Document ID: EPA-HQ-OPP-2006-0203-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-02-07T05:00Z

Monsanto Company, member and managing agent of The Acetochlor
Registration Partnership, authorizes the EPA to publish the following
summary of the petition to comply with the Food Quality Protection Act
of 1996. An electronic copy on computer disc is provided with the cover
letter for this submission. 

ENVIRONMETNAL PROTECTION AGENCY

40 CFR Part 180

[               ]

Notice of filing Pesticide Petitions to Establish Tolerance for Certain
Pesticide Chemical in or on Food

DATE:

ACTION: Notice

SUMMARY:  This notice announces the initial filing of a pesticide
petition proposing the establishment of regulations for residues of
certain pesticide chemicals in or on food commodities.

DATES: Comments may be submitted by mail, electronically, or in person.
Please follow the detailed instructions for each method as provided in
the Unit I.C. of the “SUPPLEMENTARY INFOMRATION.” To ensure proper
receipt by EPA it is imperative that you identify docket control number
[_____________] in the subject line on the first page of your response.

FOR FURTHER INFORMATION CONTACT: The product manager listed in the table
below.

Product Manager	Office location/telephone

Number/e-mail address	

Address	Petition 

Number

James A. Tompkins 

(PM 25)	Rm 239, CM # 2, 703-305-5697	1801 South Bell Street

Arlington, VA 22202-4501

e-mail: Tompkins.james@epamail.epa.gov

Summary of Petition

	Petitioner summaries of the pesticide petition are printed below as
required by section 408(d)(3) of the FFDCA.  The summaries of the
petition were prepared by the petitioner and represent the views of the
petitioner. EPA is publishing the petition summary verbatim without
editing it in anyway. The petition summary announces the availability of
a description of the analytical method available to EPA for the
detection and measurement of the pesticide chemical residues or an
explanation of why no such method is needed. ENVIRONMENTAL PROTECTION
AGENCY

[PF-   ; FRL-      ]

Pesticide Tolerance Petition; Notice of Filing

AGENCY:	Environmental Protection Agency (EPA).

ACTION:	Notice of filing.

SUMMARY:  This notice is a summary of a pesticide petition proposing
revisions in a regulation for residues of acetochlor in or on sorghum.
This summary was prepared by the petitioner. 

1.  Monsanto Company

EPA has received a pesticide petition PPXXXX from Monsanto Company, 800
N. Lindbergh Blvd., St. Louis, MO 63167, (a member of the Acetochlor
Registration Partnership (ARP) proposing pursuant to section 408(d) of
the Federal Food, Drug and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to
amend 40 CFR Part 180.470 by revising tolerances for the residues of
acetochlor (2-chloro-2'-methyl-6'-ethyl-N-ethoxymethylacetanilide) and
its metabolites containing either the 2-ethyl-6-methylaniline (EMA) or
the 2-(1-hydroxyethyl)-6- methyl-aniline (HEMA) moiety, to be expressed
as acetochlor equivalents, in or on the following raw agricultural
commodities when present therein as a result of the application of
acetochlor to soil or growing crops: sorghum, grain at 0.05 ppm;
sorghum, forage at 1 ppm; sorghum, stover at 1.5 ppm. 

EPA has determined that the petition contains data or information
regarding the elements set forth in section 408(d)(2) of the FFDCA;
however, EPA has not fully evaluated the sufficiency of the submitted
data at this time or whether the data supports granting of the petition.
 Additional data may be needed before EPA rules on the petition.

A.	Residue Chemistry

1. Plant Metabolism. The metabolism of acetochlor has been studied in
corn, soybeans and sorghum. Acetochlor metabolizes extensively to yield
a complex array of polar metabolites. The major metabolic pathways are:
(i) uptake of soil metabolites and subsequent metabolism, (ii) uptake of
acetochlor followed by oxidative metabolism and conjugation, and (iii)
uptake of acetochlor, conjugation with glutathione and subsequent
catabolism. EPA has determined that the tolerance expression contain
parent and metabolites hydrolyzed to EMA and HEMA.  

