Document ID: EPA-HQ-OPP-2005-0195-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-12-05T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF	

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

November 2, 2007

MEMORANDUM

SUBJECT:	Ethalfluralin:  Human Health Risk Assessment for (IR-4)
Proposed Uses on Dill and Potato.

PC Code: 113101

Petitions: 1E6326 and 2E6360

DP Barcodes: D323068 and D323069

		Regulatory Action: Section 3 Registration

		Risk Assessment Type: Single Chemical Aggregate

FROM:	J. R. Tomerlin, PhD., Plant Pathologist, ARIA Team

		Fungicide Branch

		Registration Division (7505P)

			and

		Christina Swartz, Chemist

		Registration Action Branch 2

		Health Effects Division (7509P)

THROUGH:	Karlyn J. Bailey, Toxicologist

		Registration Action Branch 2

		Health Effects Division (7509P)

			and

		Whang Phang, Toxicologist

		Reregistration Action Branch 1

		Health Effects Division (7509P)

TO:		Shaja Brothers

		Risk Integration, Minor Use and Emergency Response Branch

		Registration Division (7505P)

Table of Contents

  TOC \f  1.0	Executive Summary	4

2.0	Ingredient Profile	7

2.1	Summary of Registered/Proposed Uses	8

2.2	Structure and Nomenclature	8

2.3	Physical and Chemical Properties	8

3.0	Hazard Characterization/Assessment	10

3.1	Hazard and Dose-Response Characterization	10

3.2	FQPA Considerations	11

3.3	Developmental Toxicity Studies	12

3.4	Reproductive Toxicity Study	12

3.5	Additional Information from Literature Sources	13

3.6	Hazard Identification and Toxicity Endpoint Selection	13

3.6.1	Acute Population Adjusted Dose (aPAD) - Females age 13-49	13

3.6.2	Acute Population Adjusted Dose (aPAD) - General Population	13

3.6.3	Chronic Population Adjusted Dose (cPAD)	14

3.6.4	Incidental Oral Exposure (Short- and Intermediate-Term)	14

3.6.5	Dermal Absorption	14

3.6.6	Dermal Exposure (Short-, Intermediate- and Long-Term)	14

3.6.7	Inhalation Exposure (Short-, Intermediate- and Long-Term)	14

3.6.8	Level of Concern for Margin of Exposure	15

3.6.9	Recommendation for Aggregate Exposure Risk Assessments	15

3.6.10	Classification of Carcinogenic Potential	15

3.6.11	Summary of Toxicological Doses and Endpoints for Use in Human
Risk Assessments	16

3.7	Endocrine disruption	17

4.0	Dietary Exposure/Risk Characterization	18

4.1	Pesticide Metabolism and Environmental Degradation	18

4.1.1	Metabolism in Primary Crops	18

4.1.2	Metabolism in Rotational Crops	18

4.1.3	Metabolism in Livestock	18

4.1.4	Analytical Methodology	18

4.1.5	Environmental Degradation	19

4.1.6	Pesticide Metabolites and Degradates of Concern	19

4.1.7	Drinking Water Residue Profile	20

4.1.8	Food Residue Profile	20

4.1.9	International Residue Limits	21

4.2	Dietary Exposure and Risk	21

4.2.1	Acute Dietary Exposure/Risk	21

4.2.2	Chronic Dietary Exposure/Risk	21

4.2.3	Cancer Dietary Risk	22

4.3 Anticipated Residue and Percent Crop Treated (%CT) Information	22

5.0	Residential (Non-Occupational) Exposure/Risk Characterization	23

5.1	Other (Spray Drift, etc.)	23

6.0	Aggregate Risk Assessments and Risk Characterization	23

7.0	Cumulative Risk Characterization/Assessment	23

8.0	Occupational Exposure/Risk Pathway	24

8.1	Short-Term and Cancer Handler Risk	24

8.2	Cancer Postapplication Risk	26

9.0	Data Needs and Label Recommendations	26

9.1	Toxicology	26

9.2	Residue Chemistry	26

9.3	Occupational and Residential Exposure	26

10.0	References:	27

	Appendices	28

 1.0	Executive Summary

Ethalfluralin
[N-ethyl-N-(2-methyl-2-propenyl)-2,6-dinitro-4-(trifluoromethyl)-benzena
mine] is a selective preemergence herbicide registered for use on a
variety of food and feed crops.  Registered products containing
ethalfluralin include granular (G), dry flowable (DF), and emulsifiable
concentrate (EC) formulations. These formulations may be applied
preplant, postplant prior to emergence, postemergence, or
post-transplant as a soil incorporated, band, or broadcast application
using ground equipment.  Tolerances are currently established for
ethalfluralin residues in bean, dry seed; canola, seed; peanut; pea,
dry, seed; safflower, seed; soybean; sunflower, seed; and vegetable,
cucurbit, crop group 9, all at 0.05 ppm.

  SEQ CHAPTER \h \r 1 The Interregional Research Project No. 4 (IR-4)
submitted petitions for the establishment of permanent tolerances for
residues of the herbicide ethalfluralin in dill at 0.05 ppm and in
potato at 0.05 ppm.  In dill, the proposed use pattern is for a single
broadcast soil-incorporated application after seeding but before
emergence of the dill.  The proposed application rate is a maximum of 4
pints/A (1.5 lbs ai/A; pounds active ingredient/acre).  In potato, the
proposed use pattern is for a single broadcast soil-incorporated
application after seeding but before emergence of potatoes; the proposed
application rate in potato is a maximum of 2 2/3 pints/A (1.0 lb ai/A). 
No preharvest interval (PHI) is proposed for either formulation because
the proposed use patterns involve preemergence applications.

The toxicity database for ethalfluralin is complete, and indicates it
has low acute toxicity by oral, dermal, and inhalation routes of
exposure. It is moderately irritating to the eye and produces moderate
to severe skin irritation.  In one study ethalfluralin was negative for
dermal sensitization, but in another, it was considered positive.

In general, subchronic and chronic feeding studies in rats, mice, and
dogs indicate the liver as the target organ, with consistent effects of
enzymatic changes, liver weight increases, and histopathology (chronic
mouse).  A combined chronic/carcinogenicity study in rats showed no
non-neoplastic effects at the highest dose tested (32 mg/kg/day).
However, mammary gland fibroadenomas were increased in a dose-related
manner, and therefore ethalfluralin was classified as a possible human
carcinogen in 1994. The Cancer Peer Review Committee (CPRC) recommended
a quantitative approach for cancer risk assessment using a cancer
potency factor, or Q1* of 8.9 x 10-2 (mg/kg/day)-1.  The mouse
carcinogenicity study showed no increase in tumor incidence.  Consistent
with other studies, liver effects were found in the highest dose group
(163 mg/kg/day).

Ethalfluralin does not produce developmental toxicity in rats at doses
up to1000 mg/kg/day.  There are several rabbit developmental toxicity
studies available; together, these studies indicate the potential for
ethalfluralin to induce skeletal malformations at doses of >150
mg/kg/day.  Maternal toxicity was observed at similar doses. 
Ethalfluralin did not produce reproductive or offspring effects in the
3-generation reproduction studies; the parental effects consisted of
decreased body weight gains.

In a rat metabolism study with oral dosing, ethalfluralin was well
absorbed and rapidly and extensively metabolized, and 95% of the
chemical was excreted in urine and feces within seven days.  The major
route of elimination was via the feces, and the levels remaining in the
tissues were negligible.

HED has fully evaluated the toxicity database of ethalfluralin with
respect to the potential for special sensitivity of infants and
children, and concludes that there is low concern for pre- and postnatal
susceptibility for infants and children.  The FQPA safety factor has
been reduced to 1X because (1) the toxicity database is complete and
adequate to characterize potential pre- and postnatal risk for infants
and children; (2) no reproductive or developmental effects were observed
in rats; (3) there was no evidence of neurotoxicity in the submitted
studies; and (4) although there were slight developmental effects
observed (skeletal malformations) in rabbits (fetuses), they were seen
in the presence of maternal toxicity.  Additionally, the dose chosen for
acute dietary risk assessment is protective of the slight developmental
effects observed in the rabbit developmental toxicity studies.  A
developmental neurotoxicity study, or any other study to further
elucidate potential pre- and/or postnatal effects, is not required at
this time.

