UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF PREVENTION, PESTICIDES 

AND TOXIC SUBSTANCES

  SEQ CHAPTER \h \r 1 MEMORANDUM			

April 30, 2007								

SUBJECT:	ACETOCHLOR/ALACHLOR: Revised Cumulative Risk Assessment for the
Chloroacetanilides to Support the Proposed New Uses on Alachlor and
Acetochlor.  PP#8F05000 and 8F5025 (Alachlor), PP#6F4791, 1F6263 and
5F6918 (Acetochlor).  PC Codes: 121601 & 090501.  DP Barcode D336214 

	  SEQ CHAPTER \h \r 1 

								

FROM:	  SEQ CHAPTER \h \r 1 Yan Donovan, Risk Assessor

		Reregistration Branch 4

		Health Effects Division (7509P)

THROUGH:	Ray Kent, Branch Chief

		Richard Loranger, and 

		Alberto Protzel,   SEQ CHAPTER \h \r 1 Senior Scientists

		Health Effects Division (7509P)

TO:		  SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r 1 Vickie Walters/ Jim
Tompkins, PM#25

		Herbicide Branch

		Registration Division (7505P)

		

Attached is Health Effect Division’s revised cumulative risk
assessment for the chloroacetanilides to support the proposed new uses
for   SEQ CHAPTER \h \r 1 alachlor and acetochlor.   Previous cumulative
risk assessment for the chloroacetanilides was conducted by Alberto
Protzel, et al. (HED memo of 03/08/06, A. Protzel, et al.  D292317).   

The reference memorandums are listed below. 

	HED Cumulative Risk Assessment, memo of A. Protzel, et al.  (D292317,
03/08/06)

HED Alachlor Risk Assessment, memo of Yan Donovan (D330812, 01/08/07)

HED Acetochlor Risk Assessment, memo of Donna S. Davis (D D335367,
01/22/07)

	HED Dietary Exposure and Risk Assessment, memo of Yan Donovan (D336215,
04/25/07)

Revised Drinking Water Assessment; Greg Orrick from EFED (D330435,
12/13/06)

Drinking Water Assessment, Michael Barrett from EFED (D332524, 09/18/06)

Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc158113797"  1.0      
Executive Summary	  PAGEREF _Toc158113797 \h  3  

  HYPERLINK \l "_Toc158113798"  2.0	Introduction	  PAGEREF _Toc158113798
\h  4  

  HYPERLINK \l "_Toc158113799"  2.2  	Structure and Nomenclature	 
PAGEREF _Toc158113799 \h  6  

  HYPERLINK \l "_Toc158113800"  2.3  	The Cumulative Risk Assessment
Process	  PAGEREF _Toc158113800 \h  7  

  HYPERLINK \l "_Toc158113801"  3.0	Performing the Cumulative Risk
Asessment	  PAGEREF _Toc158113801 \h  7  

  HYPERLINK \l "_Toc158113802"  3.1 	Identification of the Common
Mechanism Group (CMG)	  PAGEREF _Toc158113802 \h  7  

  HYPERLINK \l "_Toc158113803"  3.2	Determination of the Candidate
Cumulative Assessment Group (CAG).	  PAGEREF _Toc158113803 \h  8  

  HYPERLINK \l "_Toc158113804"  3.3 	Dose Response Analysis: 
Determination of Relative Potency Factors and Points of Departure.	 
PAGEREF _Toc158113804 \h  8  

  HYPERLINK \l "_Toc158113805"  3.4	Exposure  Analysis	  PAGEREF
_Toc158113805 \h  10  

  HYPERLINK \l "_Toc158113806"  3.4.1	Inputs From Foods.	  PAGEREF
_Toc158113806 \h  11  

  HYPERLINK \l "_Toc158113807"  3.4.2	Inputs From Drinking Water	 
PAGEREF _Toc158113807 \h  12  

  HYPERLINK \l "_Toc158113808"  3.4.3	DEEM-FCIDTM Analysis of Exposure
From Foods and Water	  PAGEREF _Toc158113808 \h  13  

  HYPERLINK \l "_Toc158113809"  3.5	The Cumulative Risk assessment	 
PAGEREF _Toc158113809 \h  14  

  HYPERLINK \l "_Toc158113810"  3.6	Characterization of the Risk
Assessment	  PAGEREF _Toc158113810 \h  14  