2.  Analytical method. An adequate enforcement method for residues of
acetochlor in crops has been approved.  Acetochlor and its metabolites
are hydrolyzed to either EMA or HEMA, which are determined by HPLC-OCED
and expressed as acetochlor equivalents. 

3.  Magnitude of the residues.  Residue trials with grain sorghum show
that the proposed tolerances will not be exceeded when acetochlor is
used as directed.  The maximum tolerable application rate made to
sorghum in residue studies demonstrated that acetochlor does not
concentrate in the processed commodities.

B.	Toxicological Profile

1.  Acute toxicity.  The EPA has classified technical acetochlor as
toxicity category III for acute oral, dermal and inhalation toxicity,
and eye irritation.  Two dermal irritation studies are available. 
Severe irritation resulting in a classification of Toxicity Category II
was observed in a study conducted with an obsolete source of technical
acetochlor while only minimal irritation resulting in a Toxicity
Category IV classification was noted with a higher purity test material
that is more representative of current technical material.  Acetochlor
is known to be a skin sensitizer.

2.  Genotoxicity.  Acetochlor has been evaluated in an extensive battery
of in vitro and in vivo genotoxicity studies.  Acetochlor was not
mutagenic in the Ames Salmonella assay but exhibited a weakly positive
response in a mouse lymphoma gene mutation assay.  Acetochlor also
exhibited a weakly positive response in the first of two Chinese hamster
ovary hypoxanthine-guanine phosphoribosyltransferase (CHO/HGPRT) gene
mutation assays but was clearly negative in a subsequent CHO/HGPRT
assay.  Acetochlor was clastogenic at cytotoxic dose levels in an in
vitro cytogenetics assay in human lymphocytes.  However, no evidence of
clastogenicity or other genotoxic effect was observed in a number of in
vivo assays, including a rat bone marrow chromosomal aberration assay,
two mouse micronucleus assays and dominant lethal mutation assays in
rats and mice.  No evidence of DNA damage was noted in an in vitro
unscheduled DNA synthesis (UDS) assay in rat hepatocytes.  A weakly
positive response was noted in an in vivo rat hepatocyte UDS assay, but
only at an excessively high dose level associated with marked
hepatotoxicity and mortality.  Furthermore, no evidence of DNA damage
was observed in rat nasal olfactory cells (the primary oncogenic target
site for acetochlor) using gel electrophoresis following 1 or 18 weeks
of dietary exposure to acetochlor.

	The clastogenic effect observed with acetochlor in vitro has been shown
to be a result of the reactive chloroacetyl moiety and is most evident
under test conditions where glutathione concentrations are low.  This
effect has not been observed under in vivo conditions where higher
glutathione levels result in the protective binding of acetochlor to
glutathione instead of the SH-groups of chromatin and other critical
cellular proteins.  Thus, the overall weight of evidence indicates that
the positive responses observed with acetochlor in some in vitro studies
are not relevant in vivo and that acetochlor would not pose a
significant risk of genotoxicity to humans under anticipated conditions
of exposure. 

3.  Subchronic toxicity.  Two 90-day rat feeding studies have been
conducted, at dietary concentrations ranging from 20 to 6000 ppm.  The
primary effects observed in these studies were decreased weight gain and
food consumption.  Minor changes were noted in several clinical
pathology parameters and in liver and kidney weights but these were not
associated with any histopathological changes.  The overall No
Observable Adverse Effect Level (NOAEL) for both studies combined was
200 ppm (approximately 18 mg/kg/day).