A single dose effect applicable to the general population was not
observed in the toxicity database for ethalfluralin, and therefore, an
acute dietary endpoint for the general population including infants and
children was not identified.  The dose for acute dietary risk assessment
for females 13-49 years old is the No Observed Adverse Effect Level
(NOAEL) of 75 mg/kg/day, based on skeletal malformations observed at the
Lowest Observed Adverse Effect Level (LOAEL) of 150 mg/kg/day.  The dose
selected for chronic dietary risk assessment for all populations is the
NOAEL of 4 mg/kg/day from a 1-year oral toxicity study in dogs, based on
altered red cell morphology and urinary bilirubin observed at the LOAEL
of 20 mg/kg/day.  The uncertainty factor (UF) for acute and chronic
dietary assessments consists of the combined intra- and interspecies
factors of 10X, for a total UF of 100.

Occupational exposures for non-cancer risk are expected to be short-term
in duration.  An endpoint for dermal risk assessment was not identified
in the toxicity database, and therefore dermal risks are not of concern
for non-cancer effects.  A dermal absorption factor of 2.8% was used in
conducting cancer risk assessments for occupational workers.  For
inhalation exposures, an oral study was selected for risk assessment in
order to determine screening-level risks from the inhalation route. 
Inhalation toxicity of ethalfluralin is expected to be low, but in the
absence of an inhalation study, the NOAEL from a 3-generation
reproduction study (12.5 mg/kg/day), based on decreased body weight
gains (males) at the LOAEL of 37.5 mg/kg/day was selected for short-term
inhalation risk assessment.  A default assumption of 100% inhalation
absorption was used to extrapolate from the oral study to the inhalation
route.

Adequate residue chemistry data, including an acceptable analytical
enforcement method, have been submitted to support the proposed
tolerances and the risk assessment.  When ethalfluralin is used in
accordance with the proposed labels, residues in or on dill (fresh and
dry) are less than the limit of quantitation (LOQ) of 0.05 ppm. 
Likewise, the results from potato field trials show that ethalfluralin
residues are below the lowest limit of method validation (LLMV) of 0.05
ppm in potato tubers.  In the environment, ethalfluralin is expected to
dissipate by binding to soil particles and then degrading both
aerobically and anaerobically.  It also photodegrades rapidly in water,
with a half life of 6 hours.  Modeled estimated drinking water
concentrations (EDWCs) were higher for surface water sources of drinking
water obtained from the PRZM-EXAMs model than ground water
concentrations generated using the SciGrow model.  For both surface and
ground water, the scenario chosen to represent maximum potential
drinking water residues was the existing use on canola, at a maximum
application rate of 1.5 lbs ai/A.  The surface water EDWCs included
directly in the dietary model were 11 ppb for acute dietary exposure,
and 0.4 ppb for chronic exposure; the cancer assessment was further
refined with the use of drinking water monitoring data from the USDA
Pesticide Data Program (PDP).

With the proposed uses, dietary exposure from food and drinking water is
not of concern.  For acute dietary (food + water) exposure for females
13-49, the estimated dietary risk is <1 % aPAD at the 95th percentile of
exposure.  For chronic dietary (food + water) exposure, children 1-2 was
the most highly exposed subpopulation, with an estimated risk of <1%
cPAD.  Finally, cancer dietary (food + water) risk for the general US
population is 2 x 10-6.  Additional refinement with %CT estimates would
lead to a lower estimate of dietary cancer risk.  EPA generally
considers cancer risks of 10-6 or less to be below the level of concern.
 The precision which can be assumed for cancer risk estimates is best
described by rounding to the nearest integral order of magnitude on the
log scale; for example, risks falling between 3.16 x 10-7 and 3.16 x
10-6 are expressed as 10-6.  Considering the precision with which cancer
hazard can be estimated and the rounding procedure described above,
cancer risk should generally not be assumed to exceed the benchmark
level of concern of 10-6 until the calculated risk exceeds approximately
3 x 10-6.  Since the calculated cancer risk for ethalfluralin falls
below this level, estimated cancer risk is considered to be below the
level of concern.  Dietary exposure to ethalfluralin results in acute,
chronic and cancer risks below HED’s level of concern.  Additional
refinements are possible, since 100 % crop treated was used.  At this
time, there are no current or proposed residential uses for
ethalfluralin.  Therefore, aggregate exposure and risk consist of only
the dietary (food + water) pathway of exposure.  Aggregate acute,
chronic and cancer risks are not of concern for the proposed and
existing uses.

Short-term inhalation exposure and risk to occupational handlers mixing,
loading, and applying ethalfluralin are not of concern, with margins of
exposure (MOEs) considerably higher than 100.  Estimates of occupational
handler cancer risks (from combined inhalation and dermal exposure)
range from 5.9 x 10-6 to 4.4 x 10-5, which are below HED’s level of
concern (LOC) for handler cancer risk.  Estimated cancer risk from
post-application exposures to workers is 1.4 x 10-5, which does not
exceed HED’s LOC for occupational cancer risk.

Given these considerations, HED recommends for the establishment of
ethalfluralin
((N-ethyl-N-(2-methyl-2-propenyl)-2,6-dinitro-4-(trifluoromethyl)benzena
mine) herbicide tolerances of 0.05 ppm in dill and potato:

Tolerance Summary for Ethalfluralin.

Commodity	Proposed Tolerance (ppm)	Recommended Tolerance (ppm)	Commodity
definition

Dill, fresh leaves	0.05	0.05	Dill, fresh and dried

Dill, dried leaves	0.05	0.05	Dill, fresh and dried

Potato	0.05	0.05	Potato

Furthermore, HED recommends for the proposed uses of CURBIT® EC on dill
and Sonalan® HFP on potato.

Environmental Justice Considerations

Potential areas of environmental justice concerns, to the extent
possible, were considered in this human health risk assessment, in
accordance with US 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, non-dietary 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.

2.0	Ingredient Profile

Ethalfluralin
(N-ethyl-N-(2-methyl-2-propenyl)-2,6-dinitro-4-(trifluoromethyl)benzenam
ine is a dinitroaniline herbicide with established tolerances on bean,
dry, seed; canola, seed; peanut; safflower, seed; soybean; sunflower,
seed; and vegetable, cucurbit, group 9.  The tolerances are published
under 40 CFR 180.416.  Ethalfluralin is a preemergence herbicide used to
control a variety of annual grasses and broadleaf weeds on agricultural
sites.  

Under petition PP# 1E6326; the CURBIT® EC formulation (31.5% ai) was
proposed for use on dill.  The Sonalan® HFP (31.5% ai) was proposed for
use on potato under petition PP# 2E6360.

2.1	Summary of Proposed Uses

Table 2.1.  Summary of Proposed Directions for Ethalfluralin.

Applic. Timing, Type, and Equip.	Formulation	Applic. Rate

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

(lb ai/A)	PHI (days)	Use Directions and Limitations

Dill

Soil surface broadcast	CURBIT® EC	1.5	1	1.5	91 – 100	Sprinkler
irrigation may be used to incorporate compound into soil

Potato

Soil surface broadcast	Sonalan® HFP	1.0	1	1	65 - 143	Sprinkler
irrigation may be used to incorporate compound into soil

2.2	Structure and Nomenclature  TC \l2 "2.2	Structure and Nomenclature 

The structure and nomenclature of ethalfluralin is presented in Table
2.2.

2.3	Physical and Chemical Properties  TC \l2 "2.3	Physical and Chemical
Properties 

The physical and chemical properties of ethalfluralin are summarized in
Table 2.3.

