Report of the Food
Quality Protection Act
(FQPA) Tolerance
Reassessment Progress and
Risk Management Decision
(TRED) for Acetochlor
March 2006
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xvEPA
United States Prevention, Pesticides EPA 738-R-00-009
Environmental Protection and Toxic Substances March 2006
Agency (7508C)
Report of the Food Quality Protection Act
(FQPA) Tolerance Reassessment Progress
and Risk Management Decision (TRED)
for
Acetochlor
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Report of the Food Quality Protection Act (FQPA)
Tolerance Reassessment Progress and Risk
Management Decision (TRED) for
Acetochlor
Approved By:
Debra Edwards, Ph.D.
Director, Special Review and
Reregistration Division
Date
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I. Regulatory Determination
The Federal Food, Drug and Cosmetic Act (FFDCA), as amended by FQPA, requires
EPA to reassess all the tolerances for registered chemicals in effect on the day before enactment
of the FQPA on August 3, 1996. In reassessing these tolerances, the Agency must consider,
among other things, aggregate risks from non-occupational sources of pesticide exposure,
whether there is increased susceptibility to infants and children, and the cumulative effects of
pesticides with a common mechanism of toxicity. When a safety finding has been made that
aggregate risks are not of concern, the tolerances are considered reassessed. Existing tolerances
associated with acetochlor must be reassessed in accordance with FFDCA, as amended by
FQPA. Ecological and occupational assessments were originally conducted when acetochlor
was first registered in 1994. Therefore, no further ecological or occupational assessments were
conducted as part of this Report of the FQPA Tolerance Reassessment Progress and Risk
Management Decision for Acetochlor (also referred to as a TRED).
Acetochlor, 2-chloro-N-(ethoxymethyl)-N-(2-ethyl-6-methylphenyl)acetamide, is a
chloroacetanilide herbicide used for preemergence control of weeds. It is registered for use on
field corn and popcorn, although no tolerances currently exist for popcorn. Corn fields treated
with acetochlor may later be rotated to grain sorghum (milo), soybeans, wheat, and tobacco,
according to the currently registered use pattern. Residues in/on corn, popcorn and the rotational
crops listed above were considered in the acetochlor dietary risk assessment supporting the
acetochlor tolerance reassessment.
The Agency's human health and drinking water findings for the pesticide acetochlor are
summarized in the following risk assessments: Acetochlor. Revised HED Chapter of the
Tolerance Reassessment Eligibility Decision (TRED) Document dated March 1, 2006, and
Drinking Water Exposure Assessment for Acetochlor dated February 16, 2006. For further
details, please refer to these risk assessments and other technical documents pertaining to the
acetochlor TRED, which are available on the internet at http://www.regulations.gov and in the
public docket.
EPA has determined that acetochlor is a member of the chloroacetanilides group and that
the chloroacetanilides share a common mechanism of toxicity due to their ability to cause nasal
turbinate tumors. The chloroacetanilides group also includes alachlor and butachlor; however,
butachlor was not incorporated into the cumulative assessment because there are no U.S.
registrations or established tolerances. A chloroacetanilide cumulative assessment was,
therefore, conducted for acetochlor and alachlor exposures based on a common mechanism of
toxicity. The Agency concludes in the assessment that chloroacetanilide cumulative risks are
below the Agency's level of concern. For more information please refer to the document:
Cumulative Risk from Chloroacetanilide Pesticides dated March 8, 2006, which is also available
on the internet at http://www.regulations.gov and in the public docket.
The Agency has evaluated the human health risks associated with all currently registered
uses of acetochlor and has determined that there is a reasonable certainty that no harm will result
from aggregate non-occupational exposure to the pesticide chemical residue. In making this
determination, EPA has considered dietary exposure from food and drinking water and all other
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non-occupational sources of pesticide exposure for which there is reliable information. In
addition, the Agency has concluded that the cumulative risks associated with chloroacetanilide
pesticides, including acetochlor, are below the Agency's level of concern. Therefore, the twelve
(12) tolerances established for residues of acetochlor in/on raw agricultural commodities are now
considered reassessed as safe under section 408(q) of FFDCA, as amended by FQPA.
