, peanuts, and non-crop lands.

In the current petition, Interregional Research Project No. 4 (IR-4) is
proposing use of a 25% WDG formulation of chlorimuron-ethyl (DuPont
Classic® Herbicide; EPA Reg. No. 352-436) on members of the low-growing
berry subgroup (13H, except strawberry) for postemergence control of
various broadleaf weeds and yellow nutsedge.  The proposed use is for a
single broadcast foliar application at up to 0.0156 lb ai/A during fruit
development.  The proposed preharvest interval (PHI) is 60 days.  In
conjunction with this use, IR-4 is proposing permanent tolerances for
chlorimuron-ethyl on the following members of the low-growing berry
subgroup, except strawberry (subgroup 13H):

Bearberry	0.02 ppm

Bilberry	0.02 ppm

Blueberry, lowbush	0.02 ppm

Cloudberry	0.02 ppm

Cranberry	0.02 ppm

Lingonberry	0.02 ppm

Muntries	0.02 ppm

Partridgeberry	0.02 ppm

HED has re-evaluated the database for chlorimuron-ethyl and found it to
be adequate for purposes of evaluating the requested use expansion.  Due
to revisions in 40 CFR Part 158, there are now requirements for a
21/28-day dermal study (OPPTS Guideline 870-3200), an immunotoxicity
study (OPPTS Guideline 870-7800) and for acute and subchronic
neurotoxicity studies (OPPTS Guideline 870-6200).  Although the lack of
these studies now represents a data gap, HED does not believe that a
database uncertainty factor is warranted at this time.

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.

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 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 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. There are no
residential uses proposed for chlorimuron-ethyl; therefore, incidental
oral and residential dermal and inhalation risk assessments were not
conducted.

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.

Product chemistry data, residue chemistry data relevant to food use, and
environmental fate data relevant to drinking water are adequate to
assess human dietary exposure to chlorimuron-ethyl and to its
metabolites or degradates.  In general, by the time of harvest, residues
in food commodities are below the level of detection (0.02 ppm in
berries) and no finite residue is expected in livestock commodities fed
chlorimuron-ethyl-treated feed items.

HED has conducted a new dietary exposure assessment.  As per current
policy, the new assessment incorporated exposure via residues in
drinking water directly into the dietary exposure model.  The resulting
dietary risk estimates are less than 1% of the population-adjusted dose
(PAD) for all population subgroups and exposure durations; this is well
below HED’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.

HED has completed occupational exposure assessments to evaluate the
requested uses.   Occupational risk estimates associated with
application as well as post-application activities are below HED’s
level of concern.

There are no residential uses of chlorimuron-ethyl.  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 less than 1% of the cPAD.  A determination of
safety can be made for aggregate, i.e., dietary (food and water)
exposure.

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, HED 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

Based on highly conservative, health-protective assumptions, there are
no human health considerations that would preclude granting the
requested uses of chlorimuron-ethyl on cranberry and low-growing berry
Subgroup 13-07H, except strawberry.  The database for chlorimuron-ethyl
is essentially complete.

HED recommends for establishing a permanent tolerance for residues of
chlorimuron-ethyl at 0.02 ppm in/on Berry, low-growing, subgroup 13-07H,
except strawberry.  A separate tolerance for each member of the subgroup
is not necessary as the proposed revisions to the berry crop group have
been finalized (72 FR 69150, 12/7/2007).  See Appendix IV.

Due to revisions in 40 CFR Part 158, there are now requirements for a
21/28-day dermal study (OPPTS Guideline 870-3200), an immunotoxicity
study (OPPTS Guideline 870-7800) and for acute and subchronic
neurotoxicity studies (OPPTS Guideline 870-6200).  Although the lack of
these studies now represents a data gap, HED does not believe that a
database uncertainty factor is warranted at this time.  HED recommends
that these data be required as a condition of registration for the
proposed new uses.

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

TABLE 1.	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.	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"

<IP_ADDRESS>  Sufficiency of studies/data  TC "<IP_ADDRESS>  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.

<IP_ADDRESS>  Mode of action, metabolism, toxicokinetic data  TC "<IP_ADDRESS>
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 chronic reference dose (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"

<IP_ADDRESS>  Determination of Susceptibility  TC "<IP_ADDRESS>  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.