 

Empirical Formula	C13H14F3N3O4

Common name	Ethalfluralin

Company experimental name	N/A

IUPAC name
N-ethyl-α,α,α-trifluoro-N-(2-methylallyl)-2,6-dinitro-p-toluidine

CAS name
N-ethyl-N-(2-methyl-2-propenyl)-2,6-dinitro-4-(trifluoromethyl)benzenami
ne

CAS Registry Number	5523-68-6

End-use product/EP	CURBIT® EC Herbicide (Reg. No. 34704-610) and
Sonalan® HFP Herbicide (Reg. No. 62719-188)

Chemical Class	Dinitroaniline herbicide

Known Impurities of Concern	N/A

TABLE 2.3.  Physicochemical Properties

Parameter	Value	Reference

Molecular Weight	333.27	Ethalfluralin Registration Eligibility Decision
(RED), EPA 738-R-95-001, March 1995

Melting point/range	57ºC	Ethalfluralin RED, EPA 738-R-95-001, March
1995

pH	7.68	DP Num: 276090, MRID#’s 45406501 and 45406502

Density	4.783	Texas Risk Reduction Program

Water solubility (20°C)	4.783 mg/L	Texas Risk Reduction Program

Solvent solubility (temperature not specified), mg/L	> 0.50 in acetone

> 0.50 in acetonitrile

> 0.50 in chloroform

> 0.50 in cyclohexanone

> 0.165 in ethyl cellosolve

> 0.250 in heavy aromatic naphtha

> 0.082 in hexane

> 0.082 in methanol

> 0.50 in xylene

> 0.50 in methylene chloride	DP Num: 199662, MRID# 00135194

Vapor pressure (25°C)	8.538 x 10-6	Texas Risk Reduction Program

Octanol/water partition coefficient, log POW (25°C)	4.783	Texas Risk
Reduction Program

Hazard Characterization/Assessment

Based on the proposed use pattern, the ethalfluralin toxicity database
is complete for the purpose of selecting doses and endpoints for risk
assessment, and for characterization of potential pre- and/or post-natal
risk for infants and children. (See detailed Hazard Profile in Appendix
A.3) 

3.1	Hazard and Dose-Response Characterization

The data base of ethalfluralin indicates it has low acute toxicity by
oral, dermal, and inhalation routes of exposure (for details, see
Appendix A.2).  It is moderately irritating to the eye and produces
moderate to severe skin irritation.  A guinea pig dermal sensitization
study conducted by the modified Buehler method found no sensitization,
whereas a study conducted by the Magnusson and Kligman maximization
method was positive.

The data from the subchronic feeding studies in mice show liver to be
consistently affected as indicated by increases in alanine
aminotransferase (SGPT), alkaline phosphatase (ALP), and increased liver
weights.  A 3-month feeding study in dogs showed liver effects as
characterized by increases in ALP and slight fatty changes of the liver.
 A one year feeding study in rats also showed increases in liver
weights, and decreases in RBC, hematocrit, and hemoglobin.  A 21-day
dermal toxicity study in rabbits indicated no systemic toxicity at the
limit dose (1000 mg/kg/day).  In general, based on subchronic and
chronic feeding studies in rats, mice, and dogs, liver appeared to be
the target organ with consistent effects of enzymatic changes and liver
weight increases.

	A chronic feeding/carcinogenicity study in rats showed no
non-neoplastic effects at the highest dose tested (32 mg/kg/day).
However, mammary gland fibroadenomas increased in a dose-related manner,
and ethalfluralin was classified as a possible human carcinogen in 1994.
The mouse carcinogenicity study showed no increase in tumor incidence.
Liver effects, characterized by increase in ALP and focal hepatocellular
hyperplasia, were found in the highest dose group (163 mg/kg/day). The
chronic dog feeding study indicated hematological changes, elevated ALP,
and siderosis of the liver in the high dose animals (80 mg/kg/day).

Ethalfluralin does not produce developmental effects in rats at doses up
to ≥ 1000 mg/kg/day, but systemic effects observed were decreases in
maternal body weight gains and dark urine at ≥ 250 mg/kg/day. There
are several rabbit developmental toxicity studies available.  In the
first pilot study no maternal or fetoxicity was seen at doses from 10 to
150 mg/kg/day, but skeletal and visceral examinations were not
conducted.  In the second pilot study, abortion was seen in 1/3 dams at
500 mg/kg/day.  Like the first pilot study, no skeletal and visceral
examinations were conducted. Subsequently, three full developmental
toxicity studies were conducted using lower and lower dose levels
because of increased incidence of abortion found in dams at all doses in
the first study.  In one study, at 500 mg/kg/day, increased incidences
of dwarf-like appearance, open eyelids, and cleft palate were seen.  A
second study was conducted with dose levels of 75 and 250 mg/kg/day. At
250 mg/kg/day, a cluster of the external findings was reported.  No
external findings were seen in the 75 mg/kg/day group.  A third study
was conducted using doses ranging from 25 to 300 mg/kg/day. A slight
increase in the incidence of sternal variations and incomplete cranial
development was seen in 150 mg/kg/day groups. Although the increased
incidence in sternal variation, incomplete cranial development, and
resorption at 150 mg/kg/day appears to be slight, this suggests the
potential for ethalfluralin to induce malformation at doses of 150
mg/kg/day and above.  Clear maternal effects were seen in 300 mg/kg
group characterized by increased incidence of abortion (5/20); decreased
body weight gain; enlarged, fatty liver; decreased food consumption,
increased resorptions, and increased liver weights.  A decrease in food
consumption, slight increase in abortion (1/20), and a slight increased
in resorption were seen in 150 mg/kg/day dams. Therefore the dose level
of 150 mg/kg/day was established as the maternal LOAEL; the maternal
NOAEL was 75 mg/kg/day.  Evaluating all the results of these studies
together, the developmental toxicity LOAEL was established as 150
mg/kg/day based on slight increase in the incidence of sternal
variations, cranial variations, incomplete cranial development, and of
resorption; the NOAEL was 75 mg/kg/day.

	

	Ethalfluralin did not produce reproductive or offspring effects in the
3-generation reproduction studies; the parental effects consisted of
decreased body weight gains.

In metabolism studies, Fischer 344 rats were treated orally with a
single low dose, a single high dose, or repeated low doses of
radiolabeled ethalfluralin.  Absorption of ethalfluralin was estimated
at 79-87% of the dose for all dose levels.  Ethalfluralin was rapidly
and extensively metabolized, and 95% of the chemical was excreted in
urine and feces by seven days.  The major route of elimination for the
radiolabel was in the feces, 50.9-63.2%, and the levels remaining in the
tissues after 72 hours were negligible.

3.2	FQPA Considerations

In 1999, an ad hoc FQPA Safety Factor Committee evaluated the toxicity
data relevant to the determination of the FQPA Safety Factor (SF). 
Based on the oral developmental toxicity study in rabbits (MRID
00250596), the ad hoc committee determined the appropriate SF for
assessing acute dietary risk to be 3X and for assessing chronic dietary
risk to be 1X.  In a subsequent assessment conducted in 2002, the Agency
retained the 10X factor for both acute and chronic dietary exposure
assessment, pending a complete evaluation of the toxicity database with
respect to the special sensitivity of infants and children.  With the
current proposed uses on dill and potato, HED has fully evaluated the
toxicity database for ethalfluralin with respect to the FQPA SF.

In considering the FQPA SF, the hazard is evaluated in conjunction with
the toxicity endpoints selected for risk assessment.  The toxicity
endpoint selected for the acute dietary exposure assessment was based on
slightly increased number of resorptions and increased sternal and
cranial variations at the 150 mg/kg/day LOAEL of the developmental
toxicity study in rabbits.  After evaluating all the information, HED
concludes the 10X FQPA SF can be removed (reduced to 1X) for the
following reasons:

The developmental effects seen at the LOAEL of 150 mg/kg/day are slight
and are mainly sternal variations in one or two fetuses, incomplete
cranial development in 2 fetuses, and a slight increase in resorptions.

The dose used for risk assessment is the NOAEL of 75 mg/kg/day, a clear
NOAEL from the two developmental toxicity studies in rabbits.  The use
of this NOAEL for risk assessment is protective of the effects of
concern seen in the developmental toxicity studies.

There are no pre- or post-natal toxicity concerns for infants and
children, based on the results of the rat and rabbit developmental
toxicity studies or the 3-generation reproductive toxicity study in
rats.

There is no evidence of neurotoxicity in the submitted toxicity studies,
there are no data gaps, and no additional special studies have been
required.

3.3	Developmental Toxicity Studies

 ≥ 150 mg/kg/day.  Clear maternal effects were seen in the 300 mg/kg
group characterized by increased incidence of abortion (5/20); decreased
body weight gain; enlarged and fatty liver; decreased food consumption,
increased resorptions, and increased liver weights.  A decrease in food
consumption, slight increase in abortion (1/20), and a slight increase
in resorptions were seen in 150 mg/kg/day dams.  Therefore, the maternal
LOAEL and NOAEL were established at 150 mg/kg/day and 75 mg/kg/day,
respectively.  Evaluating all the results of these studies together, the
developmental toxicity LOAEL was established as 150 mg/kg/day based on a
slight increase in the incidence of sternal variations, cranial
variations, incomplete cranial development, and of resorption; the
developmental NOAEL was 75 mg/kg/day.