  HYPERLINK \l "_Toc158113811"  4.0	Conclusions	  PAGEREF _Toc158113811
\h  14  

  HYPERLINK \l "_Toc158113812"  5.0	References	  PAGEREF _Toc158113812
\h  15  

 1.0      	Executive Summary	

Structurally related chloroacetanilides include acetochlor, butachlor,
propachlor and metolachlor.  As part of the provisions of the Food
Quality Protection Act (FQPA, 1996), EPA must consider the cumulative
effects on human health that may result from exposure to different
chemicals that cause toxic effects by the same mode of action.  The
chloroacetanilides have been evaluated by the Agency and the FIFRA
Scientific Advisory Panel (SAP) as a related group of chemicals for this
purpose.  For purposes of a cumulative risk assessment, it was
determined that the common mechanism of toxicity group consists of
alachlor, acetochlor and butachlor.  The group was selected based on
common endpoints of (1) nasal turbinate tumors in rats, and a known
mechanism of toxicity for development of these tumors and (2) induction
of hepatic UDPGT, which results in increased incidence of thyroid
follicular cell tumors secondary to disruption of pituitary-thyroid
homeostasis.  [UDPGT: UDP-Glucuronosyl Transferase, the microsomal
enzyme that transfers glucuronsyl residues from UDP-glucuronic to
acceptors like the OH group in thyroid hormone (e.g. T4).  Alachlor
induces this liver enzyme and increases the clearance of T4.]   Since
there are no butachlor registered uses or import tolerances in the
United States, it was concluded that for purposes of human risk
assessment, only alachlor and acetochlor should be included, using nasal
tumors as the endpoint.   Thyroid effects were not included in the final
cumulative assessment of the chloroacetanilide herbicides because they
were determined to occur at excessively toxic dose levels, and therefore
were not considered relevant to human risk assessment.  Nasal tumors
represent the most sensitive endpoint for both compounds.  The point of
departure (POD) selected for alachlor was 0.5 mg/kg/day, based on nasal
tumors at 2.5 mg/kg/day, with a target MOE of 100 (10X each for
intraspecies and interspecies differences).  The POD for acetochlor is
10 mg/kg/day.  Relative Potency Factors were calculated using the ratio
of POD values (based on NOAELs) for alachlor (as index chemical) and
acetochlor.  Therefore, the RPFs for alachlor and acetochlor are 1 and
0.05, respectively.

There are no residential uses for these two chemicals.  Thus, the risk
assessment only includes food and water.  Because the endpoint of
interest is a cancer endpoint that arises via a mode of action that
requires prolonged exposure, only a chronic dietary analysis was
performed.  For food exposure, tolerance levels and some average
residues were used.  Acetochlor residues were converted to alachlor
equivalents by multiplying a factor of 0.05.  The total alachlor
residues were obtained by adding the alachlor residues to acetochlor
(alachlor equivalents) residues for crops that have both alachlor and
acetochlor tolerances.  DEEM default processing factors from DEEM
(Version 7.81) were used for all processed commodities that do not have
individual tolerances, except for soybeans and sunflower, where
processing factors from available processing studies were used.  For
soybeans, processing factors used in the DEEM are: 0.17 for soybean oil,
0.32 for soybean protein concentrate, and 0.21 for soybean protein
isolate.  For sunflower, a processing factor of 0.07 was used for
sunflower oil.   For drinking water exposure, the 30 year mean value of
63.6 ppb from modeling for alachlor and degradates, plus 0.11 ppb
(alachlor equivalent) from monitoring for acetochlor, totaling 64 ppb
was used.

The dietary exposure assessment was conducted using the Dietary Exposure
Evaluation Model (DEEM-FCIDTM, Version 2.03) which uses food consumption
data from the USDA’s Continuing Surveys of Food Intakes by Individuals
(CSFII) from 1994-1996 and 1998.  It was assumed that 100% crop treated
(%CT) for all commodities.  The MOE for nasal tumor (the most sensitive
cancer endpoint among the group) is greater than the target MOE of 100
for U. S. population.  Therefore, the cumulative risk is below HED’s
level of concern.  This analysis is considered conservative dietary
exposure assessment with the use of average residues for some crops,
100% crop treated, and the use of drinking water modeling data.   HED
notes that, based on the DEEM complete commodity analysis, the drinking
water exposure from alachlor modeling value counts 90% of the total
risk.  Further refinement to the analyses can be made through the use of
percentages of crops treated, and/or monitoring data for both food
residues and especially drinking water values that better reflect
residues at the time of consumption.  Since risk estimate in this
assessment is well below HED’s level of concern, a more highly refined
analysis is not needed at this time.  

