acetochlor (Harness) Pesticide Petition Filing 1/00
[Federal Register: January 24, 2000 (Volume 65, Number 15)]
>From the Federal Register Online via GPO Access [wais.access.gpo.gov]
ENVIRONMENTAL PROTECTION AGENCY
Notice of Filing Pesticide Petitions to Establish a Tolerance for
Certain Pesticide Chemicals in or on Food
AGENCY: Environmental Protection Agency (EPA).
SUMMARY: This notice announces the initial filing of pesticide
petitions proposing the establishment of regulations for residues of
certain pesticide chemicals in or on various food commodities.
DATES: Comments, identified by docket control number PF-909, must be
received on or before February 23, 2000.
ADDRESSES: Comments may be submitted by mail, electronically, or in
person. Please follow the detailed instructions for each method as
provided in Unit I.C. of the ``SUPPLEMENTARY INFORMATION.'' To ensure
proper receipt by EPA, it is imperative that you identify docket
control number PF-909 in the subject line on the first page of your
FOR FURTHER INFORMATION CONTACT: The product manager listed in the
Product Manager number/e-mail address Address Petition number(s)
Shaja R. Brothers.................. Rm. 284, CM 2, 703-308- 1921 Jefferson Davis PP 9E6025
3194, e-mail: Hwy, Arlington, VA
James A. Tompkins (PM 25).......... Rm. 239, CM 2, 703-305- Do. PP 5F4505; PP 6F4791
I. General Information
A. Does this Action Apply to Me?
You may be affected by this action if you are an agricultural
producer, food manufacturer or pesticide manufacturer. Potentially
affected categories and entities may include, but are not limited to:
Categories NAICS codes potentially
Industry 111 Crop production
112 Animal production
311 Food manufacturing
This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in the table could also be
affected. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether or not this action might apply to certain entities. If you have
questions regarding the applicability of this action to a particular
entity, consult the person listed under ``FOR FURTHER INFORMATION
B. How Can I Get Additional Information, Including Copies of this
Document and Other Related Documents?
1. Electronically. You may obtain electronic copies of this
document, and certain other related documents that might be available
electronically, from the EPA Internet Home Page at http://www.epa.gov/.
To access this document, on the Home Page select ``Laws and
Regulations'' and then look up the entry for this document under the
``Federal Register--Environmental Documents.'' You can also go directly
to the Federal Register listings at http://www.epa.gov/fedrgstr/.
2. In person. The Agency has established an official record for
this action under docket control number PF-909. The official record
consists of the documents specifically referenced in this action, any
public comments received during an applicable comment period, and other
information related to this action, including any information claimed
as confidential business information (CBI). This official record
includes the documents that are physically located in the docket, as
well as the documents that are referenced in those documents. The
public version of the official record does not include any information
claimed as CBI. The public version of the official record, which
includes printed, paper versions of any electronic comments submitted
during an applicable comment period, is available for inspection in the
Public Information and Records Integrity Branch (PIRIB), Rm. 119,
Crystal Mall 2, 1921 Jefferson Davis Highway, Arlington, VA, from 8:30
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The
PIRIB telephone number is (703) 305-5805.
C. How and to Whom Do I Submit Comments?
You may submit comments through the mail, in person, or
electronically. To ensure proper receipt by EPA, it is imperative that
you identify docket control number PF-909 in the subject line on the
first page of your response.
1. By mail. Submit your comments to: Public Information and Records
Integrity Branch (PIRIB), Information Resources and Services Division
(7502C), Office of Pesticide Programs (OPP), Environmental Protection
Agency, Ariel Rios Bldg., 1200 Pennsylvania Ave., NW., Washington, DC
2. In person or by courier. Deliver your comments to: Public
Information and Records Integrity Branch (PIRIB), Information Resources
and Services Division (7502C), Office of Pesticide Programs (OPP),
Environmental Protection Agency, Rm. 119, Crystal Mall 2, 1921
Jefferson Davis Highway, Arlington, VA. The PIRIB is open from 8:30
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The
PIRIB telephone number is (703) 305-5805.