3.4	Reproductive Toxicity Study

In a three-generation reproduction study in Fischer 344 rats, the
parental NOAEL was 12.5 mg/kg/day.  The parental LOAEL of 37.5 mg/kg/day
was based on depressed mean body weight gains in males in all
generations.  No treatment-related effects were noted on reproductive
parameters and the NOAEL was 37.5 mg/kg/day or greater.  In a
seven-month multigeneration bridging study in Fischer 344 rats, the
parental NOAEL was 20 mg/kg/day.  The parental LOAEL was 61 mg/kg/day,
based on increased liver weights.  No treatment-related effects were
noted on reproductive parameters and the reproductive NOAEL was equal to
or greater than 61 mg/kg/day.

Ethalfluralin did not produce reproductive effects in the 3-generation
reproduction studies; the parental effects consisted of decreased body
weight gains.

3.5	Additional Information from Literature Sources

Additional literature sources were not consulted for information related
to ethalfluralin toxicity.

3.6	Hazard Identification and Toxicity Endpoint Selection

Based on the currently available toxicity data, use patterns and
exposure data, the relevant toxicity endpoints and doses for risk
assessment shown in Table 3.6 were selected.  These endpoints were
considered the most appropriate, sensitive, and health protective.  

3.6.1	Acute Population Adjusted Dose (aPAD) - Females age 13-49

The dose for risk assessment is the NOAEL of 75 mg/kg/day, a clear NOAEL
from two developmental toxicity studies conducted in rabbits.  The use
of this NOAEL for risk assessment is protective of the slight
developmental effects seen in the rabbit developmental toxicity studies.

Study Selected:  Oral developmental toxicity study in rabbits

MRID No.:  00250596

Dose and Endpoint for Risk Assessment:  NOAEL = 75 mg/kg/day based on
increased number of resorptions and increased sternal and cranial
variations seen at LOAEL = 150 mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors:   A developmental
toxicity study in rabbits was used to select the dose and endpoint for
establishing the acute reference (aRfD) dose of 0.75 mg/kg/day.  The
effects seen in the rabbit developmental study could be the result of a
single dose, and therefore serve as appropriate endpoints for the
subpopulation consisting of females 13-49.  Standard uncertainty factors
applied are the 10X intra-species and 10X interspecies factors.  The
acute population adjusted dose is the same as the acute reference dose.

3.6.2	Acute Population Adjusted Dose (aPAD) - General Population

No toxicological endpoint attributable to a single dose of ethalfluralin
was identified as appropriate for any population subgroup except for
females 13 to 49 years; therefore, there are no concerns for acute
toxicity for the general US population, including infants and children.

3.6.3	Chronic Population Adjusted Dose (cPAD)

Study Selected:  One-year oral toxicity study in dogs

MRID No.:  00260434 and 00262711

Dose and Endpoint for Risk Assessment:  NOAEL = 4.0 mg/kg/day based on
altered red cell morphology and urinary bilirubin seen at LOAEL = 20
mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors:  The combined
chronic/carcinogenicity study in rats was used to select the dose and
endpoint for establishing the chronic reference dose (cRfD) of 0.04
mg/kg/day.  The duration and route of exposure in the study are
considered appropriate for assessing chronic dietary exposure and risk
for ethalfluralin.  The NOAEL selected from the dog study is protective
of liver effects seen at higher doses in both the dog study and studies
in rats and mice.  The standard 100X uncertainty factor has been
retained for chronic dietary exposure assessment.  The chronic reference
dose is 0.004 mg/kg/day, and the cPAD is the same since the FQPA SF was
reduced to 1X.

3.6.4	Incidental Oral Exposure (Short- and Intermediate-Term)

Not applicable, since there are not residential uses for ethalfluralin.

3.6.5	Dermal Absorption

A study (MRID Nos. 00132820 and 00072180) with Rhesus monkeys indicated
that 2.8% of a dermal dose was absorbed through the skin.  This factor
was used for estimated dermal exposure in the cancer risk assessment for
occupational workers.

3.6.6	Dermal Exposure (Short-Term)

A 21-day dermal toxicity study in rabbits indicates no systemic toxicity
at the limit dose of 1000 mg/kg/day.  No toxicity endpoints for
short-term dermal exposure were selected, and there is no short-term
dermal risk associated with the proposed or existing uses.  Since
exposures associated with existing and proposed use patterns are short
term in duration, no endpoints were selected for longer durations.

3.6.7	Inhalation Exposure (Short-Term)

Ethalfluralin has a low inhalation toxicity category (III).  The maximum
attainable concentration (gravimetric) was tested in an acute inhalation
toxicity study, and no deaths occurred to exposed rats.  Clinical signs
included hypoactivity, dyspnea, ataxia, chromodacryorrhea, poor
grooming, and yellow urine; these were reversible after 4 days (LC50
>0.94 mg/L; Toxicity Category III).  This maximum attainable
concentration is considered to be non-lethal.  HED had previously
concluded that a separate risk assessment was not required for
inhalation exposure (ad hoc Hazard Identification Assessment Review
Committee [HIARC], 3/4/99, W. Burnam).

HED continues to conclude that toxicity via the inhalation route of
exposure is likely to be low; however, a screening level assessment was
conducted for short-term inhalation exposure to occupational handlers.

Study Selected:  3-generation rat reproduction study

MRID No.:  00094784

Dose and Endpoint for Risk Assessment:  NOAEL = 12.5 mg/kg/day based on
decreased body weight gains in males of all generations seen at the
LOAEL = 37.5 mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors:   A 3-generation rat
reproduction study was used to select the dose and endpoint for
short-term inhalation exposure.  The dose and endpoint selected are
considered to provide a conservative screening-level assessment, since
effects on body weight gains are protective for the liver effects seen
at higher doses, and because ethalfluralin is known to have low toxicity
via the inhalation route of exposure.  An assumption of 100% inhalation
absorption is used for route-to-route extrapolation.

3.6.8	Level of Concern for Margin of Exposure

Table 3.5.8.  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	Not Applicable	Not Applicable	Not Applicable

Inhalation	100	Not Applicable	Not Applicable

3.6.9	Recommendation for Aggregate Exposure Risk Assessments

At this time, there are no current or proposed residential uses for
ethalfluralin.  Therefore, aggregate risks consist of the dietary (food
+ water) pathway of exposure.

 

3.6.10	Classification of Carcinogenic Potential

The mouse carcinogenicity study showed no increase in tumor incidence. 
Liver effects, characterized by increase in ALP and focal hepatocellular
hyperplasia, were found in the highest dose group.  The chronic dog
feeding study indicated hematological changes, elevated ALP, and
siderosis of the liver in the high dose animals.

Ethalfluralin has been classified as a possible human carcinogen (Group
C) by the CPRC (6/29/94 and 11/16/94).  The decision was based on
findings from a 2-year chronic carcinogenicity study in rats, showing an
increased incidence of mammary gland fibroadenomas and combined
adenomas/fibroadenomas in female rats.  The CPRC recommended using the
Q1* approach for risk assessment.  The Q1* is 8.9 x 10-2 (mg/kg/day)-1.

3.6.11	Summary of Toxicological Doses and Endpoints for Use in Human
Risk Assessments

Table 3.6.11a.  Ethalfluralin - Summary of Toxicological Doses and
Endpoints for Use in Dietary Human Health Risk Assessments.

Exposure Scenario	Point of Departure	Uncertainty/

FQPA SFs	Population Adjusted Dose for Risk Assessment	Study and
Toxicological Effects

Acute Dietary (General Population, including Infants and Children)	A
single dose effect relevant to the general US population including
infants and children was not identified in the toxicity studies
conducted with ethalfluralin.