Recommendations

The cumulative risk does not exceed HED’s level of concern.  
Permanent tolerances are recommended for acetochlor and alachlor as
stated in the individual risk assessment documents for the two
chemicals.

2.0	Introduction

Alachlor and acetochlor are members of the chloroacetanilide group of
chemical compounds.  It was determined that alachlor, acetochlor and
butachlor all share a common mechanism of toxicity based on common
endpoints of (1) nasal turbinate tumors in rats, and a known mechanism
of toxicity for development of these tumors and (2) induction of hepatic
UDPGT, which results in increased incidence of thyroid follicular cell
tumors secondary to disruption of pituitary-thyroid homeostasis.  A
cumulative risk assessment for the chloroacetanilides was conducted by
Alberto Protzel, et al. (HED memo of 03/08/06, A. Protzel, et al. 
D292317).  Since then, new uses have been proposed for both alachlor and
acetochlor.

Alachlor is currently registered for use on:  succulent and dry beans;
field, pop, and sweet corn; peanuts; grain sorghum; and soybeans. 
Monsanto Company has proposed new uses of the end-use products
Micro-Tech (EPA Reg. No. 524-344) on cotton and sunflower.  In addition,
the registrant has submitted a petition for the establishment of
permanent tolerances for indirect or inadvertent residues of alachlor
in/on the cereal grains crop group (excluding corn, sorghum and rice),
in/on the forage, fodder and straw of cereal grains crop group
(excluding corn, sorghum and rice), and in/on the nongrass animal feeds
crop group.  

Acetochlor is conditionally registered for use on corn to the Acetochlor
Registration Partnership (ARP), which is currently comprised of Monsanto
and Dow AgroSciences. Tolerances for soybean, sorghum, and wheat
commodities are established for the combined residues of acetochlor and
its EMA- or HEMA-producing metabolites, to be expressed in acetochlor
equivalents [40 CFR §180.470].   The registrant has submitted petitions
for tolerances on sweet corn and rotational crops of nongrass animal
feeds (Group 18), sugar beets, dried shelled beans and peas (Subgroup
6C), sunflowers, potatoes, cereal grains (Group 15).

Single chemical aggregate risk assessments have been completed for both
alachlor and acetochlor (HED memo of Y. Donovan, D330812, 01/08/07, and
memo of D. Davis, D335367, 01/22/07).

Mode of action for nasal olfactory epithelial cell tumorigenesis

	The mode of action for the development of nasal olfactory epithelial
cell tumors in the rat by alachlor has been characterized based on the
findings of a number of special in vivo and in vitro mechanistic
studies.  Studies have also been conducted on other chloroacetanilide
compounds that demonstrate that this mode of action is shared by the
related chloroacetanilides acetochlor and butachlor.  The formation of
nasal tumors is considered a non-genotoxic event resulting from a
cytotoxic benzoquinoneimine metabolite binding to nasal olfactory cell
proteins.  This metabolite is formed in situ by the metabolizing enzymes
of the nasal olfactory epithelial cells from circulating metabolites of
alachlor that are delivered to the nasal olfactory cells.  Whole body
autoradiography data show binding of radiolabeled alachlor to the nasal
mucosa in rats and to a much lesser extent, in mice.  The
benzoquinoneimine metabolite, a highly reactive compound that binds to
cellular proteins, may also cause oxidative stress and cell death. 
Cytotoxicity results in cellular proliferation, eventually leading to
fixation of spontaneous mutations and tumor formation.  Mechanistic
studies submitted to characterize nasal tumorigenesis in the rat
indicate that rats have higher rates of formation of benzoquinoneimine
formation in nasal tissue than mice, primates or humans.  Although rats
are considered to be more sensitive to formation of these tumors, the
potential for its formation in humans cannot be ruled out at this time.

	

Mode of action for thyroid follicular cell tumorigenesis:  

	Alachlor has been shown to cause an increased incidence of thyroid
tumors in male Long-Evans rats at dose levels at or above 126 mg/kg/day
in two-year dietary studies.  Data have been submitted demonstrating
that the mechanism of thyroid tumorigenesis is consistent with
disruption of thyroid-pituitary homeostasis.  This study showed
increased activity of hepatic uridine 5’-diphosphoglucuronyl
transferase (UDPGT) and liver enlargement, leading to increased
clearance of thyroid hormones and compensatory increases in pituitary
release of thyroid stimulating hormone (TSH), followed by thyroid
hyperplasia and tumorigenesis.   However, these tumors are not
considered in the human risk assessment because they were observed only
at doses at or above 126 mg/kg/day, which were considered to be in
excess of the MTD.  The mechanism of thyroid tumorigenesis observed with
alachlor is also observed for the related chloroacetanilide herbicide
acetochlor.