3. Electronically. You may submit your comments electronically by
e-mail to: ``email@example.com ,'' or you can submit a computer disk
as described above. Do not submit any information electronically that
you consider to be CBI. Avoid the use of special characters and any
form of encryption. Electronic submissions will be accepted in
Wordperfect 6.1/8.0 or ASCII file format. All comments in electronic
form must be identified by docket control number PF-909. Electronic
comments may also be filed online at many Federal Depository Libraries.
D. How Should I Handle CBI That I Want to Submit to the Agency?
Do not submit any information electronically that you consider to
be CBI. You may claim information that you submit to EPA in response to
this document as CBI by marking any part or all of that information as
CBI. Information so marked will not be disclosed except in accordance
with procedures set forth in 40 CFR part 2. In addition to one complete
version of the comment that includes any information claimed as CBI, a
copy of the comment that does not contain the information claimed as
CBI must be submitted for inclusion in the public version of the
official record. Information not marked confidential will be included
in the public version of the official record without prior notice. If
you have any questions about CBI or the procedures for claiming CBI,
please consult the person identified under ``FOR FURTHER INFORMATION
E. What Should I Consider as I Prepare My Comments for EPA?
You may find the following suggestions helpful for preparing your
1. Explain your views as clearly as possible
2. Describe any assumptions that you used.
3. Provide copies of any technical information and/or data you used
that support your views.
4. If you estimate potential burden or costs, explain how you
arrived at the estimate that you provide.
5. Provide specific examples to illustrate your concerns.
6. Make sure to submit your comments by the deadline in this
7. To ensure proper receipt by EPA, be sure to identify the docket
control number assigned to this action in the subject line on the first
page of your response. You may also provide the name, date, and Federal
II. What Action is the Agency Taking?
EPA has received pesticide petitions as follows proposing the
establishment and/or amendment of regulations for residues of certain
pesticide chemicals in or on various food commodities under section 408
of the Federal Food, Drug, and Comestic Act (FFDCA), 21 U.S.C. 346a.
EPA has determined that these petitions contain data or information
regarding the elements set forth in section 408(d)(2); 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.
List of Subjects
Environmental protection, Agricultural commodities, Feed additives,
Food additives, Pesticides and pests, Reporting and recordkeeping
Dated: January 7, 2000,
Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
Petitioner summaries of the pesticide petitions are printed below
as required by section 408(d)(3) of the FFDCA. The summaries of the
petitions were prepared by the petitioners and represent the views of
the petitioners. EPA is publishing the petition summaries verbatim
without editing them in any way. The petition summary announces the
availability of a description of the analytical methods available to
EPA for the detection and measurement of the pesticide chemical
residues or an explanation of why no such method is needed.
I. Acetochlor Registration Partnership
PP 5F4505 and 6F4791
EPA has received pesticide petitions (PP 5F4505 and 6F4791) from
Acetochlor Registration Partnership, c/o Zeneca Ag Products, 1800
Concord Pike, Wilmington DE 19850 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 by establishing a tolerance for residues of
acetochlor (2-chloro-2'-methyl-6'-ethyl-N-ethoxymethylacetanilide and
it metabolites containing the ethyl methyl aniline (EMA) and the
hydroxy methyl aniline (HEMA) moiety, to be expressed as acetochlor,
EMA and HEMA and expressed as acetochlor equivalents in or on the raw
agricultural commodity field, corn, forage at 3.0 part per million
(ppm) (5F4505); corn, sweet, grain (K+CHWHR) at 0.05 ppm; corn, sweet,
fodder at 1.0 ppm; and corn, sweet, forage at 1.4 ppm. (6F4791). PP
5F4505 also proposes to divide 40 CFR 180.470 into two sections: (a)
Specific tolerances (containing the tolerances for field corn and sweet
corn) and (b) Indirect or inadvertent tolerances (containing the
tolerances for the rotational crops sorghum, soybean, wheat, and
nonanimal grass feeds). PP 6F4791 also proposes that tolerances be
established for the indirect or inadvertent residues of acetochlor in
or on the the raw agricultural commodities when present therein as a
result of the application of acetochlor to growing crops and other
nonfood crops as follows: nongrass animal feeds, forage at 0.6 ppm and
nongrass animal feeds, hay at 1.0 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 and soybeans. 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.
Acetochlor is completely metabolized in plants to produce a number of
polar metabolites. EPA has determined that the residues of concern are
those which contain the 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 to HEMA which are
determined by GC-MSD and expressed as acetochlor.