Acute Dietary

(Females 13-49 years of age)	NOAEL = 75 mg/kg/day	UFA = 10x

UFH = 10x

FQPA SF= 1x	aPAD = 0.75 mg/kg/day	Rabbit Dev. Toxicity Study

LOAEL = 150 mg/kg/day based on increased number of resorptions and
increased sternal and cranial variations

Chronic Dietary (All Populations)	NOAEL = 4 mg/kg/day	UFA = 10x

UFH =10x

FQPA SF= 1x	cPAD = 0.04 mg/kg/day	Dog, Chronic Oral Toxicity Study

LOAEL = 20 mg/kg/day based on altered red blood cell morphology and
urinary bilirubin

Cancer (oral, dermal, inhalation)	Q* = 8.9 x 10-2 (mg/kg/day)-1 based on
increased mammary gland fibro-adenomas & combined adenomas/fiboadenomas
in female rats	Rat 2-year chronic/carcinogenicity study

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and  used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (interspecies).  UFH =
potential variation in sensitivity among members of the human population
(intraspecies).  FQPA SF = FQPA Safety Factor.  PAD = population
adjusted dose (a = acute, c = chronic).



Table 3.6.11b  Summary of Toxicological Doses and Endpoints for
Ethalfluralin 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, Short-term durations (1 to 30 days)

	Dermal risks are not of concern because no systemic effects were
observed up to the limit dose (1000 mg/kg) in a dermal study.

Inhalation, Short-term durations (1 to 30 days)	12.5 mg/kg/day	UFH=10X

UFA=10X

IA = 100%	LOC occupational = 100	3-Generation Reproduction study in Rats

The LOAEL = 37.5 based on decreased body weight gains in males in all
generations.

Cancer (oral, dermal, inhalation)	Q1* = 8.9 x 10-2 (mg/kg/day)-1 based
on increased mammary gland fibro-adenomas and combined
adenomas/fiboadenomas in female rats. [For the dermal route, a dermal
absorption factor of 2.8% was used]	Rat, 2-year chronic/carcinogenicity
study

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 date (i.e., lack of a critical study).  MOE =
margin of exposure.  LOC = level of concern.  N/A = not applicable.  IA
= inhalation absorption factor.

3.7	Endocrine disruption

The Environmental Protection Agency (EPA) is required under the Federal
Food, Drug and Cosmetic Act (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 Federal Fungicide Insecticide and Rodenticide Act (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, ethalfluralin
may be subjected to further screening and/or testing to better
characterize effects related to endocrine disruption.

4.0	Dietary Exposure/Risk Characterization

4.1	Pesticide Metabolism and Environmental Degradation

4.1.1	Metabolism in Primary Crops

  SEQ CHAPTER \h \r 1 The Ethalfluralin RED Document concluded that the
qualitative nature of the residue in beans and peanuts is understood. 
The major portion of the radioactivity was characterized as lignin,
cellulose, and protein. The parent, ethalfluralin, was a minor residue. 
The terminal residue of concern in plants is ethalfluralin per se; the
current tolerance expression for plants is adequate.  Previously, a
cucurbit metabolism study was considered outstanding and was required
before plant metabolism could be considered fully understood.  A
cucumber study was subsequently submitted and the metabolism data
requirement was determined to be fulfilled.

In 1995, the HED Metabolism Assessment Review Committee (MARC) concluded
that the residue of concern for both tolerance and risk assessment
purposes is ethalfluralin per se.

4.1.2	Metabolism in Rotational Crops

Field rotational crop studies are not required since no residues of
concern were found at significant levels in rotational crops. 
Furthermore, tolerances for rotational crop commodities and plantback
restrictions need not be established.  

4.1.3	Metabolism in Livestock

  SEQ CHAPTER \h \r 1 The Ethalfluralin RED Document concluded that the
qualitative nature of the residue in animals is adequately understood
based on acceptable poultry and ruminant metabolism studies.  The
residue of concern in milk, eggs, and animal tissues is ethalfluralin
per se.  However, as a result of the low levels of radiolabeled residues
found with exaggerated (200x) feeding levels, HED has waived
requirements for animal feeding studies.  It was also concluded that
residues of ethalfluralin from up to a 10x dietary burden would not be
quantifiable (<0.05 ppm).  Therefore, according to 40 CFR §180.6
(a)(3), if there is no reasonable expectation of finite residues in
livestock commodities, then no tolerances are needed for eggs, milk,
fat, and meat byproducts of cattle, goats, hogs, horses, poultry, and
sheep.  Previously established ethalfluralin tolerances in edible
livestock commodities have been revoked.  In addition, the proposed uses
do not result in the need for tolerances for ethalfluralin in livestock
commodities.

4.1.4	Analytical Methodology

  SEQ CHAPTER \h \r 1 Adequate residue analytical methods are available
for the purpose of tolerance enforcement.  Two gas chromatograph (GC)
methods, Methods I and II, both with electron capture detection (ECD)
are listed in the Pesticide Analytical Manual (PAM, Vol. II, Section
180.416).  Methods I and II are applicable for the analysis of
ethalfluralin residues in/on plant and animal commodities, respectively.
 The limits of detection (LODs) are 0.01 and <0.01 ppm for methods I and
II, respectively.

The methods for enforcement are adequate in light of the tolerance
expression and have passed Agency validation.  The method used in the
dill and potato field trials is suitable for data collection.

4.1.5	Environmental Degradation

Based on laboratory studies, ethalfluralin is expected to dissipate by
binding to soil particles and then degrading both aerobically and
anaerobically.  There are no major degradates detected; in laboratory
studies, several minor degradates were identified, all of which retain
the trifluromethyl phenolic ring structure.  Freundlich Kads values
ranged from 12 to 97 ml/g and in the field ethalfluralin did not leach. 
Laboratory metabolism half-lives in soil were 46 days for aerobic
systems and 14 days for anaerobic systems.  Ethalfluralin does not
hydrolyze, but does photodegrade rapidly in water with a half-life of
approximately 6 hours.  The laboratory volatility study indicates this
is not a major route of dissipation.

4.1.6	Pesticide Metabolites and Degradates of Concern

Ethalfluralin per se is the only compound of toxicological significance.

Plant metabolism studies were considered in which ethalfluralin,
universally radiolabeled in the benzene ring, was applied to beans,
peanuts, and cucumbers.  In the beans and peanuts trials, the
radiolabeled residue consisted of lignin, complex polar materials, and
cellulose.  In contrast, the cucumber study yielded 42% total
radioactive residue (TRR) as 2,2,2-trifluoroacetamide in vines and 86%
TRR (0.014 ppm) as 2,2,2-trifluoroacetamide in cucumbers.  Ethalfluralin
was 0% - 2% in these studies.  The apparent difference in cucumber
versus bean and peanut metabolism may be a reflection of different
post-treatment intervals.  At the time, the HED MARC concluded that the
residue of concern for both regulatory (tolerance) and risk evaluation
purposes is parent ethalfluralin only.

Table 4.1.6  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	Ethalfluralin	Ethalfluralin

	Rotational Crop	Ethalfluralin	Ethalfluralin

Livestock	Ruminant	Not Applicable	Not Applicable

	Poultry	Not Applicable	Not Applicable

Drinking Water	Ethalfluralin	Not Applicable

4.1.7	Drinking Water Residue Profile

Tier II drinking water assessments for surface water for ethalfluralin
were performed based on Index Reservoir settings.  The maximum
simulation, the 1-in-10 year peak value, used for acute dietary
exposure, was calculated for the use on canola using a maximum
application rate of 1.15 lb ai/A.  The estimated drinking water
concentration (EDWC) from this simulation was 11 ppb.  The maximum
simulation for chronic exposures, or the 1-in-10 probability yearly, was
calculated for the use on dill, with a maximum application rate of 1.5
lb ai/A.  The EDWC from this simulation was 0.4 ppb.  For cancer risk
assessment, the average of yearly means was estimated to be 0.2 ppb.

For ground water sources, the Tier I drinking water assessment predicted
maximum EDWCs of 0.02 ppb for both acute and chronic exposure for the
use on dill, with a maximum application rate of 1.5 lb ai/A.  Table
4.1.7 summarizes the EDWC values.  These values were used directly in
the DEEM dietary risk assessments, the 11 ppb value in the acute
assessment and the 0.4 ppb value in the chronic assessment.