  SEQ CHAPTER \h \r 1 2.2  	Structure and Nomenclature

Table 2.2 a Alachlor Nomenclature.

Chemical structure	

Common name	Alachlor 

Trade and other names	Lasso, Alanex

IUPAC name	2-Chloro-N-(2,6-diethylphenyl)-N-(methyoxymethyl)acetamide

CAS name	2-chloro-2′,6′-diethyl-N-methoxymethylacetanilide

CAS registry number	15972-60-8

End-use products (EPs)	Micro-Tech (EPA Reg. No. 524-344) 



Table 2.2b	Acetochlor Nomenclature

Chemical structure	

 



Common name	Acetochlor

Molecular Formula	C14H20ClNO2

Molecular Weight	269.8

IUPAC name	2-chloro-N-ethoxymethyl-6'-ethylacet-o-toluidide

CAS name	2-chloro-N-(ethoxymethyl)-N-(2-ethyl-6-methylphenyl)acetamide

CAS #	34256-82-1

PC Code	121601

End-use Product	7.5 lb/gal EC (Acetochlor EC Herbicide, EPA Reg. No.
66478-2)





  SEQ CHAPTER \h \r 1 2.3  	The Cumulative Risk Assessment Process  

The first cumulative risk assessment completed by the Agency was for the
organophosphorus (OP) class of pesticides.   As elaborated in OPP’s
cumulative guidance document (USEPA 2002a), the cumulative risk
assessment process unfolds in several steps.  In brief, these include:

A. Identification of the Common Mechanism Group (CMG).

B. Determination of the Candidate Cumulative Assessment Group (CAG)

C. Determination of Points of Departure (dose response analysis)

D. Exposure analysis (exposure scenarios for all routes and durations,
establish exposure input parameters).  

E. Conduct final cumulative risk assessment.

F. Characterize the cumulative risk assessment.

3	e	.0	Performing the Cumulative Risk Asessment

	

3.1 	Identification of the Common Mechanism Group (CMG)

A cumulative risk assessment begins with the identification of a group
of chemicals, called a common mechanism group (CMG), that induce a
common toxic effect by a common mechanism of toxicity. Pesticides are
determined to have a "common mechanism of toxicity" if they act the same
way in the body--that is, the same toxic effect occurs in the same organ
or tissue by essentially the same sequence of major biochemical events. 


The chloroacetanilide pesticides have been previously evaluated by the
Agency to determine if some of them comprise a common mechanism group. 
Details of the analysis appear in the document The Grouping of a Series
of
Chloro捡瑥湡汩摩⁥敐瑳捩摩獥䈠獡摥漠⁮⁡潃浭湯䴠捥
慨楮浳漠⁦潔楸楣祴⠠单偅⁁〲㄰⸩䤠⁮牢敩ⱦഠ

● Acetochlor, Alachlor and Butachlor may be grouped together based on
a common end-point (nasal turbinate tumors in rats) and a known
mechanism of toxicity for this endpoint.   All three compounds produce
tumors of the nasal olfactory epithelium in rats by way of a non-linear,
non-genotoxic mode of action that includes cytotoxicity of the olfactory
epithelium, followed by regenerative cell proliferation of the nasal
epithelium that can then lead to neoplasia if cytotoxicity and
proliferation are sustained (see more details below).

● Acetochlor, Alachlor and Butachlor may also be grouped together
based on an common end-point and a known mechanism of toxicity (UDPGT
induction).   All three compounds produce tumors of the thyroid
follicular cells in rats by way of a non-genotoxic mode of action that
includes UDPGT induction, increased TSH, alterations in T3/T4 hormone
production and thyroid hyperplasia.

The grouping of Acetochlor, Alachlor, and Butachlor based on a common
mechanism of action was presented to the FIFRA Scientific Advisory Panel
(SAP) as a draft on March 19, 1997. The SAP agreed with the Agency’s
conclusion that there is sufficient evidence to support the proposed
grouping for the nasal turbinate tumors and for the thyroid follicular
tumors (USEPA, 1997). 