3. Magnitude of residues. Field residue trials in field corn with
acetochlor were conducted in 32 plots in 8 states. The maximum combined
residues (acetochlor and metabolites) were 2.52 ppm in corn forage,
0.217 ppm in corn fodder and 0.04 ppm in corn grain.
Fourteen field residue trials in sweet corn with acetochlor were
conducted in 12 states. The maximum combined residues (acetochlor and
metabolites) were 1.35 ppm in corn forage, 0.97 ppm in corn fodder and
0.05 ppm in grain.
Seventeen rotational crop residue trials were conducted in 17
states representing the top corn, alfalfa and clover producing regions
in the U.S. The maximum combined residue (acetochlor and metabolites)
in alfalfa forage was 0.540 ppm and the maximum alfalfa hay residue was
1.870 ppm. The maximum clover forage residue was 0.567 ppm, the maximum
clover residue was 1.244 ppm.
B. Toxicological Profile
1. Acute toxicity. Acute toxicology data place technical acetochlor
in toxicity category III for eye irritation, toxicity category III for
acute oral, acute dermal, and acute inhalation. Technical acetochlor is
in category IV for primary skin irritation and it is a skin sensitizer.
2. Genotoxicty. In mutagenicity testing, submitted by Monsanto,
acetochlor was weakly positive in the Chinese hamster ovary/
hypoxanthine-guanine phosphoribosyltransferase (CHO/HGPRT) gene
mutation assay with and without activation in the mouse lymphoma assay.
Acetochlor was negative in a DNA damage repair assay in rat
hepatocytes, a Salmonella assay, and two (2) in vivo chromosomal
In mutagenicity tests conducted by ZENECA, acetochlor induced a
reproducible, positive, mutagenic response in strain TA 1538 of
Salmonella typhimurium with metabolic activation at 100 milligrams /
plate (mg/p) (however, this was less than the 2X background mutation,
but was significant at p less than 0.05). Significant increases in
number of revertant colonies were not induced in strains TA 1535, TA
1537, TA98, and TA100. The effect in strain TA1538 although
reproducible in the first study was not observed in a more extensive
follow up study. Acetochlor was not
clastogenic in a mouse micronucleus test at doses tested (898 and 1,436
milligrams/kilograms (mg/kg) in males; 1,075 and 1,719 mg/kg in
females). Acetochlor was clastogenic in cultured human lymphocytes both
in the presence and absence of S9 mix at 100 mg/milliliters (ml), and
in the absence of S9 mix at 50 mg/ml. It has subsequently been shown
that the chloroacetyl substituent on acetochlor is the clastogenic
moeity, however two structurally related chemicals containing this
moiety have been shown to be non-carcinogens as defined by the US NTP.
Acetochlor induced a weak DNA repair (measured by UDS) in rat
hepatocytes derived from animals exposed in vivo at 2,000 mg/kg. At
this dose there is significant hepatotoxicity (depletion of
glutathione, severe liver necrosis and substantial release of hepatic
enzymes). Acetochlor was negative in the unscheduled DNA synthesis
(UDS) assay at a maximum tolerated dose (MTD) of 1,000 mg/kg. In a
structural chromosome aberration study, acetochlor at doses 1,000 and
2,000 mg/kg resulted in reduced pregnancy incidence, decreased implants
per pregnancy incidence, increased preimplantion loss, and decreased
time implant per pregnancy at weeks 2, 3 and 4 of this study. Early and
late intrauterine deaths were not affected in this study. The Agency
concluded there was positive evidence of mutagenicity at the mid- and
high-dose levels in this study. The Acetochlor Registration Partnership
has submitted new data which show that there were no mutagenic effects
in this study. Acetochlor was negative in a DNA damage (comet) assay
conducted using nasal tissue derived from rats treated with a supra-MTD
of 1,750 ppm of acetochlor in the diet for either 7 days or 18 weeks.
3. Reproductive and developmental toxicity. In a developmental
study submitted by Monsanto, with rats fed dosages of 0, 50, 200, and
400 mg/kg/day, acetochlor did not induce developmental toxicity in rats
up to 400 mg/kg/day, the highest dose tested (HDT). The maternal no
observed adverse effect level (NOAEL) was 200 mg/kg/day based on
matting and/or staining of the anogenital region, a decrease in mean
maternal weight gain during the treatment period, and in adjusted mean
weight gain on gestation day 20 at 400 mg/kg/day (HDT).