Two subchronic dog studies were conducted in which acetochlor was
administered via capsule at dose levels ranging from 2 to 200 mg/kg/day.
 In a 119-day study, excessive toxicity, including emaciation, decreased
body weight and a high rate of mortality, was noted at 200 mg/kg/day. 
Changes in several clinical pathology parameters, increased organ
weights and histopathological lesions of the liver, kidney and bone
marrow were observed at 200 and 75 mg/kg/day.  Slightly increased serum
ALT activity in males and slightly increased relative liver weights in
females were also noted at 25 mg/kg/day, the lowest dose tested. 
However, due to lack of corroborative clinical pathology and/or
histopathological findings, these were not considered to be indicative
of a treatment-related adverse effect.  In a 90-day study, decreased
body weight gain, clinical signs of toxicity, clinical pathology changes
and increases in relative liver weight were noted at 60 mg/kg/day, the
highest dose tested (HDT).  No effects were observed at 10 mg/kg/day,
the next lowest dose level.  Thus, based on the results of both studies
combined,  25 mg/kg/day is considered to be the overall NOAEL for
subchronic toxicity of acetochlor in dogs.

	Subchronic (21-day) dermal toxicity studies have been conducted with
both rats and rabbits.  The NOAEL for systemic effects in rabbits was
400 mg/kg/day based on mortality and decreased body weight at 1,200
mg/kg/day. No signs of systemic toxicity were noted in rats at dose
levels up to 100 mg/kg/day (HDT).   

4.  Chronic toxicity and oncogenicity.  Two one-year dog studies have
been conducted with acetochlor.  In the first study, dogs were
administered acetochlor via capsule at dose levels of 0, 4, 12, and 40
mg/kg/day.  Slightly decreased food consumption, markedly decreased body
weight gain, testicular atrophy and some indications of liver toxicity
were observed at 40 mg/kg/day.  A possible indication of liver toxicity
was also noted in one animal at 12 mg/kg/day but no effects on any
parameter were noted at 4 mg/kg/day.  In a second study, dogs were
administered acetochlor via capsule at dose levels of 0, 2, 10, and 50
mg/kg/day.  Excessive toxicity (including weight loss, emaciation,
clinical signs of toxicity, alterations in a number of clinical
pathology parameters, macroscopic lesions in a number of organs, and
histopathological changes in the brain, kidneys and testes) was evident
at 50 mg/kg/day and resulted in the premature sacrifice (post week 39)
of a number of high-dose animals for humane reasons.  Histopathological
changes in the kidneys were also observed at 10 mg/kg/day.  No
treatment-related effects were noted at 2 mg/kg/day. Thus, based on both
studies, the overall NOAEL for chronic toxicity of acetochlor in dogs is
considered to be 4 mg/kg/day.

Three chronic rat feeding studies have been conducted with acetochlor,
at dietary concentrations ranging from 18 to 5000 ppm (approximately 0.8
to 297 mg/kg/day for both sexes combined).  The overall results from the
three studies indicate that the Maximum Tolerated Dose (MTD) for
acetochlor in rats is approximately 1000 ppm (54 mg/kg/day).  The
primary indications of toxicity at this level were decreased body
weights, mild liver effects (as evidenced by increased liver weights and
clinical pathology changes) and kidney lesions.  Increased incidences of
 nasal olfactory and thyroid follicular tumors were observed at dose
levels greater than or equal to 1000 ppm.  The EPA also considered a
single nasal tumor at 500 ppm in one study to be treatment related,
although a single nasal tumor was also observed in a control animal from
a subsequent acetochlor study.  An increased incidence of liver tumors
occurred only at 5000 ppm, a dose level which greatly exceeded the MTD,
and is thus not considered relevant for human risk assessment.  Based on
all 3 studies, the overall NOAEL for chronic toxicity in the rat was
considered to be 200 ppm (approximately 10 mg/kg/day).  This dose level
was also considered to be the unequivocal NOEL for oncogenicity.