For the cancer assessment, an anticipated residue value generated from
the USDA PDP drinking water monitoring data was used; there were no
residues detected in 1,253 samples analyzed from 2003 – 2005.  The ½
LOD value of 23 ppt (0.023 ppb) was used directly in the dietary
assessment.  These data were considered to be appropriate to use for the
cancer risk assessment for the following reasons:  1) application rates
for both existing and proposed uses are similar; while peak drinking
water estimates differ slightly from one crop to another, EFED’s
modeled drinking water numbers for the average of yearly means did not
differ significantly by crop, supporting the notion that the existing
monitoring data can support proposed uses; 2) the drinking water
monitoring data were collected from a variety of states which include
potential ethalfluralin use areas; 3) the lack of findings of detectable
residues is supported by the modeled estimates and by the fate
properties of ethalfluralin (e.g., 6-hour half-life for aqueous
photolysis).

Table 4.1.7.  Summary of Modeled Surface Water and Groundwater
Concentrations for Ethalfluralin.

	Ethalfluralin

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

Acute	11	0.02

Chronic (non-cancer)	0.4	0.02

Chronic (cancer)	0.2	0.02

aFrom the Tier II PRZM-EXAMS - Index Reservoir model.  Input parameters
are based on a 172.8 ha watershed draining into a 5.3 ha reservoir with
a depth of 2.74 m.

bFrom the SCI-GROW model assuming Koc values ranging form 32 – 180
mL/g and half lives ranging from 13 – 1000 days.

4.1.8	Food Residue Profile

Residue data submitted in support of the proposed uses have been
evaluated in a memorandum dated 9/4/07 (DP Barcode No. D306146, D306147
and D333867; J.R. Tomerlin).  The submitted field trial data are
adequate to support the proposed use pattern, and were conducted in
accordance to the Agency’s guidelines with respect to geographic
representation.

Ethalfluralin residues in or on dill (fresh and dry) were less than the
limit of quantitation (LOQ) of 0.05 ppm when ethalfluralin was applied
according to the proposed use patterns.  Likewise, the results from
potato field trials show that ethalfluralin residues were below the
lowest limit of method validation (LLMV) of 0.05 ppm for all treatments
in potato tubers when the test substance was applied according to the
proposed potato use pattern; further examination of the raw data
(chromatograms) indicated that residues in potato tubers and processed
fractions were below the calculated limit of detection (LOD) of 0.016
ppm.  Field trials were supported by adequate storage stability data.

Regarding processed potato fractions, there was no evidence of
concentration in any processed potato fraction; however, the residue
profile for ethalfluralin suggests that concentration of residues is
unlikely.  Given that residues were not detected (i.e., were below the
calculated LOD of 0.016 ppm), no concentration was assumed in the
dietary assessment, and no additional potato processing data are
required.

4.1.9	International Residue Limits

There are currently no Codex, Canadian, or Mexican Maximum Residue
Limits (MRLs) for residues of ethalfluralin on dill or potato, therefore
there are no international harmonization issues associated with this
action.

4.2	Dietary Exposure and Risk

™ model.  For the cancer dietary (food + water) assessment, monitoring
data from the USDA PDP were used for soybean, watermelon, and drinking
water, and the LOD value of 0.016 ppm was used for potatoes.  Risk
estimates are summarized in Table 4.2.3.

4.2.1	Acute Dietary Exposure/Risk

Estimated dietary (food + water) exposure for females 13-49 years was
0.0006 mg/kg/day, equivalent to <1 % of the aPAD, at the 95th percentile
of exposure, which is well below HED’s level of concern for acute
dietary risk (100 % PAD).

4.2.2	Chronic Dietary Exposure/Risk

The chronic non-cancer dietary analysis for ethalfluralin resulted in an
exposure estimate of 0.00006 mg/kg/day for the U.S. population, or <1 %
of the cPAD, which is below HED’s level of concern.  Similarly, the
exposure estimate of 0.00013 mg/kg/day for the most exposed population
subgroup, children 1 to 2 years, is <1 % of the cPAD, and therefore not
of concern.

4.2.3	Cancer Dietary Risk

The risk estimate for chronic cancer dietary exposure (0.000022
mg/kg/day) to ethalfluralin for the U.S. population yields a cancer risk
of 2 x 10-6.  Additional refinement with %CT estimates would lead to a
lower estimate of dietary cancer risk.  EPA generally considers cancer
risks of 10-6 or less to be below the level of concern.  The precision
which can be assumed for cancer risk estimates is best described by
rounding to the nearest integral order of magnitude on the log scale;
for example, risks falling between 3.16 x 10-7 and 3.16 x 10-6 are
expressed as 10-6.  Considering the precision with which cancer hazard
can be estimated and the rounding procedure described above, cancer risk
should generally not be assumed to exceed the benchmark level of concern
of 10-6 until the calculated risk exceeds approximately 3 x 10-6.  Since
the calculated cancer risk for ethalfluralin falls below this level,
estimated cancer risk is considered to be below the level of concern.

Table 4.2.3.  Results of Acute and Chronic Dietary (Food + Water)
Exposure and Risk Estimates for Ethalfluralin.

Population Subgroup	PAD, mg/kg/day	DEEM-FCID

Exposure, mg/kg/day	% PAD

Acute Dietary Estimates 95th Percentile of Exposure

Females 13 – 49 years old	0.75	0.000604	< 1

Chronic Dietary Estimates

U.S. Population	0.04	0.000064	< 1

All infants (< 1 yr)	0.04	0.000099	< 1

Children 1-2 yrs	0.04	0.000133	< 1

Children 3-5 yrs	0.04	0.000124	< 1

Children 6-12 yrs	0.04	0.000085	< 1

Youth 13-19 yrs	0.04	0.000063	< 1

Adults 20-49 yrs	0.04	0.000054	< 1

Adults 50+ yrs	0.04	0.000053	< 1

Females 13-49 yrs	0.04	0.000051	< 1

Cancer Dietary Estimate

U.S. Population	Q1* = 0.089	0.000022	2 x 10-6

4.3	Anticipated Residue and Percent Crop Treated (%CT) Information

For the acute and chronic non-cancer dietary assessments, anticipated
residues from field trials were used; studies evaluated for the RED
indicated residues were below the LOD of 0.01 ppm for dry bean, peanuts,
dry peas, soy beans, and sunflower seed.  Tolerance level residues were
assumed for all other existing uses, and the proposed tolerances were
used for dill and potato.  For the cancer dietary exposure assessment,
anticipated residues from the USDA Pesticide Data Program (PDP) were
used for soybean, watermelon and drinking water.  No residues were
detected during monitoring of these commodities, and the ARs were based
on nondetect residues, estimated at ½ LOD.  For the cancer assessment,
an anticipated residue of the LOD of 0.016 ppm was used for potatoes. 
For all the dietary assessments, HED used the conservative assumption of
100 % crop treated.

5.0	Residential (Non-Occupational) Exposure/Risk Characterization

An assessment is not required, since there are no existing or proposed
uses of ethalfluralin in residential settings.

5.1	Other (Spray Drift, etc.)

 

Spray drift is a potential source of exposure to residents nearby to
spraying operations.  This is particularly the case with aerial
application, but, to a lesser extent, could also be a potential source
of exposure from the ground application method employed for
ethalfluralin.  The Agency has been working with the Spray Drift Task
Force, EPA Regional Offices, and State Lead Agencies for pesticide
regulation and other parties to develop the best spray drift management
practices.  On a chemical by chemical basis, 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, a membership
of U.S. pesticide registrants, and is developing a policy on how to
appropriately apply 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 with specific products with significant risks
associated with drift.

6.0	Aggregate Risk Assessments and Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add)
pesticide exposures and risks from three major sources: food, drinking
water, and residential exposures.  For ethalfluralin, no residential
exposure is expected, and aggregate risk consists of food and drinking
water exposure only; these risks are not of concern as indicated in
Table 4.2.3.

7.0	Cumulative Risk Characterization/Assessment

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 ethalfluralin and any other
substances and ethalfluralin 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 ethalfluralin has
a common mechanism of toxicity with other substances.  For information
regarding EPA’s efforts to determine which chemicals have a common
mechanism of toxicity and to evaluate the cumulative effects of such
chemicals, see the policy statements released by EPA’s Office of
Pesticide Programs (OPP) concerning common mechanism determinations and
procedures for cumulating effects from substances found to have a common
mechanism on EPA’s website at   HYPERLINK
http://www.epa.gov/pesticides/cumulative/.
http://www.epa.gov/pesticides/cumulative/. 