The Agency is issuing this TRED document for acetochlor as announced in a Notice of
Availability published in the Federal Register. The Agency previously released the EPA's
human health risk assessment and related documents for acetochlor for public comment on
November 23, 2005. The Agency considered all submitted comments in preparing this TRED.
Responses to these comments are also available on the internet at http://www.regulations.gov
and in the public docket.
II. Tolerance Reassessment
A. FQPA Assessment Supporting Tolerance Reassessment Decision
The Agency has conducted risk assessments to ensure that the acetochlor tolerances meet
the safety standards established by FFDCA, as amended by FQPA. These recent risk
assessments for acetochlor include evaluation of potential susceptibility to infants and children;
and dietary, drinking water, and aggregate risk from these various exposure pathways. EPA also
considered potential cumulative risks for acetochlor and other substances sharing a common
mechanism of toxicity. See also Section II.B of this document.
EPA has determined that risk from exposure to acetochlor, as well as cumulative risk
from total exposure to chloroacetanilides pesticides, are within their own applicable "risk cups".
In other words, EPA is able to conclude that the tolerances for acetochlor meet the FQPA safety
standards. In reaching this determination, the Agency has considered the available information
on the potential sensitivity of infants and children, as well as the chronic and acute food
exposure. There are no residential uses of acetochlor nor are there residential post application
exposures expected from currently registered uses. Therefore, an aggregate assessment was
conducted for exposures through food and drinking water only. Results of this aggregate risk
assessment indicate that the human health risks from these combined exposures are within
acceptable levels; that is, combined risks from all exposures to acetochlor "fit" within the
individual risk cup for this chemical. In addition, the Agency has concluded that the cumulative
risks associated with chloroacetanilide pesticides, including acetochlor, are below the Agency's
level of concern. The Agency's risk assessment conclusions are summarized below.
FQPA Safety Factor Considerations. The FFDCA, as amended by the FQPA, directs
the Agency to use an additional tenfold (10X) safety factor to take into account potential pre-
and post-natal toxicity and completeness of the data with respect to exposure and toxicity to
infants and children. FFDCA authorizes the Agency to modify the tenfold safety factor only if
reliable data demonstrate that the resulting level of exposure would be safe for infants and
children.
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Available developmental toxicity studies in two species and three two-generation
reproductive toxicity studies in the rat did not show evidence of increased susceptibility of the
offspring. There are low concerns and no residual uncertainties with regard to pre- and/or post-
natal toxicity. However based on evidence of neurotoxicity, which was observed in studies in
the dog and in the rat including frank neuropathology in a chronic dog study, the Agency is
requiring that a developmental neurotoxicity (DNT) study be submitted by the registrant.
Pending submission and Agency review of this study, an FQPA safety factor of 10X was
retained for deriving the acute dietary reference dose for acetochlor to account for the absence of
the DNT study. A 10X FQPA safety factor was not used in calculation of the chronic dietary
reference dose because the results of the DNT are not expected to affect this risk assessment.
Dietary Risks from Food and Drinking Water. Acute, chronic, and cancer dietary (food and
drinking water) risk assessments were conducted that considered all registered acetochlor uses
(corn and rotational crops) using the Dietary Exposure Evaluation Model software with the Food
Commodity Intake Database (DEEM-FCID), which uses food consumption data from the
USDA's Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 and 1998.
Although there is no existing tolerance for popcorn, a dietary risk assessment that included
popcorn was completed since it is a registered use. Field corn field trial data were translated to
popcorn for this assessment. The acute, chronic, and cancer dietary (food) exposure assessment
incorporated tolerance or proposed tolerance level residues for all crops and percent crop treated
data provided by the Acetochlor Registration Partnership (ARP). Processing data were available
for numerous commodities and incorporated into the assessment. See also Acetochlor. Acute,
Chronic, and Cancer Dietary Exposure Assessments for the Tolerance Reassessment Eligibility
Decision (TRED) Document dated June 30, 2005 for detailed information.