In a developmental study submitted by ZENECA , with rats fed
dosages of 0, 40, 150, and 600 mg/kg/day, the developmental NOAEL was
150 mg/kg/day based on increased resorptions, post-implantation loss,
and decrease in mean fetal weight at 600 mg/kg/day (HDT). The maternal
toxicity NOAEL for this study was 150 mg/kg/day based on animals
sacrificed moribund, clinical observations, and decreased body weight
gain at 600 mg/kg/day (HDT).
In a developmental study submitted by Monsanto, with rabbits fed
dosages of 0, 15, 50, and 190 mg/kg/day, acetochlor did not induce
developmental toxicity in rabbits up to 190 mg/kg/day (HDT). The
maternal toxicity NOAEL was 50 mg/kg/day based on loss of body weight
during dosing at 190 mg/kg/day (HDT).
In a developmental study submitted by ZENECA, with rabbits fed
dosages of 0, 30, 100, and 300 mg/kg/day, acetochlor did not induce
either maternal or developmental toxicity up to 300 mg/kg/day (HDT).
In a 2-generation reproduction study submitted by Monsanto, with
rats fed dosages of 0, 30.4, 74.1, and 324.5 mg/kg/day (males) or 0,
44.9, 130.1, and 441.5 mg/kg/day (females), the reproductive NOAEL was
30.4 mg/kg/day for males and 44.9 mg/kg/day for females, based on
decreased body weight gain of F2b pups at 74.1 mg/kg/day for males and
130.1 mg/kg/day for females. A NOAEL for systemic effects was not
In a 2-generation reproduction study submitted by ZENECA, with rats
fed dosages of 0, 1.6, 21, and 160 mg/kg/day, the reproductive NOAEL
was 21 mg/kg/day based on significant reductions in pup weight at
lactational day 21 and total body weight gain during lactation at 160
mg/kg/day (HDT). The parental NOAEL was 21 mg/kg/day based on
reductions in body weight, accompanied by slight reductions in food
consumption and significant increases in relative organ weights at 160
Conclusion. Acetochlor is not considered to be a material that
causes developmental or reproductive toxicity. The lowest NOAEL for
fetotoxicity was 21 mg/kg/day in a 2-generation reproduction study and
the lowest NOAEL for fetotoxicity in a developmental study was 150 mg/
4. Subchronic toxicity. A 3-month feeding study submitted by
Monsanto with rats fed dosages of 0, 40, 100, and 300 mg/kg/day
resulted in a NOAEL of 40 mg/kg/day based on loss of body weight and
decreased food consumption at 100 mg/kg/day.
A 3-week dermal study submitted by Monsanto with rabbits fed
dosages of 0, 100, 400, and 1,200 mg/kg/day resulted in a NOAEL for
systemic effects of 400 mg/kg/day based on mortality and decreased body
weight at 1,200 mg/kg/day, (HDT). The lowest effect level (LEL) for
dermal irritation was 100 mg/kg lowest dose tested (LDT). A NOAEL for
dermal irritation was not established.
A 3-week dermal study submitted by ZENECA with rats fed dosages of
0.1, 1.0, 10, or 100 mg/kg/day resulted in minimal to mild skin
irritation after 21 days. Signs of systemic toxicity were not apparent
at any level. Higher doses were not possible because of severe dermal
toxicity at higher doses.
5. Chronic toxicity. In a 1-year feeding study submitted by
Monsanto, with dogs fed dosages of 0, 4, 12, and 40 mg/kg/day, the
NOAEL was 12 mg/kg/day based on decreased body weight gains in males,
decreased terminal body weight in females, testicular atrophy with
accompanying decreases in absolute and relative testicular weight,
increase in relative liver weights in male and females, and clinical
chemistry changes at 40 mg/kg/day (HDT).
In a 1-year feeding study submitted by ZENECA, with dogs fed
dosages of 0, 2, 10, and 50 mg/kg/day, the NOAEL was 2 mg/kg/day based
on increased salivation, ornithine carbamyl transferase, and
triglyceride values accompanied by decreased blood glucose levels and
liver glycogen levels at 10 mg/kg/day. Interstitial nephritis, tubular
degeneration of the testes and hypospermia were reported.