8.0	Occupational Exposure/Risk Pathway

Exposure to ethalfluralin is expected to occur for occupational handlers
applying products containing the active ingredient in accordance with
the proposed use pattern.  For handlers, inhalation exposure and risk
were estimated for non-cancer effects, and combined dermal and
inhalation exposures were assessed for cancer risks.  No
chemical-specific data were submitted to support the proposed uses, so
handler risks were calculated by using the proposed application rates
and application parameters to determine unit exposures from the
Pesticide Handlers Exposure Database (PHED).

Post-application exposure is also expected, when occupational workers
re-enter treated areas to conduct crop maintenance activities.  These
exposures are considered to be short-term in nature.  Since there is no
non-cancer risk associated with short-term dermal exposure, only a
cancer risk assessment was completed for occupational post-application.

8.1	Short-Term and Cancer Handler Risk

Based upon the proposed use patterns, HED believes the most likely
methods of application will be by ground-boom spray and granular
broadcast machinery.  Regarding the proposed new uses, HED further
believes that the most highly exposed occupational pesticide handlers
will be mixer/loaders using open-pour loading of liquid formulations,
mixer/loaders using open-pour loading of granules, applicators using
open-cab, ground-boom sprayers and applicators using open-cab, broadcast
granular spreaders.  

HED believes pesticide handlers will typically be exposed to short-term
duration (1 - 30 days) exposures but not to intermediate-term (1 - 6
months) duration exposures.  Although intermediate-term exposures might
be possible for commercial applicators, it is considered unlikely that
pesticide handlers would be exposed continuously for 30 days or more.  

Private (i.e., grower) applicators may perform all functions, that is,
mix, load and apply the material.  Nevertheless, according to guidance
from HED’s Exposure Science Advisory Committee (ExpoSAC; SOP Number
12, 3/29/00), handler functions were assessed separately.

No chemical specific data were available with which to assess potential
exposure to pesticide handlers.  The estimates of exposure to pesticide
handlers are based upon surrogate study data available in the PHED (v.
1.1, 1998).  For pesticide handlers, it is HED practice to estimate
dermal exposure for workers wearing “baseline” protective clothing,
namely, a single layer of work clothing consisting of a long sleeved
shirt, long pants, shoes plus socks and no protective gloves. 
Additionally, estimates are made for “baseline” plus protective
gloves or other personal protective equipment (PPE) as might be
necessary.

In addition to the PHED surrogate data used in the current assessment,
HED used standard assumptions with respect to body weight, acres treated
per day, and maximum application rates.

In conducting dermal and inhalation cancer risk assessments, HED
typically assumes 10 days per year of exposure over a 35 year
“working” lifetime and a 70 year expected lifespan for private
growers who might apply/handle a compound or perform agricultural
functions.  HED assumes 30 days per year of exposures for commercial
occupational pesticide handlers and agricultural workers who might
“follow” crops as opposed to occasional exposure from work on one or
few farms by “private” individuals.  (Pers. Comm. J. Dawson to M.
Dow, HED/OPP, 4 April 2005).  The Lifetime Average Daily Dose (LADD) is
calculated as shown in the following equation:

LADD = ADD x 10 (or 30) working days exposed/year x 35 year working life
span

365 days/year x 70 year expected life span

The Average Daily Dose (ADD) is the sum of dermal exposure + inhalation
exposure.  Post-application inhalation exposure is considered
negligible.  The label requires the use of protective gloves by
occupational pesticide handlers, therefore exposures were estimated only
for handlers wearing protective gloves.  The cancer risk estimates were
below the level of concern for occupational cancer risk (1 x 10-4).

Table 8.1a.  Short-Term Occupational Exposure Estimates for
Ethalfluralin.  

Exposure Scenario

(Scenario #)	Crop	Daily

Dermal

Dose

(mg/kg/day)	Daily

Inhalation

Dose

(mg/kg/day)	Dermal

MOE	Inhalation

MOE

Mixer/Loader

Liquid, Open-pour	Canola, Dill and Potato	0.0028	0.0051	N/A	2450

Granular, Open-pour

0.00081	0.0051	N/A	2450

Applicator

Groundboom, Open cab	Canola, Dill and Potato	0.0017	0.0032	N/A	3900

Granular Broadcast, Open cab

0.00083	0.0051	N/A	2450

All estimates assume baseline PPE plus gloves. 

Table 8.1b  Estimates of Occupational Cancer Risk for Ethalfluralin

Crop or Target	Exposure Scenario	Application Rate

(lb ai/acre)	Area Treated Daily

(acres)	Short-Term

Dermal + Inhalation

mg/kg/day 	Cancer Risk

	Private Handler	Commercial Handler

Canola, Dill and Potato	Mixer/Loader

Liquid, Open pour	1.5	200	0.0079	9.6 x 10-6	2.9 x 10-5

	Mixer/Loader

Granular, Open pour	1.5	200	0.0059	9.8 x 10-6	1.8 x 10-5

	Applicator

Groundboom, Open Cab	1.5	200	0.0049	5.9 x 10-6	2.2 x 10-5

	Applicator

Granular Broadcast, Open Cap	1.5	200	0.0059	7.2 x 10-6	4.4 x 10-5

8.2	Cancer Postapplication Risk

It is possible for agricultural workers to have post-application
exposures to pesticide residues during the course of typical
agricultural activities.  HED in conjunction with the Agricultural
Re-entry Task Force (ARTF) has identified a number of post-application
agricultural activities that may occur and which may result in
post-application exposure to pesticide residues.  HED has also
identified Transfer Coefficients (TC) (cm²/hr) for each activity which
express the amount of foliar contact over time, during each of the
activities identified.  For the proposed new crop use sites, the highest
TC is 1,500 cm2/hr for scouting or irrigation activities in canola and
potato.  Therefore, as a screening level assessment HED has used a TC of
1,500 cm²/hr.

Lacking compound specific dislodgeable foliar residue (DFR) data, HED
typically assumes 20% of the application rate is available as DFR on day
zero after application.  This is adapted from the ExpoSAC SOP No. 003
(5/7/98, Revised 8/7/00).

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

ADD mg/kg/day = DFR µg/cm2 * TC cm2/hr * hr/day * 0.001 mg/µg * 1/70
kg 

and where:

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

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

2.58 µg/cm2 * 1,500 cm2/hr * 8 hr/day * 0.001 mg/µg * 0.028 (% dermal
absorption) ( 70 kg bw = 0.012 mg/kg bw/day.

Estimated cancer risk from post-application exposures is 1.4 x 10-5,
which does not exceed HED’s level of concern for occupational cancer
risk.

9.0	Data Needs and Label Recommendations

9.1	Toxicology

None.

9.2	Residue Chemistry

None.

9.3	Occupational and Residential Exposure

None.

10.0	References:

DP Num: 199662, S. Funk, undated, MRID# 00135194

DP Num: 200166, F. Chow, 7/27/94

Memo, B. Fisher to R. Landolt, 8/3/94

DP Num: 200165, L. E. Morris, 8/18/94

MRID Nos. 00145955, 00094754, and 43394001 – cited in the
Ethalfluralin RED, EPA 378-R-95-001, March 1995

Reregistration Eligibility Decision (RED): Ethalfluralin, EPA
738-R-95-00a, March, 1995

TXR 0050808, Case 2260, S. Funk, 5/25/95

DP Num: 212755, MRID No. 43532201, S. Funk, June 1995

DP Num: 233501, M. Nelson, 8/7/97

HIARC, W. Burnam, 3/4/99

DP Num: 252707, M. Nelson, S. Williams-Foy, S.-C. Wang, 3/12/99

DP Num: 272778, D. Dotson, 4/11/01

DP Num: 276090, B. F. Kitchens, 10/16/01, MRID#’s 45406501 and
45406502

DP Num: 295884, J. Lin, 10/5/05

DP Num: 296985, J. Lin, 10/5/05

DP Num: 333865, M. Dow, 12/7/06

DP Num: 339217, W. Phang, 4/23/07

DP Num: 306146, J. R. Tomerlin, 9/4/07

DP Num: 333868, C. Swartz, 10/19/07

Appendix A – Toxicity Profiles for Ethalfluralin

A.1.	Toxicology Data Requirements.