<IP_ADDRESS>  Degree of Concern Analysis and Residual Uncertainties for Pre-
and/or Postnatal Susceptibility  TC "<IP_ADDRESS>  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 <IP_ADDRESS>).  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  Residential and Occupational Dermal 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)

  TC \l3 "3.5.6	Dermal Exposure (Short-, Intermediate- and Long-Term)

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 "3.5.8  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 "3.5.9
 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   TC \l3 "3.5.9	Recommendation for
Aggregate Exposure Risk Assessments 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 "3.5.10
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
"3.5.11  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.  TC \l3 "3.5.10	Classification of
Carcinogenic Potential   TC \l3 "3.5.10	Classification of Carcinogenic
Potential

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"

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 lbs. per acre 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).

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 were summarized in the most recent risk
assessment (D301317, R. Griffin, 8/31/2004).  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 (2x
rate).  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 (4x rate), 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.  The residue of concern in both
soybeans and peanuts is chlorimuron-ethyl per se.

A previously submitted corn metabolism study was reviewed in conjunction
with the current petition.  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,
2/7/89, H. Fonouni; and PP#5F3186; 12/16/85, C. Deyrup).

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.  HED would not typically consider the metabolism data on
soybeans and peanuts to be representative of berries.  However, because
the proposed uses are on minor crops (low-growing berries) and the
pre-harvest interval (60 days) is similar to the minimum harvest
intervals for soybean and peanuts, HED will not require a new metabolism
study for this petition.  For the purpose of this petition only, the
residue of concern in/on berries is chlorimuron-ethyl per se.

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.

Because cranberries are not a rotated crop, no data pertaining to
rotational crops are required to support the proposed use.

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

There are no livestock feedstuffs associated with the proposed use on
cranberries and low-growing berries.  Therefore, data requirements for
livestock metabolism are not relevant to this tolerance petition.

5.1.4	Analytical Methodology  TC \l3 "5.1.4	Analytical Methodology

Proposed Enforcement Methods

D335807, A. Parmar, 1/6/2009

The current enforcement method is adequate for soybeans and peanuts;
however, there has been no testing to ensure the method is adequate for
chlorimuron-ethyl in cranberries.  Since the cranberry data collection
method is very different from the current enforcement method, the EPA
could not conclude that the enforcement method would be likely to be
sufficient for cranberry (and other berries).  Since there's no
cranberry metabolism study, radiovalidation data cannot be generated.

The registrant has submitted analytical method AMR 3210-94 Entitled:
Analytical Method (Column Switching/Heart Cut) For the Determination of
Residues of Chlorimuron Ethyl (DPX-F6025) and Metsulfuron Methyl
(DPX-T6376) in Rice Grain (MRID# 47263901).  This method includes the
extraction procedure used in study 03023 chlorimuron-ethyl: Magnitude of
the Residue in Cranberry and this method would now be considered the
enforcement method for cranberry (MRID# 47004901).  Since the concurrent
recoveries were satisfactory (average recovery was above 80%), the
method was demonstrated to be adequate for cranberry.

This method was not supported with an ILV.  Instead, IR-4 provided a
rationale supporting a waiver of the ILV.  During IR-4 communications
with the Analytical Chemistry Branch (ACB) (C. Stafford) it was agreed
that the rice analytical method trial would be a viable surrogate for
the cranberry ILV.  IR-4 submitted sufficient information for HED to
conclude that the rice analytical method is a viable surrogate for the
cranberry ILV trial.  ACB agrees that in lieu of a cranberry ILV, the
review of the cranberry method and rice method can together serve as the
primary method plus ILV data (Personal Communications C. Stafford and R.
Loranger).  HED will accept the rice analytical method as a surrogate
for the cranberry analytical method ILV based on the following:

ACB feels that given the aqueous solubilities of sulfonylureas, the
aqueous extraction is likely to be adequate.

The methods employ similar extraction procedures, solvents, and
equipment.

The methods were performed at separate labs belonging to DuPont & IR-4.

Both methods resulted in adequate recoveries with similar recovery
efficiencies.  The cranberry method validation recovery was 82% with a
standard deviation of 3%.  The rice method validation recovery was 75%
with a standard deviation of 8% (Table 5.14).