In a chronic feeding/carcinogenicity study submitted by Monsanto,
in which rats were fed dose levels of 0, 22, 69, and 250 mg/kg/day, a
NOAEL for chronic effects was not established.
In a repeat chronic feeding/carcinogenicity study submitted by
Monsanto, in which rats were fed dose levels of 0, 2, 10, and 50 mg/kg/
day, the NOAEL for chronic effects was 10 mg/kg/day.
In a chronic feeding/carcinogenicity study submitted by ZENECA, in
which rats were fed dose levels of 0, 0.8, 7.9, and 79.6 mg/kg/day, the
NOAEL for chronic effects was 7.9 mg/kg/day.
Conclusion. The lowest NOAEL for chronic effects in dogs was 2 mg/
kg/day and the lowest NOAEL for chronic effects in rats was 7.9 mg/kg/
day. EPA has established the Reference Dose (RfD) for acetochlor at
0.02 mg/kg/day based on the 2.0 mg/kg/day NOAEL in the ZENECA dog study
and the application of a 100-fold safety factor.
In a chronic feeding/carcinogenicity study submitted by Monsanto
with mice fed dosages of 0, 75, 225, and 750 mg/kg/day (high dose
determined to be 973 mg/kg/day by the ARP) carcinogenic effects noted
included increased incidence of liver carcinomas in high-
dose males, total lung tumors in females at all dose levels, carcinomas
of lungs in females fed 75 and 750 (973) mg/kg/day, uterine histiocytic
sarcomas in females at all dose levels, and total benign ovarian tumors
in mid-dose females. Other dose-related changes included: (1) Increased
mortality and decreased mean body weights in both high-dose males and
females, (2) decreased red blood cell count, hematocrit, and hemoglobin
in high-dose females at terminal sacrifice, (3) increased white blood
count in high-dose males at terminal sacrifice, (4) increased platelet
count in mid-and high-dose females at terminal sacrifice, (5) increased
mean liver weight and liver-to-body-weight ratios at study termination
in all dose groups of males and in high-dose females; increased
absolute and relative kidney weights in all dose groups of males at
termination; increased absolute and relative adrenal weights in all
groups of males and in high-dose females at study termination; and (6)
increased interstitial nephritis in high-dose males and females.
In a chronic feeding/carcinogenicity study submitted by ZENECA with
mice fed dosages 0, 1.1, 11, and 116 mg/kg/day in males and 0, 1.4, 13,
and 135 mg/kg/day in females, carcinogenic effects noted included an
increase in pulmonary adenoma in both male and females at the high
dose. Pulmonary tumors were confirmed as adenomas or carcinomas of the
lung parenchyma and were all of the alveolar type. The NOAEL for
systemic toxicity in females was 13 mg/kg/day based on a significant
increase in anterior polar vacuoles in the lens of the eye at 135 mg/
In a chronic feeding/carcinogenicity study submitted by Monsanto,
with rats fed dosages of 0, 22, 69, and 250 mg/kg/day (males) or 0, 30,
93, and 343 mg/kg/day (females), carcinogenic effects noted at 250
(highest dose determined to be 297 mg/kg/day) mg/kg/day in males and
343 mg/kg/day in females included hepatocellular carcinoma in both
sexes and thyroid follicular cell adenoma in males. Nasal papillary
adenomas were noted in male rats at 69 mg/kg/day and above and in
females at 93 mg/kg/day. A NOAEL for chronic effects was not
In a repeat chronic feeding/carcinogenicity study submitted by
Monsanto, in rats fed dosages of 0, 2, 10, and 50 mg/kg/day oncogenic
effects noted at 50 mg/kg/day (HDT) included neoplastic nodules of the
liver, follicular adenoma/cystadenoma of the thyroids and papillary
edema of the mucosa of the nose/turbinates in high dose animals. The
NOAEL for chronic effects was 10 mg/kg/day based on decreased body
weights and body weight gain in both sexes, high cholesterol levels in
males, increased absolute and relative kidney and liver weight in
males, and increased testicular weights at 50 mg/kg/day (HDT).