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	21/28-Day Dermal	

870.3250	90-Day Dermal	

870.3465	90-Day Inhalation		yes

yes

yes

no

no	yes

yes

yes

---

---

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	

870.5375	Mutagenicity—Structural Chromosomal Aberrations	

870.5395	Mutagenicity—Other Genotoxic Effects		yes

yes

yes

yes	yes

yes

yes

yes

870.6100a	Acute Delayed Neurotox. (hen)	

870.6100b	90-Day Neurotoxicity (hen)	

870.6200a	Acute Neurotox. Screening Battery (rat)	

870.6200b	Chronic Neurotox. Screening Battery (rat)	

870.6300	Develop. Neuro		no

no

no

no

no	---

---

---

---

---

870.7485	General Metabolism	

870.7600	Dermal Penetration		yes

no	yes

yes

A2. Ethalfluralin Acute Toxicity Profile.

Guideline No./ Study Type	MRID No.	Results	Toxicity Category

870.1100 

Acute oral toxicity  rats	00135189	LD50 >5000 mg/kg/	IV

870.1200 

Acute dermal toxicity rabbit	00135189	LD50 >5000 mg/kg/	IV

870.1300

Acute inhalation toxicity rats	00135189	LC50> 0.94 mg/L	III

870.2400

Acute eye irritation rabbits	00135189	Moderate	II

870.2500

Acute dermal irritation rabbits	41613909	Moderate to severe	II

870.2600

Dermal sensitization guinea pigs	00094788	sensitizer	--

A.3. Ethalfluralin Subchronic, Chronic and Other Toxicity Profile.

A.3. Subchronic, Chronic and Other Toxicity Table.

Guideline No.

Study Type	MRID No./(year)

Classification/Doses	Results

870.3100

90-Day Oral Toxicity, mice	0094774 (1978)

Acceptable

0, 68, 136, 285, 538, 1205 mg/kg/day	NOAEL = 136 mg/kg/day

LOAEL = 285 mg/kg/day based on increased absolute and relative liver
weights and increased ALP in males.

870.3100

90-Day Oral Toxicity, rats	00135191 (1978)

0, 14, 29, 63, 146, 313 mg/kg/day	NOAEL = 29 mg/kg/day

LOAEL = 63 mg/kg/day based on increased liver weights (absolute and
relative), decreased RBC, hematocrit and hemoglobin, and increased
relative kidney weights

870.3150

90-Day Oral Toxicity, dogs	00135193 (1974)

Acceptable

0, 6.3, 27.5, 125 mg/kg/day

Note – dose of 125 later adjusted to 80 mg/kg/day	NOAEL = 80 mg/kg/day

LOAEL = 125 mg/kg/day based on vomiting and anorexia.

870.3200

21-Day dermal toxicity, rabbits	00145767 (1985)

Acceptable/guideline

0, 1000 mg/kg/day (6 hours/day)	NOAEL=1000 mg/kg/day (HDT)

LOAEL= >1000 mg/kg/day; no systemic effects were seen at the HDT. 
Dermal effects included erythema, edema, and epidural fissures at 1000
mg/kg/day.

870.3700

Prenatal developmental toxicity, rats	0015337 (1985)

Acceptable

0, 50, 250, 1000 mg/kg/day	Maternal NOAEL=50 mg/kg/day

Maternal LOAEL=250 mg/kg/day based on decreased body weight gain and
dark urine.

Developmental NOAEL=1000 mg/kg/day

Developmental LOAEL>1000 mg/kg/day, no effects seen at the HDT.

870.3700

Prenatal developmental toxicity, rabbits	00250596 (1983)

[Includes Pilot studies – R-7048, B-7438, B-7079, B-7160]

Doses ranged from 0, 10 – 1000 mg/kg/day

Taken in total, the studies are acceptable.	Maternal NOAEL=75 mg/kg/day

Maternal LOAEL=150 mg/kg/day based on abortions and decreased food
consumption.

Developmental NOAEL=75 mg/kg/day

Developmental LOAEL=150 mg/kg/day based on slightly increased
resorptions, and increased sternal and cranial variations.

870.3800

Reproduction and fertility effects, rats	0094784 (1981)

0, 5, 12.5, 37.5 mg/kg/day 

42300301 (1992)

0, 8, 20, 61 mg/kg/day

The 2 studies together are acceptable.	Parental/Systemic NOAEL=12.5
mg/kg/day

Parental/Systemic LOAEL=37.5 mg/kg/day based on decreased body weight
gains in males of all generations.

Reproductive NOAEL=37.5 mg/kg/day (HDT)

Reproductive LOAEL>37.5 mg/kg/day; no systemic effects observed at the
highest dose tested.

870.4100a

Chronic toxicity, rats	00094775 (1979)

Acceptable

M: 0, 3.9, 9.7, 28.4 mg/kg/day

F: 0, 4.9., 11.9, 34.4 mg/kg/day	NOAEL=9.7/11.9 mg/kg/day

LOAEL=28.4/34.4 mg/kg/day based on significant increased blood
creatinine and BUN values at termination.

870.4100a

Chronic toxicity, mice	0009477 (1981)

Acceptable, Nonguideline

M: 0, 12, 47, 173 mg/kg/day

F: 0, 12, 49, 184 mg/kg/day	NOAEL=12 mg/kg/day

LOAEL=47/49 mg/kg/day based on increased ALP and increased relative
liver weights.

870.4100b

Chronic toxicity, dogs	00153371, 92062014 (1985)

Acceptable

0, 4, 20, 80 mg/kg/day	NOAEL=4 mg/kg/day

LOAEL= 20 mg/kg/day based on increased urinary bilirubin, variations in
erythrocyte morphology, increased thrombocyte count, and increased
erythroid series of the bone marrow.

870.4300

Combined chronic toxicity/carcinogenicity, rats	00094776 (1981)

92062013 (1981)

Acceptable

0, 4.2, 10.7, 32.2 mg/kg/day	NOAEL=32.2 mg/kg/day(HDT)

LOAEL=>32.2 mg/kg/day; no systemic effects were seen at the HDT.

Mammary gland fibroadenomas were found in dosed female rats at
statistically significant incidences in mid and high doses.

870.4300

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	LOAEL=41.9 mg/kg/day based on focal hepatocellular hyperplasia in both
sexes and increased liver, kidney, and heart weights in females.  No
increase in neoplasms was attributed to the treatment.

870.5100

Bacterial reverse mutation test	00128693 (1983)

00128694 (1983)

Acceptable	Ethalfluralin was weakly mutagenic in activated strains
TA1535 and TA100 of Salmonella typhimurium, but not in strains TA1537,
TA1538 and TA98 in an Ames assay.  In a modified Ames assay with
Salmonella typhimurium and Escherichia coli, ethalfluralin was weakly
mutagenic in strains TA1535 and TA100, with and without activation, and
in strain TA98 without activation, at the highest dose.

870.5300

In vitro mammalian cell mutation test	00128696 (1983)

Acceptable

	No mutagenicity was found in the mouse lymphoma assay for forward
mutation.

870.5550

Unscheduled DNA synthesis in mammalian cells in culture	00128695 (1980)

Acceptable	Ethalfluralin did not induce unscheduled DNA synthese in rat
hepatocytes.

870.5375

In vitro mammalian chromosome aberration test	00152219 (1985)

Acceptable	In Chinese hamster ovary cells, ethalfluralin was negative
without S9 activation, but it was clastogenic with activation.

870.7485

Metabolism and pharmacokinetics	42822901 (1993)

Acceptable	Rats were treated orally with a single low dose, a single
high dose, or repeated low doses of radiolabeled ethalfluralin. 
Absorption of ethalfluralin was estimated at 79-87% of the dose for all
dose levels.  Ethalfluralin was rapidly and extensively metabolized, and
95% of the chemical was excreted in the urine and feces by seven days. 
The major route of elimination for the radiolabel was in the feces,
50.9-63.2%, and the levels remaining in the tissues after 72 hours were
negligible.

870.7600

Dermal penetration	00132820 (1982)

Acceptable	A dermal penetration study with rhesus monkeys indicated that
2.7% of a dermal dose was absorbed through the skin.

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