The dietary risk assessment included residues of the parent, acetochlor, and the
metabolites 2-ethyl-6-methylaniline (EMA) and 2-hydroxyethyl-6-methylaniline (HEMA) in/on
the primary crops, corn and popcorn. In addition to EMA and HEMA, the dietary risk
assessment also included residues of the metabolite hydroxymethyl ethyl aniline (HMEA) in/on
rotational crops (i.e., crops grown in fields previously treated with acetochlor). These
metabolites, EMA, HEMA, HMEA, are only found in plants, thus, they were not included in the
drinking water assessment. Refer to the Environmental Degradates section below for additional
information about metabolites found in drinking water.
EPA obtained drinking water residues from the Acetochlor Registration Partnership
(ARP) acetochlor water monitoring program. The ARP monitored a total of 175 Community
Water Supplies (CWSs) in nine mid-western and three Mid-Atlantic States for the acetochlor
surface water monitoring program. The selection process was designed to include a wide array
of CWSs with watersheds in areas of corn production, with an emphasis on including worst-case
watersheds i.e., smaller watersheds (not on the Great Lakes and continental rivers) in areas of
high corn production. Residues of acetochlor from this monitoring program were incorporated
directly into the DEEM-FCID model. EPA considers both acute (one day) and chronic (lifetime)
drinking water risks and exposure to pesticides through contamination of surface and ground
water sources. The acetochlor risk estimates for acute, chronic, and cancer dietary exposure
reflect combined food and drinking water exposure. For detailed information see the document
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titled, Revised Drinking Water Exposure Assessment for Acetochlor dated February 16, 2006.
The population adjusted dose (PAD) is the dose predicted to result in no unreasonable
adverse effects to any human subpopulation, including sensitive members of such subpopulation.
Estimated dietary risks less than 100% of the PAD are not of concern to the Agency. The acute
dietary risk assessment showed that for all registered commodities, the acute dietary risk
estimates (food and drinking water) do not exceed the Agency's level of concern at the 99.9th
percentile of exposure for all populations. The general U.S. population comprises 2% of the
acute population adjusted dose (aPAD), with the highest exposed population subgroup being
infants less than 1 year old at 6% of the aPAD. The aPAD is the dose at which a person could be
exposed on any given day with no adverse health effects, and was derived from an acute rat
neurotoxicity study in which decreased motor activity in females was observed.
EPA's chronic dietary risk assessment indicates that dietary risk from acetochlor residues
in food and drinking water are low and also not of concern. The resulting chronic dietary
exposure estimates using the DEEM-FCID model were less than 1% of the chronic population
adjusted (cPAD) for the U.S. general population and all population subgroups including the most
highly exposed population subgroup, all infants (<1 years old). The cPAD is the dose at which a
person could be exposed over the course of a lifetime with no adverse health effects, and was
derived from a chronic oral toxicity study in beagle dogs in which increased salivation and
histopathology in the testes, kidney and liver were observed.
The Agency classified acetochlor as "likely to be carcinogenic to humans" based on
increased incidence of lung tumors in male and female mice, histiocytic sarcoma in female mice
and nasal epithelial tumors, and thyroid follicular cell adenomas in male and female rats. A
nonmutagenic (with threshold) mode of action was established for the nasal and thyroid tumors;
however, no mode of action was established for the other observed tumors. In the absence of
supporting mechanistic data for the formation of lung tumors and histiocytic sarcomas in mice, a
linear low-dose extrapolation was used to estimate cancer risk for those tumors. The cancer
dietary exposure assessment incorporated tolerance or proposed tolerance level residues for all
crops and percent crop treated data provided by the ARP, assuming consumption of those foods
over a 70 year lifetime. Processing data were available for all commodities and incorporated
into the assessment. The assessment also included the overall multi-year time weighted
annualized mean surface water concentration generated from the ARP acetochlor water
monitoring program. The chronic exposure value was multiplied by a linear low-dose response
factor (Qi*) of 3.27 x 10"2 based on animal studies to determine the lifetime cancer risk estimate.