In a 2-year chronic feeding/carcinogenicity study submitted by
ZENECA, with rats fed dosages of 0, 0.8, 7.9, and 79.6 mg/kg/day,
carcinogenic effects noted at 79.6 mg/kg/day (HDT) included a
significant increase in nasal epithelial adenomas and thyroid
follicular cell adenomas in both sexes at 79.6 mg/kg/day. Also, at that
dose nasal carcinoma was present in two males and one female rat at
this dose. Rare tumors in the form of benign chondroma of the femur and
basal cell tumor of the stomach were also observed at 79.6 mg/kg/day.
The systemic NOEL was 7.9 mg/kg/day based on decreased body weight
gain, decreased food efficiency, increased organ to body weight ratios,
increased plasma GGT and cholesterol at 79.6 mg/kg/day (HDT).
Conclusions. Three oncogenicity studies have been conducted with
acetochlor in rats and two have been conducted in mice. In rats,
increased incidences of tumors in nasal, thyroid and liver tissues were
found only at dose levels equal to or exceeding the MTD. Liver tumors
were found in only one rat study and at the highest dose tested (297mg/
kg/day), a dose which greatly exceeded the MTD. The nasal tumors, found
only at and above the MTD, are the only biologically relevant and
reproducible oncogenic effect in rats.
In mice, increased incidences of tumors in liver, lung, and uterine
tissues were observed. The liver tumors were observed only in one
study, at the HDT (973mg/kg/day) a dose which greatly exceeded the MTD
as evidenced by increased mortality of approximately 90%. The lung
tumors and uterine histiocytic sarcomas were observed in all treated
female groups in one study, but there was no dose-response relationship
which makes the relationship to treatment and relevance equivocal. Lung
tumors occurred only in high dose animals in the second mouse study and
their incidence rate was within the historical control range for the
laboratory. The rat and mouse liver tumors and the mouse lung and
histiocytic sarcomas have been subjected to an independent pathology
Overall, the only clear oncogenic responses in rats or mice are
found only at high dose levels at or above the MTD. This suggests that
such tumors are not produced by genotoxic mechanisms, but by other
threshold-dependent mechanisms. The weight of the evidence of all the
genotoxicity studies conducted with acetochlor also supports the
conclusion that tumor formation is not driven by genotoxic mechanisms.
An overview of the genotoxicity studies with acetochlor has been
reported by Ashby, et al. in Human and Experimental Toxicology, 15,
702, 1996 (EPA MRID NO. 44069503).
Mechanistic studies with alachlor, a structural analog of
acetochlor which produces the same nasal and thyroid tumors in the rat,
provide additional evidence that rodent tumors incident to acetanilide
dosing are produced by indirect threshold mechanisms that are unique to
the rat and not relevant to humans under realistic exposure levels. The
Acetochlor Registration Partnership (ARP) has conducted and submitted a
number of studies on the mechanism of tumor formation with acetochlor.
The ARP believes these studies establish the basis for the use of a
Margin of Exposure (MOE) for the cancer risk assessment for acetochlor.
6. Animal metabolism. The metabolism of acetochlor has been studied
in goats, laying hens and rats. EPA has concluded that the nature of
the residue in ruminants and poultry are adequately understood and the
residue of concern is the same as that in corn.
7. Metabolite toxicology. EPA has determined that the residues of
concern are those which contain the EMA and HEMA.
8. Endocrine disruption. Acetochlor is not a member of a class of
chemicals associated with direct adverse effects on the endocrine
system. The subchronic, chronic, developmental and reproductive studies
with acetochlor satisfy the present data requirements, and they have
measured many toxic endpoints which are sensitive to endocrine-
modulation activity. Acetochlor has not produced effects in these
toxicity studies that can be related to direct interference with female
or male endocrine systems.
C. Aggregate Exposure
1. Dietary exposure. The nature of the residue in plants and
animals is understood. Acetochlor metabolizes extensively to yield a
number of polar metabolites. Tolerances have been established at 40 CFR
180.470 for raw agricultural commodities of field corn and indirect or
inadvertent residues in or on sorghum, soybean and wheat. The
tolerances are combined acetochlor, and metabolites that contain the
EMA and HEMA moieties expressed as acetochlor. 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.
i. Food --a. Acute. An acute dietary analysis was performed based
on the EPA selected acute NOAEL of 150 mg/kg/day for developmental
toxicity. The results of this analysis produced MOEs of greater than
70,000 for all 23 subgroups of the U.S. population. The most highly
exposed subgroup, non-nursing infants, has a MOE of 77,000. EPA
generally considers MOEs of greater than 100 to provide adequate acute
dietary safety. Therefore, this evaluation demonstrates that acetochlor
does not represent an acute dietary concern.
b. Chronic. The theoretical maximum residue contribution (TMRC) for
the general U.S. population from all established uses combined with the
proposed tolerance on corn forage is 1.11 x 10-4 mg/kg/day.