A number of mechanistic studies have been conducted to determine the
mode of action for the thyroid and nasal tumors observed in the chronic
rat feeding studies with acetochlor.  These studies have demonstrated
that both tumors are produced non-genotoxic, threshold-mediated
mechanisms to which the rat is especially sensitive.  The thyroid tumors
are caused by induction of a liver enzyme, UDP-glucuronyltransferase
(UDPGT), that results in decreased levels of thyroid hormone and a
compensatory increase in thyroid stimulating hormone (TSH), which acts
upon the rat thyroid to induce hyperplasia and ultimately neoplasia. 
This is a well-known mechanism in rats that is widely believed to have
little or no relevance to humans.  The nasal tumors result from the
formation of reactive iminoquinone metabolites by the rat olfactory
tissue.  These metabolites bind to the cysteine residues in nasal
proteins and cause oxidative stress.  The resulting cytotoxicity and
regenerative cell proliferation, if sustained, eventually results in
formation of olfactory tumors.  However, large species differences at
several steps in the production of the reactive quinoneimine metabolites
indicate that this mode of action would be unlikely to occur in humans,
particularly at anticipated levels of exposure.  

 Two mouse oncogenicity studies have been conducted with acetochlor, at
dietary concentrations ranging from 10 to 5000 ppm (approximately 1.2 to
973 mg/kg/day).  Increased mortality, decreased weight gain, anemia and
signs of kidney and liver toxicity were noted at 1500 and 5000 ppm. 
Renal toxicity and anemia were also noted at 1000 ppm (approximately 126
mg/kg/day), which was considered to be the MTD.  Some minor differences
from controls were noted at 100 ppm but were not considered to be
toxicologically significant.  Thus, the ARP concluded that 100 ppm
(approximately 12 mg/kg/day) was the NOAEL for mice.  The EPA, however,
considered the slight differences at 100 ppm to be indicative of a
treatment-related adverse effect and concluded that 10 ppm
(approximately 1.1 mg/kg/day) was the NOAEL.  A treatment-related
increased incidence of liver tumors was noted in male mice at 5000 ppm. 
However, these tumors were not considered relevant for human risk
assessment since they occurred only at a dose level that greatly
exceeded the MTD.  Slightly increased incidences of lung tumors and
histiocytic sarcomas were also noted but were considered unrelated to
treatment by panels of independent expert pathologists.  Thus, based on
the results of these two studies, the ARP believes that acetochlor was
not oncogenic to mice at dose levels relevant for human risk assessment.
 The EPA, however, has concluded that the slightly increased incidences
of histiocytic sarcomas and lung tumors were related to acetochlor
administration and are relevant for human risk assessment.

5.  Reproductive and developmental toxicity.  Studies in rats and
rabbits indicate that acetochlor has only minimal potential to induce
reproductive or developmental toxicity, and that such effects occur only
in the presence of significant maternal toxicity.  No evidence of
increased sensitivity to offspring was noted in either species.

Two rat developmental toxicity studies have been conducted, at dose
levels ranging from 40 to 600 mg/kg/day.  In the first study, rats were
administered acetochlor by gavage at dose levels of 0, 50, 200, and 400
mg/kg/day.  Decreased maternal weight gain and clinical signs of
toxicity were observed at 400 mg/kg/day.  A slight decrease in mean
fetal weights was also noted at 400 mg/kg/day.  However, this was not
considered to be treatment-related because the difference was not
statistically significant and the mean value was well within the
historical control range.  EPA, however, disagreed and has concluded
that this was evidence of developmental toxicity.  In a second study,
rats were administered acetochlor at dose levels of 0, 40, 150, and 600
mg/kg/day.  Both maternal and fetal toxicity were observed at 600
mg/kg/day, as evidenced by animals sacrificed moribund, clinical
observations, decreased maternal weight gain, increased
post-implantation loss and decreased fetal weight.  No maternal or
developmental effects were noted at 150 mg/kg/day.  Thus, based on the
results from both studies combined, the ARP considers 200 mg/kg/day to
be the overall NOAEL for maternal toxicity and 400 mg/kg/day to be the
overall NOAEL for developmental toxicity.