The FIFRA SAP noted in their report (USEPA, 1997), additionally, that
even though the evidence illustrated that a common mechanism could be
used to group certain chemicals for the development of thyroid tumors,
it was recommended that this endpoint not be used in combining margins
of exposure because the toxic effects were noted at doses above the
Maximum Tolerated Dose (MTD).  While the full range of doses employed
can be used to determine common mechanisms, endpoints occurring solely
at doses above the MTD should not be used in risk assessments.
Furthermore, humans are more refractory to the induction of thyroid
follicular cells tumors due to prolong stimulation of thyroid
stimulating hormone compared to rats.

Thus, for the purposes of this document, the induction of nasal
olfactory epithelium tumors in rats was regarded as the most sensitive
and relevant common mechanism endpoint to base the cumulative risk
assessment of the chloroacetanilides. 

3.2	Determination of the Candidate Cumulative Assessment Group (CAG).

	

Once the CMG is defined, a subset of this group, the Common Assessment
Group (CAG) is selected, for which the cumulative risk assessment will
be performed.  This final selection incorporates into the CAG those
pesticides from the Common Mechanism Group whose uses, routes, and
pathways of exposure will present sufficient exposure and hazard
potential to warrant inclusion in the quantitative estimates of risk. 

The CMG subject of this document consists of acetochlor, alachlor and
butachlor.   At present only alachlor and acetochlor are registered
pesticides in the US.  There are no registered uses or import tolerances
for butachlor.   Therefore no exposure is expected from butachlor. 
Thus, a cumulative risk assessment will be performed using a CAG
comprising only of acetochlor and alachlor. 

	

3.3 	Dose Response Analysis:  Determination of Relative Potency Factors
and Points of Departure.

The Agency’s revised Guidelines for Carcinogen Risk Assessment (USEPA,
2005b) divide dose response assessment into two parts.  The first is
assessment of the dose response near the lower end of the observed range
(the point of departure or POD).   The second part is extrapolation of
the dose-response curve from the POD into the low-dose range.  

Once the POD is determined, it is used as the starting point for
subsequent extrapolations and analyses.  If data are available,
biologically based dose-response (BBDR) modeling may be done to
extrapolate to lower doses below the POD.  In the absence of BBDR
models, for linear extrapolation (i.e. genotoxic carcinogens), the POD
may be used to calculate a slope factor, and for non-linear
extrapolation (the present case for acetochlor and alachlor) the POD may
be used in the calculation of a Margin of Exposure (MOE).

The revised Guidelines for Carcinogen Risk Assessment (USEPA, 2005b),
discuss the relative advantages of several approaches to obtaining the
POD for cancer risk assessment:

● When tumor data are used, a POD is obtained from the modeled tumor
incidences. Conventional cancer bioassays, with approximately 50 animals
per group, generally can support modeling down to an increased incidence
of 1–10%.  A no-observed-adverse-effect level (NOAEL) generally is not
used for assessing the potential for carcinogenic response when one or
more models can be fitted to the data. 

	● When good quality precursor data are available and are clearly tied
to the mode of action of the compound of interest, models that include
both tumors and their precursors may be advantageous for deriving a POD.
Such models can provide insight into quantitative relationships between
tumors and precursors, possibly suggesting the precursor response level
that is associated with a particular tumor response level.

On the other hand, the Guidelines note that if the precursor data are
drawn from small samples or if the quantitative relationship between
tumors and precursors is not well defined, then the tumor data will
provide a more reliable POD.

In this document, tumor incidences will be used for POD determination
because they constitute a robust set of data and use of observed tumor
NOAELs will be used as a conservative screening approach.  Since
experimental NOAELs are determined by the doses selected by the
investigator, the “true NOAEL” may actually be a higher value.

Determination of the POD using nasal tumor incidences.

(Refer to Alberto Protzel’s 03/08/06 memo for detailed discussion)

The summary of the incidences of nasal tumors in rats treated
chronically with acetochlor or alachlor indicates that, for Acetochlor,
the incidence of nasal tumors in Sprague-Dawley rats increases
significantly with dose in all studies. The available data define a POD
for acetochlor of 10 mg/kg/day for nasal tumors in S-D rats.

For Alachlor, summary of the data indicates that the incidences of nasal
tumors in Long-Evans rats increases significantly with dose in all
studies. The available data define a POD for alachlor of 0.5 mg/kg/day
for nasal tumors in Long-Evans rats.