The estimated dietary (food and drinking water) cancer risk for the general U.S. population was
8.40 x 10"7, and was below the Agency's level of concern (1 x 10"6). Therefore, no mitigation
measures are necessary to address dietary risks from food and drinking water.
Residential Risks. Currently there are no registered residential uses nor potential
residential post-application exposures for acetochlor, thus no residential exposure assessment
was conducted.
Aggregate Risk. In examining aggregate exposure, EPA takes into account the available
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and reliable information concerning exposures from pesticide residues in food and other
exposures including drinking water and non-occupational exposures, e.g., exposure to pesticides
used in and around the home (residential). Risk assessments for aggregate exposure consider
short-, intermediate- and long-term (chronic) exposure scenarios considering the toxic effects
which would likely be associated with each exposure duration. Since there are no residential uses
of acetochlor, the considerations for aggregate exposure are those from food and drinking water
only. As discussed above, the results of the acute, chronic and cancer aggregate assessments
indicate that the combined exposure to acetochlor from food and drinking water is below the
Agency's level of concern. Therefore, no mitigation measures are necessary to address
aggregate risks.
Environmental Degradates. The drinking water assessment was conducted using the
parent acetochlor as the residue of concern. However, there are two degradates of acetochlor
which may be found in drinking water. These degradates, acetochlor sulfonic acid (ESA) and
acetochlor oxanilic acid (OXA), were not included in the water risk assessment based on
comparison of the available toxicity data for acetochlor and the ESA and OXA degradates and
structure-activity relationships which showed that neither ESA nor OXA degradates are likely to
be carcinogenic and that both are significantly less toxic than the parent acetochlor.
However, extensive surface and ground water monitoring data for acetochlor and its two
degradates have been collected as required by the Agency under the conditional registration of
acetochlor. These monitoring studies showed that both the ESA and OXA degradates have been
detected in water samples (both groundwater and surface water). Concentrations of the
degradates in surface water were in the same order of magnitude as acetochlor while
groundwater concentrations of the degradates were significantly higher than those of the parent.
Given the potential for relatively high levels of degradates in drinking water, worst-case margin-
of-exposure (MOE) calculations were conducted to estimate potential drinking water risks for
the two degradates. MOEs ranged from >21,000 to 122,000 for ESA and 45,000 to 264,000 for
OXA and, therefore, were below the Agency's level of concern.
B. Cumulative Assessment
As previously stated, acetochlor is a member of the chloroacetanilides group which shares
a common mechanism of toxicity due to the members' ability to cause nasal turbinate tumors.
The chloroacetanilide group also includes the chemicals alachlor and butachlor. This
determination can be found in the chloroacetanilides common mechanism group (CMG) decision
document published in 2001 entitled "The Grouping of a Series of Chloroacetanilide Pesticides
Based on a Common Mechanism of Toxicity"
(http://www.epa.gov/oppfeadl/cb/csb_page/updates/commechs.htm). Butachlor, however, has
no registered uses or tolerances and has been excluded from the risk assessment. Thus, the
Common Assessment Group (CAG), on which the risk assessment was conducted, consists of
acetochlor and alachlor only.
Development of nasal olfactory epithelium tumors in rats has been attributed to a non-
linear, non-mutagenic mode of action. Thus, as per the 2005 EPA Cancer Guidelines, the Agency
used a margin-of-exposure (MOE) calculation for the cumulative risk assessment as one would do
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for a threshold noncancer toxicity risk assessment. Because the threshold approach was used for
assessing the risks, uncertainty factors (UFs) of lOx (interspecies) and lOx (intraspecies) were
used. Further, since there is no evidence of potential pre- and post-natal susceptibility, the FQPA
safety factor was reduced to Ix. Therefore, MOEs above 100 were considered to be below the
Agency's level of concern (LOG).