Two rabbit developmental toxicity studies have been conducted, at dose
levels ranging from 15 to 300 mg/kg/day.  No developmental toxicity was
noted at any dose level.  The overall NOAEL for maternal toxicity was
100 mg/kg/day based on decreased weight gain at 190 mg/kg/day, and
decreased weight gain and mortality at 300 mg/kg/day. 

Three multigeneration rat reproduction studies have been completed, at
dietary concentrations ranging from 18 to 5000 ppm.  In the first study,
acetochlor was administered at dietary concentrations of 0, 500, 1500
and 5000 ppm.  Decreased numbers of live pups at birth and decreased pup
weights (particularly during the latter portion of lactation) were
observed at 5000 ppm.  However, this level also induced excessive
parental toxicity as indicated by substantially decreased body weights
(up to 33% in females) and kidney lesions.  Decreased parental body
weights and a slight decrease in pup weights were also noted at 1500
ppm.  Based on these results, 500 ppm (approximately 30 to 46 mg/kg/day)
was considered to be the NOAEL for both parental and offspring toxicity.
 In a second study, acetochlor was administered at dose levels of 0, 18,
175 and 1750 ppm.  No effect on reproductive performance was noted at
any dose level.  Decreased body weights, slightly reduced food
consumption and increased relative organ weights in parents, and
decreased pup weight gain during lactation, were noted at 1750 ppm. 
Thus, 175 ppm (approximately 13 to 18 mg/kg/day) was considered to be
the NOAEL for both parental and offspring toxicity.  In the most recent
study, acetochlor was administered to rats at dietary concentrations of
0, 200, 600 and 1750 ppm.  Effects observed in adult animals at 1750 and
600 ppm included decreased body weights; increased liver, kidney and/or
thyroid weights; and histopathological changes (including benign tumors)
of the nasal olfactory epithelium.  Decreased pup weights were noted at
both 600 and 1750 ppm.  Decreased numbers of uterine implantations and a
delay in vaginal opening in F1 pups were also noted at 1750 ppm. 
However, the delayed vaginal opening was attributed to the delay in
reaching critical body weight, and not a specific developmental effect,
since the body weight of the 1750 ppm pups at time of vaginal opening
was comparable to that of controls.  Based on these results, 600 ppm
(approximately 57 to 71 mg/kg/day) was considered to be the NOAEL for
reproductive effects while 200 ppm (approximately 19 to 22 mg/kg/day)
was the NOAEL for overall toxicity.  

	6.  Neurotoxicity.  No evidence of a direct or specific effect on the
nervous system was observed in acute and subchronic neurotoxicity
studies conducted in the rat.  In the acute study, acetochlor produced
general signs of toxicity, including mortality and transient changes in
motor activity, following a single oral dose of 1500 mg/kg.  A
statistically significant decrease in motor activity was also noted one
day after dosing in females at 500 mg/kg.  However, this was not
considered to be treatment related because the activity level of these
animals was higher than prior to dosing and there was no change in
habituation.  Therefore, 500 mg/kg/day was considered by the ARP to be
the NOAEL.  EPA, however, has concluded that the NOAEL for this study
was 150 mg/kg/day.

	In the subchronic study, acetochlor was administered to rats for 13
weeks at dietary concentrations of 0, 200, 600 and 1750 ppm.  Decreased
weight gain and food consumption were observed at 1750 ppm but no
evidence of neurotoxicity was observed at any dose level.  The NOAEL for
this study was 600 ppm (approximately 52 mg/kg/day).  

7.  Animal metabolism.  Numerous in vivo studies have been conducted to
evaluate the absorption, distribution, metabolism and/or excretion of
acetochlor in rats, mice, monkeys, goats and hens.  In addition, the
metabolism of acetochlor has also been evaluated in vitro using liver
and nasal tissues from rats, mice and monkeys, and nasal tissues in
humans.  These studies have shown that acetochlor is well absorbed
following oral administration and is extensively metabolized and rapidly
excreted.  No major sex differences were noted.  However, significant
species differences were observed, particularly with respect to the
formation and distribution of the metabolite(s) believed responsible for
the occurrence of nasal tumors in the rat.  