TABLE 5.14.	Summary of Recoveries of Chlorimuron-Ethyl from Fortified
Cranberry and Rice Samples.

Matrix	Spike Level

(ppm)	Sample Size

(n)	Recoveries

(%)	Mean ± Std. Dev.

(%)

Method validation

Cranberries	0.02	3	81, 77, 87	82  ± 5

	0.2	3	82, 83, 81	82 ± 1

	Total	6	77-87	82 ± 3

Concurrent Recovery

Cranberries	0.02	8	84, 81, 82, 81, 77, 87, 80, 75	81 ± 4

Method validation

Rice	0.02	7	57, 82, 83, 85, 59*, 79, 65	73 ± 12

	0.04	7	78, 75, 76, 80, 75*, 82, 70 	77 ± 3.9

	0.10	7	74, 69, 85, 80, 81*, 80, 67	77 ± 6.7

	Total	21	57-85	75 ± 8.1

* net % recoveries are: (ppm found fortified sample - ppm found control
sample)

Current Enforcement Methods

Two HPLC methods are available for enforcing tolerances of
chlorimuron-ethyl in soybeans and peanuts. The original enforcement
method for soybeans (AMR-459-85) is found in Pesticide Analytical Manual
(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.

Neither current enforcement method has been validated using a crop
matrix similar to berries.

Data Collection Method Review

47004901.der (cranberry)

Samples from the cranberry field trials were analyzed for
chlorimuron-ethyl using an HPLC/photoconductivity method that was
derived from two other methods.  Samples were extracted and purified
using procedures from “Analytical Method (Column Switching/Heart Cut)
for the Determination of Residues of Chlorimuron-Ethyl (DPX-F6025) and
Metsulfuron-Methyl (DPX-T6376) in Rice Grain, DuPont Report No. AMD
3210-94”.  Residues were then quantified using procedures from
“Analysis of Chlorimuron-Ethyl in Crops by High Performance Liquid
Chromatography”.

For this method, cranberry samples were extracted with 0.1 M phosphate
buffer, centrifuged, adjusted to pH 5, and filtered.  The filtrate was
then eluted through an EMPORE ™ C18 extraction disk, which retained
the chlorimuron-ethyl.  Residues were eluted from the C18 disk with
ethyl acetate, concentrated to dryness, and redissolved in 0.03 M
phosphate buffer (pH 5).  Residues were next partitioned into
dichloromethane, concentrated to dryness and then redissolved in the
HPLC mobile phase (hexane/isopropanol/methanol, 80:10:10 (v/v/v), with
0.2% glacial acetic acid and 0.1% water).  Residues of chlorimuron-ethyl
were determined by normal-phase HPLC using a silica column with an
isocratic mobile phase and a photoconductivity detector.  The
statistically calculated LOQ and LOD were 0.0084 and 0.0028 ppm,
respectively.

The method was adequately validated in conjunction with the analysis of
field trial samples using control samples of cranberry fortified with
chlorimuron-ethyl at 0.02 and 0.2 ppm.

Conclusions.  An adequate HPLC photoconductivity method was used for
data collection and is also adequate for tolerance enforcement.  The
validated LOQ for chlorimuron-ethyl residues in berries is 0.02 ppm.

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.

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.  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, Ph.D.).

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 soybean and peanut
commodities may be feed items, finite residues of chlorimuron-ethyl are
not expected in livestock commodities due to the very low (less than
detection) levels of chlorimuron-ethyl seen in residue field trials.
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.

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	N/A	N/A

	Poultry	N/A	N/A

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 the Lowgrowing Berry Subgroup 13-07H, except strawberry (D341850, W.
Shaughnessy, 7/24/2007).  To account for exposure to potential residues
in water under the most conservative scenario, the value of 2.4 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.”

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 4x10-12 atmosphere.  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.  Overall, chlorimuron-ethyl is expected to dissipate by
metabolism in soil and transport in water by run-off, or leaching.