The chloroacetanilide cumulative risk assessment involved only two pathways of
exposure (food and drinking water) via the oral route of exposure. Because the nasal olfactory
epithelium tumors are a systemic chronic endpoint, only a chronic dietary analysis was
conducted using the Dietary Exposure Evaluation Model software with the Food Commodity
Intake Database (DEEM-FCID™, Version 2.03). Results of the DEEM-FCID™ analysis
produced cumulated MOEs greater than 13,000 for all populations. Therefore, the cumulated
MOE values estimated for the subject CAG are below the Agency's level of concern. Because
these cumulative MOE values were obtained using high-end exposures, they are considered to be
protective. More detailed information related to the chloroacetanilide cumulative risk
assessment can be found in the document: Cumulative Risks from Chloroacetanilide Pesticides
dated March 8, 2006, which is available on the internet at http://www.regulations.gov and in the
public docket.
C. Endocrine Disrupter Effects
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 Disrupter 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 Disrupter
Screening Program (EDSP).
Studies in the rat evaluating thyroid and liver effects following dietary administration of
acetochlor at various dose levels indicate that acetochlor may disrupt thyroid-pituitary
homeostasis via increased hepatic UDPGH-mediated increased clearance of the thyroid hormone
thyroxine (T4). Slightly increased incidence of thyroid follicular cell tumors have been observed
in rat two-year bioassay studies at higher dose levels. Although thyroid follicular cell tumors
were considered to be related to treatment, they were not considered as part of the cancer
quantification, due to relatively low incidence and evidence for disruption of thyroid hormonal
homeostasis as the mode of action. Structure-activity relationship data on the related
chloroacetanilide herbicides alachlor and butachlor support this conclusion. The available data
do not indicate that acetochlor disrupts androgen or estrogen hormone systems.
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When additional appropriate screening and/or testing protocols being considered under
the Agency's EDSP have been developed, acetochlor may be subjected to further screening
and/or testing to better characterize effects related to endocrine disruption.
D. Tolerance Summary
The current tolerance expression for residues of acetochlor resulting from direct
application to primary crops is adequate. The Agency has determined that the tolerance
expression for residues in/on corn, popcorn, and rotational crop commodities should include only
acetochlor and its metabolites containing the 2-ethyl-6-methylaniline (EMA) and 2-
hydroxyethyl-6-methylaniline (HEMA) moiety, expressed in acetochlor equivalents. A
summary of acetochlor tolerance reassessments is presented in Table 1.
Tolerances Listed Under 40 CFR §180.470:
Adequate residue data have been submitted to reassess the established tolerances for corn
commodities. The available field trial data indicate that the current tolerances on corn grain and
stover are adequate, but the tolerance on corn forage should be increased to 3.0 ppm based on
data from the early postemergence use. Adequate field rotational crop trials are also available to
support the currently established tolerances on commodities of rotational sorghum, and wheat.
The tolerance on soybean grain should be increased to 0.1 ppm based on the submitted rotational
crop data.
As the tolerances on field corn commodities are for the direct application to a primary
crop, these general tolerances on corn will be reassigned to 40 CFR §180.470(a). Likewise,
tolerances on sorghum, soybeans, and wheat commodities are for inadvertent residues on
rotational crops; therefore, these tolerances will be reassigned to 40 CFR §180.470(d).
The 40CFR §180.470 should be revised and separated into subparts (a) through (d).
Subpart (a) should contain tolerances resulting from the direct application of acetochlor to a
primary crop; (b) Section 18 emergency exemptions, (c) tolerances with regional registrations,
and (d) tolerances resulting from indirect or inadvertent residues.