8.  Metabolite toxicology.  A number of studies have been conducted to
evaluate the potential effects that may be associated with the t-ethane
sulfonic (ESA) and t-oxanilic (OXA) acid metabolites of acetochlor. 
These are environmental degradates that are formed by soil microbes and
have been detected in ground and surface water. These metabolites are
highly polar and water soluble, and lack the reactive chlorine of parent
acetochlor.  The results from the toxicology studies indicate that
acetochlor ESA and OXA are more poorly absorbed, more rapidly excreted
and exhibit a lower degree of toxicity than parent acetochlor. 
Furthermore, they do not produce the preneoplastic changes responsible
for the rat nasal and thyroid tumors that occur with parent acetochlor,
and thus are unlikely to be carcinogenic.  Consequently, the EPA has
concluded that the ESA and OXA metabolites should not be included in the
acute, chronic or cancer risk assessments for acetochlor.

	9.  Endocrine disruption.  No evidence of a direct effect of acetochlor
on the endocrine system has been observed.  As previously noted,
acetochlor did produce a secondary effect on thyroid hormone homeostasis
at high dose levels in rats as a result of induction of the hepatic
enzyme UDPGT.  However, this is a relatively common finding in rats that
is generally thought to have little to no relevance to human risk
assessment, particularly at the low doses to which humans are likely to
be exposed.  Similarly, the observation of delayed vaginal opening at
the high-dose level in the most recent reproduction study is also
considered to be a secondary effect resulting from decreased body weight
gain in the pups.  Neither of these findings is considered to pose a
significant concern for human risk assessment.

C.	Aggregate Exposure

1.  Dietary exposure - Food.  Acetochlor is currently registered for use
only on field corn.  Tolerances for acetochlor and/or its metabolites
containing the EMA or HEMA moieties have been established for field corn
and the rotational crops sorghum, soybean and wheat.  Tolerances for
residues resulting from the direct application of acetochlor to sweet
corn and indirect or inadvertent residues in the rotational crops dry
beans and peas, cereal grains (except rice), potatoes, sugar beets,
sunflowers and non-grass animal feeds are pending.  Tolerances for
direct application to grain sorghum are proposed as part of this
petition.  No tolerances have been established for livestock commodities
because there is no reasonable expectation of finite residues based on
the results of exaggerated rate feeding studies.

Potential acute and chronic dietary exposures were estimated using the
Dietary Exposure Evaluation Model-Food Consumption Intake Database
(DEEM-FCID™, version 2.16, Exponent, Inc).  Food consumption was based
on data from the 1994-1996 USDA Continuing Surveys of Individual Intakes
(CSFII) and the 1998 Supplemental Children’s Survey.  Residues were
based on the results of field trials and processing studies with
acetochlor.  Maximum residues were used for assessing acute exposure
from those foods identified by the EPA as single-serving commodities. 
Average residues were used for assessing acute exposures from those
foods identified by the Agency as being blended commodities and for
assessing chronic exposure.  Where appropriate and where reliable data
were available, adjustments were made for percent crop treated.

2.  Dietary exposure - Water.  The ARP has conducted extensive
monitoring of surface and ground water for residues of acetochlor and
has included the results of these studies in the overall dietary
exposure assessment using the DEEM-FCID software.  These monitoring data
were collected in corn-growing areas during a period of high use of
acetochlor, in watersheds of much higher vulnerability than the
watersheds where acetochlor is proposed for use on sorghum.  Therefore,
these monitoring data are appropriate for characterizing potential
ground and surface water residues from the proposed use of acetochlor on
sorghum. Tap water was assumed to always be derived from a single local
source selected to represent a 99th percentile site within the
acetochlor use area.  Since only 10% of the US population uses a tap
water source within the acetochlor use area, the concentrations at such
a site are also considered to represent the upper 99.9th percentile of
acetochlor residues in tap water for the entire US population.  The 99th
percentile, one-year mean and seven-year mean concentrations taken
directly from the ARP surface water monitoring results were used for
acute, chronic and cancer risk assessments, respectively.  The surface
water monitoring results were used because they showed higher residues
than ground water.  The tap water concentrations thus computed were 4.14
ppb, 0.30 ppb, and 0.14 ppb for the acute, chronic and cancer risk
assessments, respectively.