Determination of a Relative Potency Factor for Acetochlor.

The POD values (based on NOAELs) are summarized in Table 3.3.  The POD
for acetochlor is 10 mg/kg/day and the POD for alachlor is 0.5
mg/kg/day.   Relative Potency Factors were calculated using the ratio of
POD values (based on NOAELs) for alachlor (as index chemical) and
acetochlor.   As shown in Table 3.3, the RPFs for alachlor and
acetochlor are 1 and 0.05, respectively.

Table 3.3.  Summary of  POD values for Nasal Tumors in Rats Treated
Chronically in the Diet  with Acetochlor or Alachlor

Compound	POD 

(Mg/kg bw/day)	RPF1	Rat Strain/Sex	Comments

Alachlor

(Index Chemical)	0.5	1	Long-Evans / Female	A conservative value, the
incidence of 1/43 at 2.5 may well be the beginning of the dose response
of a rare tumor, and thus toxicologically significant.

Acetochlor	10	0.05	Sprague-Dawley / Male & Female	The incidence is 1/70
at 22 mg/kg/day in study PR-80-006.

 This effect is likely toxicologically significant.



1 With Alachlor as index chemical; RPF = POD of alachlor divided by the
POD of acetochlor. Acetochlor (in alachlor equivalents) = Concentration
of acetochlor x RPF.

Exposure   SEQ CHAPTER \h \r 1  Analysis

There are no residential uses for these two chemicals.  Thus, the risk
assessment only includes food and water.  Because the endpoint of
interest is a cancer endpoint that arises via a mode of action that
requires prolonged exposure, only a chronic dietary analysis was
performed.  

The nature of the residue in plants and animals for alachlor is
adequately understood. The residues of concern are parent alachlor and
its metabolites which can be converted to 2,6-diethylaniline (DEA) and
2-ethyl-6-(1-hydroxyethyl)aniline (1-HEEA) upon basic hydrolysis.  HED
believes that these metabolites of concern in food commodities are also
the metabolites of concern for causing the nasal tumor.  The residues of
concern in drinking water are parent plus three degradates.  HED
believes that these degradates of concern in drinking water assessment
are also the degradates of concern for causing the nasal tumor.

  SEQ CHAPTER \h \r 1 

Table 3.4a. Summary of Residues for Tolerance Expression and Risk
Assessment	(Alachlor)

Residues of Concern

Matrix	For Risk Assessment	For Tolerance Expression

Plants 

	Parent plus the DEA- and HEEA-yielding metabolites	Parent plus the DEA-
and HEEA-yielding metabolites

Rotational crop	Parent plus the DEA- and HEEA-yielding metabolites
Parent plus the DEA- and HEEA-yielding metabolites

Livestock:

	Parent plus the DEA- and HEEA-yielding metabolites	Parent plus the DEA-
and HEEA-yielding metabolites

Water	Parent plus degradates II, IX, and XIII	N/A

	

The qualitative nature of acetochlor residues in corn is adequately
understood based on a corn metabolism study.  HED concluded that the
residues of concern in corn include parent and any metabolites
containing the ethyl methyl aniline (EMA) or hydroxyethyl methyl aniline
(HEMA) moiety, expressed in acetochlor equivalents.  The nature of the
residue in rotational crops is adequately understood based on the
results of confined rotational crop studies in lettuce, radishes and
wheat. HED concluded that rotational tolerances should be expressed as
acetochlor and its EMA and HEMA producing metabolites, and residues of
hydroxymethyl ethyl aniline (HMEA) type metabolites would not be
included in the tolerance expression, but should be included in the risk
assessment.  HED assumes that these metabolites of concern in plants are
also the metabolites of concern for causing the nasal tumor.

The qualitative nature of acetochlor residues in animals is also
adequately understood.  Based on adequate studies examining the
metabolism of various acetochlor plant metabolites in both ruminants and
poultry, the Agency concluded that the acetochlor residues of concern in
ruminants and poultry include acetochlor and it metabolites containing
the EMA and HEMA moieties as well as   SEQ CHAPTER \h \r 1
N-(6-ethyl-3-hydroxy-2-methylphenyl) oxamic acid (referred to as
“Metabolite 57”).  Based on the metabolism studies and the available
livestock feeding studies, the Agency has also determined that
tolerances are not required for livestock commodities to support the
current use on corn.  Although there are a variety of livestock feed
items associated with the proposed use on sweet corn and rotational
crops, none of these feed items are expected to significantly increase
the potential dietary exposure of livestock.  Therefore, tolerances on
animal commodities are not required for the proposed use on sweet corn
or for the inclusion of the requested rotational crops.