For non-nursing infants less than 1 year old, the most highly exposed
subgroup, the TMRC is 3.24 x 10-4 mg/kg/day. The TMRC is
calculated assuming that all of the corn crop is treated with
acetochlor, that all crop commodities bear tolerance-level residues,
and that all rotation crops are grown in soil treated with acetochlor
and thus all rotation crop commodities have tolerance level residues. A
refined dietary exposure estimate, based on 30% of corn acres treated,
actual maximum residues found in crop commodities, and reduction of
residues in some processed commodities was calculated for the same
population groups. The refined and more accurate exposure estimate,
called the Anticipated Residue Contribution (ARC), is 1.0 x
10-5 for the U.S. general population and 2.7 x
10-5 for non-nursing infants. The TMRC represents only 0.55%
of the RfD for the general population. The ARC represents only 0.05% of
ii. Drinking water. Acetochlor is not registered for direct
application to bodies of water. Seasonal run-off from treated fields
can be transported to surface water. Since March 1995, the ARP has been
monitoring drinking water from 175 community water systems (CWSs) which
take their water supplies from surface water sources. The 175 CWSs take
water from watersheds of all sizes in major acetochlor use areas but
primarily from small watersheds located in areas of high-intensity corn
production. Water samples taken every 2 weeks from mid March through
early September from each CWS are analyzed for acetochlor. The results
to date show that acetochlor was non-detected in about 80% of all
individual samples of drinking water, with peak concentrations
occurring mainly in May and June, the peak use season for acetochlor.
Only about 10% of the participating CWSs had time-weighted annualized
mean concentrations (AMC) above 0.1 parts per billion (ppb). There were
no CWSs that had AMCs exceeding 2 ppb, the annual AMC limit set for
acetochlor in the EPA-ARP registration agreement.
Although acetochlor is not expected to leach through most
agricultural soils, there is a potential for limited ground water
contamination in areas of highly permeable soils. To address this
possibility, acetochlor products are labeled to prohibit use in fields
where the depth to ground water is less than 30 feet and where the
soils are ``sands'' with less than 3% organic matter; ``loamy sands''
with less than 2% organic matter; or ``sandy loams'' with less than 1%
organic matter. However, shallow ground water contamination can also
result from misuse, improper well construction and the movement of
surface water into direct conduits to ground water. The ARP has been
conducting a ground water monitoring (GWM) program consisting of 175
wells immediately adjacent to acetochlor treated fields since 1995. The
wells are located in a variety of soil types to cover the range from
light permeable soils to heavy less vulnerable soils, reflecting the
soils on which corn is grown in the seven major corn-producing states.
The ARP GWM wells are agricultural monitoring wells and do not
adequately represent the drinking water wells across the entire
country. Therefore, sporadic detections at very low levels cannot be
extrapolated to provide accurate estimates of acetochlor in drinking
water derived from ground water. A series of eight Prospective Ground
Water (PGW) studies are being conducted by the ARP to monitor the
movement of acetochlor to ground water under intensively instrumented
fields, across a range of soil textures. Two studies initiated during
1995 are nearing completion and neither show any indication of
acetochlor movement. Four studies commenced during 1996 and continue to
show no acetochlor ground water contamination. Traces of acetochlor
were detected at one of these sites at one sampling interval, soon
after application. The residues were extremely low (0.06 ppb) and had
dissipated by the next sampling interval.
The conditions of the registration of acetochlor include
cancellation triggers based on detection scenarios in the Surface Water
Monitoring Program, the Ground Water Monitoring Program and the
Prospective Ground Water Program that will preclude any significant,
widespread contamination of drinking water.
For the purpose of chronic risk assessment, a level of 0.1 ppb
seems to represent a reasonable, upper-bound level for acetochlor in
drinking water. Based on 0.1 ppb in the water and an assumed water
consumption of 2 liters per day for an adult weighing 70 kg, the upper
bound exposures would be 2.9 x 10-6 mg/kg/day.