Other dietary sources of water, e.g., bottled and commercially processed
water, were assumed to be derived from a blend of water sources
originating throughout the entire acetochlor use area.  Therefore, the
average concentration of acetochlor determined in the surface drinking
water monitoring program (0.03 ppb) was used for these blended sources. 
These estimates are considered conservative since many of these sources
of water are carbon-filtered prior to use and/or may come from regions
outside of the acetochlor use area. 

3.  Non-Dietary Exposure.  There are no residential or non-agricultural
uses of acetochlor.  Therefore, non-dietary, non-occupational exposure
to acetochlor is expected to be negligible.  In addition, 21-day dermal
toxicity studies with acetochlor indicate a very low potential for
systemic toxicity, even after repeated dermal exposures.  Thus,
potential risks from non-occupational, non-dietary exposure to
acetochlor are considered to be negligible and were not included within
the aggregate risk assessment.

D.	Cumulative Effects

	Acetochlor is a close structural analog of alachlor, another member of
the chloroacetanilide family of herbicides that also produces nasal
olfactory and thyroid follicular tumors in rats.   Mechanistic studies
indicate that these two chemicals share common modes of action for both
the nasal and thyroid tumors.  However, the EPA and FIFRA Scientific
Advisory Panel have concluded that the thyroid tumors are not an
appropriate endpoint for cumulative risk assessment for acetanilides
because increased incidences of these tumors were marginal and/or
occurred only at high dose levels, and were produced via a well-known,
non-genotoxic mechanism to which the rat is especially sensitive. 
Therefore, a cumulative risk assessment for combined residues of
alachlor and acetochlor should be based only on the potential for
formation of nasal olfactory tumors. 

E.	Safety Determination

	

	1. Endpoint Selection.    Potential acute and chronic risks from
exposure to acetochlor were determined using the toxicology endpoints
utilized by EPA in the March 2006 Tolerance Reassessment Eligibility
Decision (TRED) document.  Acute risks for all population subgroups were
assessed using an acute RfD of 0.15 mg/kg.  This was based on a NOAEL of
150 mg/kg from the acute rat neurotoxicity study and a 1000-fold
uncertainty factor.  Although no evidence of increased sensitivity to
offspring was noted in rats or rabbits following in utero and/or
postnatal exposure, the EPA applied an additional 10X database
uncertainty factor due to the lack of a developmental neurotoxicity
(DNT) study.  Chronic (non-cancer) risks were assessed using a chronic
RfD of 0.02 mg/kg/day which was derived from a NOAEL of 2.0 mg/kg/day
from the second one-year dog study and a 100-fold uncertainty factor. 
No additional database or FQPA uncertainty factor was utilized for the
chronic risk assessment since the Agency concluded that the NOAEL from a
DNT study would be greater than the NOAEL from the one-year dog study
and would thus not impact the risk assessment.  