Based on the residue data for currently registered uses and rotational crops, tolerances for
livestock commodities are not required at the present time.
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Tolerances Needed Under 40 CFR §180.470(a):
Acetochlor is registered for use on popcorn; however, there are no existing tolerances
associated with this use. Adequate data submitted by the ARP are available and a dietary
assessment was conducted which included the use of acetochlor on popcorn. Information is
being reviewed to determine whether the tolerance can be established, and the Agency will
address this issue when it considers pending new use petitions.
Tolerances Needed Under 40 CFR §180.470(d):
The available rotational crop field trial data on wheat forage and straw indicate that
residues are also likely to occur on wheat hay. A tolerance for wheat hay can be set using the
residue data for wheat forage and adjusting for the differences in dry weight between the two
commodities. Based on maximum residues of 0.457 ppm in/on wheat forage (25% dry wt),
maximum expected residues in/on wheat hay (88% dry wt.) would be 1.61 ppm. Therefore, a
permanent tolerance of 2.0 ppm needs to be established for wheat hay. The addition of this
tolerance will not change the current calculated maximum dietary burden for cattle.
Table 1. Tolerance Reassessment Summary for Acetochlor
Commodity
Current
Tolerance
(ppm)
Range of
Residues (ppm)
Tolerance
Reassessment
(ppm)
Comment/ '[Correct Commodity
Definition]
Tolerances Listed Under 40 CFR §180.470
Corn, field, forage
Corn, field, grain
Corn, field, stover
Sorghum, forage
Sorghum, grain
Sorghum, grain,
stover
Soybean, forage
Soybean, grain
Soybean, hay
Wheat, forage
Wheat, grain
Wheat, straw
1.0
0.05
1.5
0.1
0.02
0.1
0.7
0.02
1.0
0.5
0.02
0.1
0.05-2.52
0.05
0.05-1.08
O.02-0.093
0.02
O.02-0.068
O.2-0.648
O.02-0.101
O.024-1.064
O.02-0.457
O.02
O.02-0.104
3.0
0.05
1.5
0.1
0.02
0.1
0.7
0.1
1.0
0.5
0.02
0.1
Tolerances on corn commodities
should be reassigned to
§180.470(a) as these tolerances are
for the direct use on corn.
Tolerances on sorghum, soybean,
and wheat commodities should be
reassigned to §180.470(d) as these
are tolerances for inadvertent
residues in/on rotational crops.
The correct commodity definition
for Sorghum, grain is Sorghum,
grain, grain and for Soybean, grain
is Soybean, seed.
Tolerances Needed under 40 CFR §180.470(a)
Corn, pop, grain
0.5
1.5
0.05
0.05-1.08
0.05
1.5
A permanent tolerance should be
set at 0.05 ppm based on maximum
residues in field corn grain.
A permanent tolerance should be
set at 0.05 ppm based on maximum
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Table 1. Tolerance Reassessment Summary for Acetochlor
Commodity
Corn, pop, stover
Current
Tolerance
(ppm)
Range of
Residues (ppm)
Tolerance
Reassessment
(ppm)
Comment/ '[Correct Commodity
Definition]
residues in field corn stover.
Tolerances Needed under 40 CFR §180.470(d)
Wheat, hay
None
1.611
2.0
A permanent tolerance should be
set at 2.0 ppm based on maximum
residues in wheat forage corrected
for moisture content.
1. Maximum expected residues in wheat hay (88% dry wt), based on maximum residues of 0.457 ppm in wheat
forage (25% dry wt.).
III. Data Requirements
There are data that must be submitted to support the continuing registration of
acetochlor. These data are not expected to change the regulatory conclusions for acetochlor
described in this document. A generic data call-in (DCI) will be issued and will require
development and submission of these listed data:
Toxicology
870.6300 A developmental neurotoxicity study is required.
870.6200 Validation studies (positive controls) are required for the rat
neurotoxicity studies.
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