The FIRST and SciGrow models were used to conduct the Tier 1 surface and
ground drinking water assessments.  For the proposed label use rates,
the FIRST model predicted raw surface drinking water acute and chronic
exposure concentrations of 5.7 ppb and 2.4 ppb, respectively.  The
SciGrow model predicted an acute and chronic groundwater exposure
concentration of 1.76 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	5.7	1.76

Chronic (non-cancer)	2.4	1.76

Chronic (cancer)	2.4	1.76

a From the FIRST model assuming a maximum seasonal use rate of 0.063 lb
ai/A.

b From the SCI-GROW model assuming a maximum seasonal use rate of 0.063
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

47004901.der (Cranberry)

IR-4 submitted cranberry field trial data supporting the proposed uses
of chlorimuron-ethyl (WDG) on low-growing berries, except strawberry.
Cranberry is the representative crop for subgroup 13-07H.  The results
from these studies are discussed below and the residue data are
summarized in Table 5.1.10.

TABLE 5.1.10.	Summary of Residue Data from Crop Field Trials with
Chlorimuron-Ethyl (WDG).

Commodity	Total Applic. Rate

(lb ai/A)	PHI (days)	Residue Levels (ppm) 1,3

	n	Min.	Max.	HAFT 2	Median

(STMdR)	Mean

(STMR)	Std. Dev.

Cranberry	0.015-0.017	57-63	10	<0.0044	<0.0044	<0.0044	--	<0.0044	0

1	The calculated LOQ and LOD were 0.0084 and 0.0028 ppm, respectively.
The LLMV was 0.02 ppm.

2	HAFT = Highest Average Field Trial.

3	The value of <0.0044 ppm was derived by correcting non-detectable
residues (<0.0028 ppm) for a potential storage stability declines of
37%.  Corrected Residue Value: 0.0044 ppm = 0.0028 ppm (LOD) / 37%
(Potential Storage Decline)

Five field trials were conducted during 2001 in Zones 1, 5 and 12, with
chlorimuron-ethyl (25% WDG) applied to cranberries as a single broadcast
foliar application during fruit development at 0.015-0.017 lb ai/A (1x
rate).  Applications were made using ground equipment in volumes of
20-22 gal/A, and included the use of either a crop oil concentrate (COC)
at 1.0% in 1 test or a non-ionic surfactant (NIS) at 0.25% in 4 tests.
Single control and duplicate treated samples of mature cranberries were
harvested from each test at 57-63 days after treatment (DAT).  The
proposed PHI is 60 days.

Following a single broadcast foliar application of chlorimuron-ethyl
(WDG) at a 1x rate, uncorrected residues of chlorimuron-ethyl were
non-detectable (<0.0028 ppm) in/on all 10 samples of cranberries
harvested at 57-63 DAT.  If residue values are corrected to account for
a potential 37% decline during frozen storage, the resulting residues
(<0.0044 ppm) are still well below the method LOQ (0.0084 ppm) and the
LLMV (0.02 ppm).

Conclusions.  The cranberry field trial data are adequate and support
the proposed use pattern for low-growing berries, except strawberry.  An
adequate number of tests were conducted in the appropriate geographical
regions, and samples were analyzed for residues of concern using an
adequate data collection method.  Although the available storage
stability data indicate that residues in/on cranberries should be
corrected for a potential decline of 37% during frozen storage, the
corrected residue data still indicate that residues in/on cranberries
would be well below the proposed 0.02 ppm tolerance.

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

No international harmonization issues are associated with this petition,
as there are no established or proposed Canadian, Mexican or Codex MRLs
for residues of chlorimuron-ethyl on the proposed crops.

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

D340291, A. Parmar, 1/6/2009

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 was identified by the Chlorimuron Risk Assessment
Team; 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 Lowgrowing Berry
Subgroup 13-07H, except strawberry.

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% 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	0.000078	0.1%	N/A

All Infants (< 1 year old)

0.000234	0.3%

	Children 1-2 years old

0.00014	0.2%

	Children 3-5 years old

0.000134	0.1%

	Children 6-12 years old

0.000091	0.1%

	Youth 13-19 years old

0.000063	0.1%

	Adults 20-49 years old

0.000069	0.1%

	Adults 50+ years old

0.000067	0.1%

	Females 13-49 years old

0.000067	0.1%

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"

There are no chlorimuron-ethyl containing products registered for use in
residential areas and no new use is being proposed at this time.
Therefore, a residential exposure assessment is not applicable.