Table 3.4b.    Residues of Concern for Tolerance Expression and Risk
Assessment  (Acetochlor)



Matrix	

Residues included in Risk Assessment	

Residues included in Tolerance Expression



Plants – Sweet Corn & Sorghum	

Parent  and metabolites containing the EMA or HEMA moiety	

Parent and metabolites containing the EMA or HEMA moiety



Rotational Crops – Nongrass Animal Feeds (Group 18), Sugar Beets,
Dried Shelled Beans and Peas (Subgroup 6C), Sunflowers, Potatoes, Cereal
Grains (Group 15), and Forage, Fodder, and Straw of Cereal Grains (Group
16)	

Parent and metabolites containing the EMA,  HEMA, or HMEA moiety	

Parent and metabolites containing the EMA or HEMA moiety



Drinking Water	

Parent only	

N/A



Inputs From Foods.

(HED Dietary Exposure and Risk Assessment, memo of Yan Donovan (D336215,
04/25/07).

Dietary exposures from both alachlor and acetochlor are considered for
the cumulative assessment.  Combined residues were used for crops that
have both alachlor and acetochlor tolerances.

Acetochlor.  Tolerance levels were used for existing and new proposed
uses.  A factor of 0.05 is applied to all acetochlor tolerances to
obtain the residue values of alachlor equivalent.  Although the
tolerances on rotational crops did not include hydroxymethyl ethyl
aniline (HMEA) type metabolites, HED believes that after the application
of the relative potency factor of 0.05, the contribution from HMEA can
be considered negligible.

Alachlor.   Tolerance levels and average residues for some crops were
used.  The total alachlor residues were obtained by adding the alachlor
residues to acetochlor (alachlor equivalents) residues for crops that
have both alachlor and acetochlor tolerances. DEEM default processing
factors from DEEM (Version 7.81) were used for most processed
commodities that do not have individual tolerances, except for soybeans
and sunflower, where processing factors from available processing
studies were used.  For soybeans, processing factors used in the DEEM
are: 0.17 for soybean oil, 0.32 for soybean protein concentrate, and
0.21 for soybean protein isolate (HED memo of 5/18/98, K. Boyle, Revised
RED for Alachlor, page 62).  For sunflower, a processing factor of 0.07
was used for sunflower oil (HED memo of 9/19/06, S. Hummel, D330696 and
D332403, page 19).

Inputs From Drinking Water

Alachlor

Estimated Drinking Water Concentrations (EDWC) of alachlor were
generated using the maximum use patterns (sunflower and woody
ornamentals).  Exposure estimates reflect total toxic residues (TTR)
that include alachlor and its degradates of risk concern.  The surface
water and groundwater EDWCs were calculated with the screening models
PRZM/EXAMS and SCI-GROW, respectively.

Table 3.4.2a.  Tier II TTR EDWCs in surface water and groundwater from
alachlor uses on cotton and sunflower based on the maximum use patterns,
sunflower and woody ornamentals.

Source	Peak Exposure (ppb)	Annual Mean Exposure (ppb)	30-year Mean
Exposure (ppb)

Surface water	123	74.7	63.6

Groundwater	2.48	<2.48	<2.48



The surface water EDWCs in Table 3.4.2a have been adjusted by default
Percent Cropped Area (PCA) factors to account for the potential fraction
of the basin where the crop is planted.  The 30-year mean value of 63.6
ppb from surface water should be used in the cancer assessment.

Acetochlor

The PRZM/EXAMS multi-year (30-year simulation) chronic exposure level
estimate for acetochlor on sorghum is 2.13 ug/L. and serves as the
endpoint for use in cancer risk estimation (there is no range for this
estimate based upon the way the model is currently configured).  This
falls within in the range of multi-year chronic exposure levels from the
field corn use estimated by  PRZM/EXAMS (i.e.,  0.98 to 3.41 at five
different sites using the available standard modeling scenarios for corn
; long-term EDWCs  for corn were higher than for the sorghum scenario at
two of the five sites modeled).  

Table 3.4.2b.  Summary of EDWCs for usage of Acetochlor on Sorghum

Exposure

Assessment

Methodology	Acute 

Conc

(ug/L)	1/10 Year

Chronic Conc

(ug/L)	Cancer/

Chronic Conc

(ug/L)

PRZM/EXAMS	42.4	4.11	2.13



For this cumulative cancer assessment, after applying the relative
potency factor of 0.05, the drinking water contribution from the use of
acetochlor is 0.11 ppb alachlor equivalent.