	The EPA has classified acetochlor as “likely to be carcinogenic to
humans” based on increased incidences of nasal and thyroid tumors in
rats, and histiocytic sarcomas and lung tumors in mice.  The Agency has
concluded that the rat nasal and thyroid tumors were produced by
non-genotoxic, threshold-mediated modes of action and that the potential
risks for these tumors should be assessed using a non-linear,
margin-of-exposure (MOE) approach.  However, no mode of action data were
available for the mouse histiocytic sarcomas and lung tumors. 
Therefore, the Agency recommended that potential carcinogenic risks for
acetochlor should be be quantified using linear low-dose extrapolation
with a cancer slope factor (Q*) of 0.0327 (mg/kg/day)-1 based on the
incidence of lung tumors in male mice.  Contrary to the EPA conclusion,
the mouse lung tumors and histiocytic sarcomas were not considered to be
treatment related by an independent Pathology Working Group, the
Agency’s own consulting pathologist or the scientific experts of the
European Chemical Bureau.  Therefore, the ARP has commented to the EPA
that these tumors should not be considered in the carcinogenic
weight-of-evidence evaluation, let alone serve as the basis for
low-dose, linear extrapolation.  The Agency has not yet responded to the
ARP comments.  Therefore, for the purposes of this document, the
potential oncogenic risks from long-term exposures to acetochlor have
been evaluated using both a linear (Q*) and non-linear (MOE) approach. 
The cancer slope factor of 0.0327 (mg/kg/day)-1 recommended by EPA was
used for linear extrapolation while the unequivocal oncogenic NOEL of 10
mg/kg/day for nasal tumors in the two-year rat feeding studies was
utilized as the point of departure for the non-linear approach.     

	A cumulative risk assessment was also conducted to assess the potential
risks for nasal tumors from combined exposures to alachlor and
acetochlor.  A non-linear (MOE) approach based on the respective
carcinogenic NOELs was utilized for this assessment since these tumors
are produced by a non-genotoxic, threshold-mediated mode of action. 
Acetochlor was assumed to have 1/20th the relative potency of alachlor
based on unequivocal oncogenic NOELs of 10 and 0.5 mg/kg/day,
respectively.   

 

2.  Acute Exposure and Risk.  Based on the above assumptions, the
current and proposed uses of acetochlor would result in estimated 99.9th
percentile acute dietary (food and water) exposures of 7.26 x 10-4
mg/kg/day for the overall US population and 1.64 x 10-3 mg/kg/day for
non-nursing infants, the most highly exposed population subgroup.  
These exposures represent approximately 0.5% and 1.1% of the aRfD,
respectively.  In general, exposures utilizing less than 100% of the RfD
are not of concern.  Therefore, there is a reasonable certainty that
acute dietary exposure to acetochlor will not pose a significant risk to
human health, including infants and children.

3.  Chronic Exposure and Risk.  Based on the above assumptions, chronic
dietary (food and water) exposure of the overall US population to
acetochlor is estimated to be 1.9 x 10-5 mg/kg/day.  This represents
approximately 0.1% of the cRfD.  Chronic dietary exposure to non-nursing
infants, the most highly exposed population subgroup, is estimated to be
3.9 x 10-5 mg/kg/day, which represents about 0.2% of the cRfD.  Both of
these values are well below 100% of the cRfD.  Therefore, there is a
reasonable certainty that dietary (food and water) exposure to
acetochlor will not pose a significant risk of chronic toxicity to the
US population, including infants and children.

4.  Cancer Risk.  (i) Acetochlor: Based on the above assumptions, the
average daily lifetime exposure to residues of acetochlor in food and
water was estimated to be 1.6 x 10-5 mg/kg/day.  This results in an MOE
of about 625,000 relative to the unequivocal oncogenic NOEL of 10
mg/kg/day.  Using linear extrapolation with a cancer slope factor of
0.0327 (mg/kg/day)-1, the 95% upper confidence limit of the lifetime
cancer risk associated with this level of exposure was estimated to be
5.2 x 10-7.  Cancer risks of less than 1 x 10-6 are generally considered
to be negligible.  Thus, regardless of the risk assessment methodology
utilized, there is a reasonable certainty that lifetime aggregate
exposure to acetochlor will not pose a significant risk of cancer.  

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  Based on the data summarized herein, there is a reasonable certainty
that no harm will result to the US population, including infants and
children, from the current and proposed uses of acetochlor.  

F.	International Tolerance

There are no Codex Maximum Residue Levels established for residues of
acetochlor on agricultural commodities.