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, HED 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 HED’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"

D341849, S. Oonnithan; Dec 12, 2008

The proposed use (one application) of Classic® Herbicide on cranberries
and related berries per season is expected to result in short-term (1-30
days) exposures to mixers, loaders, and applicators.  However,
commercial operators may use the product at different locations for more
than a month during the growing season resulting in potential handler
exposures of intermediate-term durations (i.e., 30 days to six months).
The potential exposure scenarios resulting from the use of Classic®
Herbicide on cranberry and related berries by individual growers and
commercial operators are summarized in Table 9.0.

Table 9.0.  Chlorimuron-ethyl: Exposure Scenarios Resulting From the
Proposed Use of Classic® Herbicide on Cranberries and Related Berries.

Scenario Nos.	Scenarios 	Application equipment  	Exposure durations

1	mixing/loading	ground boom	short- and intermediate-term

2	Applying	"	"

The petitioner has not submitted a product specific occupational
exposure study to estimate risks to mixers, loaders, and applicators of
Classic® Herbicide on cranberries.  Therefore, surrogate unit exposure
values from the Pesticide Handler’s Exposure Database (PHED) and
standard values for acres treated from ExpoSAC Policy # 9 were used to
calculate the exposures to handlers under each of the scenarios
identified in Table 9.0.

For chlorimuron-ethyl, the same endpoint was selected for both dermal
and inhalation exposure routes.  Also the same endpoint serves for both
short- and intermediate-term exposure durations.   Therefore the
estimated combined MOEs are the same for both exposure durations.  The
algorithms and inputs used to estimate the daily doses and MOEs are
provided in Table 9.1 and foot-notes.

The registered label of Classic® Herbicide has the Signal Word as
CAUTION; the recommended personal protective equipment (PPE) as baseline
clothing (long-sleeved shirt and long pants and shoes with socks) plus
chemical resistant gloves.  The label re-entry interval is 12 hours.

The estimated exposures and risks to mixers, loaders, and applicators
for the proposed new uses of chlorimuron-ethyl on cranberry and
low-growing berry subgroup 13H (except strawberries)  are summarized in
Table 9.1.  The combined short- and intermediate-term Margin of
Exposures (MOEs) to mixers, loaders, and applicators ranged from 7,400
to 33,000 which are not of concern (LOC = 100), provided label PPE
recommendations are followed (long-sleeve shirt, long pants, shoes,
socks, and no respirator).   The label mandates use of rubber gloves
under PPE, which should provide additional protection to handlers from
dermal exposures.

                 Table 9.1  Non-cancer Short- and Intermediate-term
Risks to Mixers, Loaders, and Applicators

                                                               From the
Use of Chlorimuron-ethyl on Cranberry.

Scen.        No. 1	Job handled	Equip. and Area treated/day  	PPE &
(Eng. control) 2  	Dermal           Exposure 3	Inhalation
Exposure 4	Total dose                   mg kg/day 5	Total sh.- and
interm.-term MOE 6

1	Mixing / Loading	Ground boom

80 acres	Baseline   (open)	unit exp.  0.066

dose/day	  0.0012	unit exp.  0.00077

dose/day   0.000014	0.00122	7,400

2	Applying	Ground boom

80 acres	Baseline   (open cab)	unit exp.  0.014

dose/day	  0.00026	unit exp    0.00074           dose/day   0.000014
0.00027	33,000

1. Scenario #s are from Table 9.0.

2. Personal protective equipment (PPE), base line = long sleeved shirt,
long pants and shoes with socks.  Engineering controls include open
systems for mixing and loading and open/enclosed cabs for applicators.

3. Dermal dose (mg/kg/day) =  [appl. rate (0.016 lb ai/A) * area
treated/day (80 A) * dermal unit exp. (mg/lb ai) * dermal absorp.
(100%)] / body weight (70 kg).

4.  Inhalation dose (mg/kg/day) =  [appl. rate (0.016 lb ai/A) * area
treated/day (80 A) * inh. unit exp. (mg/lb ai) * inh. absorp. (100%)] /
body weight (70 kg).

5. Total dose (mg/kg/day) = dermal + inhalation doses.

6. Total MOE = NOAEL (9.0 mg/kg/day) / total dose (mg/kg/day).  For
chlorimuron-ethyl, both short- and intermediate-term NOAELs are the
same; therefore, the MOEs for both durations also are the same.