DEEM-FCIDTM Analysis of Exposure From Foods and Water

The cumulative cancer assessments used the Dietary Exposure Evaluation
Model (DEEM-FCIDTM, Version 2.03) which uses food consumption data from
the USDA’s Continuing Surveys of Food Intakes by Individuals (CSFII)
from 1994-1996 and 1998.  It is assumed that 100% crop treated (%CT) for
all commodities.

This analysis is considered a conservative dietary exposure assessment
with the use of average residues for some crops, 100% crop treated, and
the use of drinking water modeling data.   HED notes that, based on the
DEEM critical commodity analysis, the drinking water exposure from
alachlor modeling value counts 90% of the total risk.  Further
refinement to the analyses could be made through the use of percentages
of crops treated, and/or monitoring data for both food residues and
especially drinking water values that better reflect residues at the
time of consumption.  Since risk estimate in this assessment is well
below HED’s level of concern, a more highly refined analysis is not
needed at this time.  



Table 3.4.3.  Results of Cumulative Cancer Risk (Nasal Tumor) from FOOD
and Water



Population Subgroup	

NOAEL

(mg/kg/day)	

Exposure (mg/kg/day)	

MOEs



General U.S. Population	

0.5	

0.001508	

330



The Cumulative Risk assessment

As presented in table 3.4.3, the MOE for nasal tumor (the most sensitive
cancer endpoint among the CAG) is greater than the target MOE of 100. 
Therefore, the cumulative risk is below HED’s level of concern.  

Characterization of the Risk Assessment

	

1

2

@

N

‰

‹

Ž

³

Ö

Ú

ß

ð

ñ

ü

V

i

‰

Š

‹

Ž

 

g

&

,

>

T

]

f

g

k

l

t

z

…

"…

¬



½

Á

Â

ø

ù

ú

û

ÿ

h-

$g



ú

Ø	@

Ø	@

Ø	@

„Ð^„Ðgd-

Ø	@

j;

j¸

ô

ô

ô

ô

ô

ô

ô

ô

ô

ô

ô

ô

ô

ô

ô

ô

瑹厸	

瑹⎋

×

×

&

×

	@

퀀ࠂ䀇

퀀ࠂ䀇

	@

摧䣀À

	@

愀Ĥ摧㠤

@

@

ˆÿò

FQPA factor is 1. Thus, MOEs above 100 are considered to be outside of
the Agency’s level of concern (LOC).

Under FQPA, the potential for increased sensitivity to adverse effects
from a pesticide to children during gestation and postnatal development
must be considered.  As discussed in Alberto Protzel’s 03/08/06 memo,
no evidence has been found that the developing fetus or young animal has
increased sensitivity, compared to the adult, to chloroacetanilide
-induced nasal olfactory epithelial tumors.

Dietary exposure assessments were conducted using tolerance levels and
some anticipated residues.  It is assumed that 100% crop treated for all
commodities.  Modeling drinking water values were used in this dietary
assessment.  Thus it is considered a conservative assessment.  HED notes
that, based on the DEEM complete commodity analysis, the drinking water
exposure from alachlor modeling value takes up 90% of the total risk.  
Refinements can be made using PDP data when they are available in the
future.

Conclusions

A revised cumulative risk assessment of a Cumulative Assessment Group
(CAG) of Chloroacetanilide pesticides has been conducted to reflect the
new proposed uses for alachlor and acetochlor.  The CAG for this
document consists of two chemicals: alachlor and acetochlor.  An
original member of the Common Mechanism Group, butachlor, has been
excluded from the present risk assessment because at present there are
no registered uses or tolerances for this chemical in the US.  The MOE
for nasal tumor, which is the most sensitive cancer endpoint among the
CAG, is greater than 100.   Cumulative risk is not of concern.

5.0	References

 

OPP’s cumulative guidance document (USEPA 2002a),

Grouping of a Series of Chloroacetanilide Pesticides Based on a Common
Mechanism of Toxicity (USEPA 2001),

Revised Guidelines for Carcinogen Risk Assessment (USEPA, 2005b).

 PAGE   

Page   PAGE  5  of   NUMPAGES  15 

Page   PAGE  13  of   NUMPAGES  15 