Post-Application

The petitioner did not submit a chemical specific post-application
exposure study providing a dislodgeable foliar residue (DFR) value
needed to calculate the exposure to the workers when they enter treated
fields.  Therefore, HED used the default assumption that 20% of the
application rate is available for transfer on day "0" after application.
 Using this default value and activity-specific surrogate transfer
coefficient values for crop-related post-application activities (from
ExpoSAC Policy No. 3.1), the potential post-application dermal exposures
per day (daily doses) were estimated.  The inputs and equations used in
these calculations are provided as foot-notes to Table 9.2 below.

Table 9.2  Short-term Risks to Workers Entering Berry Fields Treated
with Classic® Herbicide

                                                           Containing
Chlorimuron-ethyl.

Crops &         Appl. rate	DFR1                µg/cm2	Post-appl.
   activity	TC 2	Dermal dose  (mg/kg/day) 3	Short-term MOE 4

cranberry and other berries

0.016 lb ai/A	0.035	hand harvesting, raking, pruning	400 (low)	0.0016
5,600

	1500 (high)	0.006	1,500

1.  TC (transfer coefficient) for cranberry from ExpoSAC Policy No. 3.1.

2.  DFR (dislodgeable foliar residue, µg/cm2) = application rate (0.016
lb ai/A) * default residue transferred on

    day"0" (20%) * (1-D)t 100% * CF1 (conv. factor for ug / lb ai, 4.54
E+08) * CF2 (conv. factor for acre/cm2 ,

    2.47 E-08).

3. Dermal dose (mg/kg/day) = [TC (cm²/hr) * DFR (µg/cm2) * CF3 (conv.
factor for mg/ug, 0.001) * dermal

    absorption factor (100%) * hours worked (8)] / body weight of worker
(70 kg).

4. MOE =  short-term NOAEL (9.0 mg/kg/day) / dermal dose  (mg/kg/day).

The estimated short-term MOEs to workers are 1,500 to 5,600 (LOC =100)
for post-application workers when they enter chlorimuron-ethyl treated
fields of cranberry and other berries on the day of treatment (Table
9.2).  Therefore, risks are not of concern after the label REI of 12
hours.

Restricted Entry Interval:  Technical chlorimuron-ethyl has moderate
acute toxicity by oral, dermal, and inhalation routes (Categories III
and IV) and is not a skin sensitizer.  The Toxicity Categories for
dermal and eye irritation exposures are III and IV, respectively.  At
this level of acute toxicity, the 12 hour REI provides adequate
protection to post application workers.

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

10.1  Toxicology

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.)

HED recommends that these data be required as a condition of
registration for the proposed new uses of chlorimuron-ethyl.

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.

This information may be provided in a future tolerance petition for
chlorimuron-ethyl.

10.3 Occupational and Residential Exposure

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

References:

			D335807, A, Parmar; Jan 6, 2009.  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.  Petition Number 6E7153.

	D340291, A. Parmar; Jan 6, 2009.  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, Suku Oonnithan; December 12, 2008.  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 \l2 "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

Reproductive NOAEL 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

177/214 mg/kg/day

Reproductive LOAEL = not established

Offspring NOAEL = 17/21mg/kg/day

Offspring LOAEL = 177/214 mg/kg/day based on reduced pup weight (20/19%
in F1a M/F; 7/12% in F1b M/F; 13/13% in F2a M/F; 20/18% in F2b M/F ) and
histopathologic findings in the cerebellum (cellular changes in the
internal granular and external germinal layers)

Parental NOAEL (M/F)  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?

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onsidered 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"

Appendix IV. 	Recommended Tolerance Summary for Chlorimuron-Ethyl.

Commodity	Proposed Tolerance (ppm)	Recommended Tolerance (ppm)	Comments;
Correct Commodity Definition

Bearberry	0.02	0.02	Adequate data are available on the representative
crop of cranberry.

As the subgroup definitions for the berry and small fruit crop group
have been finalized, a single tolerance should be established for the
Berry, low growing, subgroup 13-07H, except strawberry, which covers the
proposed crop uses.

Bilberry	0.02

Blueberry, lowbush	0.02

Cloudberry	0.02

Cranberry	0.02

Lingonberry	0.02

Muntries	0.02

Partridgeberry	0.02

Chlorimuron-ethyl               Human Health Risk Assessment
          DP Barcode  D361368

PC Code 128901

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