For the purpose of assessing short term risk, a level of 2 ppb, the
probable MCL, represents a reasonably conservative, upper bound level
for acetochlor in drinking water. Based on 2 ppb in the water and an
assumed water consumption of 2 liters per day for an adult weighing 70
kg and 1 liter per day for a child weighing 10 kg, the short-term
exposure for the adult would be 5.7 x 10-5 mg/kg/day and for
the child, 2.0 x 10-4 mg/kg/day.
2. Non-dietary exposure. Acetochlor is not registered for any use
which would result in non-occupational, non-dietary exposure for the
general population. Acetochlor is registered for use on corn, a
commercial crop which is grown in fields remote from public-use areas.
Acetochlor products are Restricted Use, for use only by Certified
Applicators which means the general public cannot buy or use
D. Cumulative Effects
Toxicological testing of the chloroacetamide herbicide family in
animals with high doses has produced a number of observed effects.
Certain effects in some tissues are observed in two, three, or four
members of the family, but there is no single effect that represents
conclusive evidence of a common mechanism of toxicity existing
throughout the chloroacetamide family.
EPA has not established procedures for determining when pesticides
share a common toxic mechanism, or provided a definition of
``concurrent exposure.'' At this time there is no established procedure
for risk assessment of pesticides which may have a common mechanism by
may differ in potency and exposure. Following an EPA proposal to the
FIFRA Scientific Advisory Panel meeting on March 20, 1997 (Docket No.
OPP-00466) that nasal tumors in alachlor, acetochlor, butachlor, and
perhaps metolachlor may be formed by a common toxic mechanism, Monsanto
Company has derived an equation to calculate a MOE for the combined,
concurrent exposure to multiple chloroacetamide herbicides that may
share a common mechanism for nasal tumors. The mechanism is thought to
be metabolic production of
an electrophilic 3,5-dialkyl-benzoquinone-4-imine (DABQI) or similar
compounds at sufficient levels to cause cytotoxicity, proliferation of
nasal cells and neoplasms in nasal tissues. The equation, as presented
in ``Summary Information and Assessment as Required for the
Reregistration of Alachlor by the Food Quality Protection Act of 1996''
[MRID 44252200] is:
([Chlor1][Chlor1]) + ([Chlor2][Chlor2]10) +
([Chlor3][Chlor3]10) + Etc
In which, [ChlorX] represents the Aggregate Exposure to each
individual chloroacetamide herbicide which shares the common mechanism
with alachlor (ala), and [ChlorX]10 represents
the toxicological dose of that same herbicide which produced a
measurable (10%) increase in tumors in tested animals (i.e., the
ED10). This equation gives the cumulative MOE relative to
the ED10 and is valid assuming approximately constant
relative potencies among the chloroacetamides at exposures below the
ED10. Since the ED10 will almost always exceed
the NOAEL, this MOE will be smaller than the NOAEL-based MOE.
The ARP adopts this equation for the purpose of the cumulative risk
assessment for chloroacetamides and to show that acetochlor uses meet
the FQPA standard of reasonable certainty of no harm even if a common
mechanism of toxicity is presumed to exist for several
E. Safety Determination
1. U.S. population --i. U.S. general population -acetochlor alone.
The upper bound Aggregate Exposure estimate for short-term exposures to
acetochlor is 6.7 x 10-5 mg/kg/day. The Toxicity Endpoint
Reference Committee has established 150 mg/kg/day as the acute dietary
endpoint for risk assessment. Comparing the aggregate exposure to this
endpoint indicates that short-term exposures have a margin of safety of
The Aggregate Exposure estimate for chronic exposures to acetochlor
is 1.29 x 10-5 mg/kg/day. This exposure utilizes only 0.065%
of the RfD of 0.02 mg/kg/day. EPA generally has no concern about
exposures below 100% of the RfD for the U.S population.
For cancer risk assessment, the ARP proposes that acetochlor be
assessed by the MOE method that has been approved for cancer risk
assessment of alachlor, a close structural analog which produces the
same nasal and thyroid tumors in the rat. The appropriate cancer
reference endpoint for acetochlor is the lowest NOAEL for tumors which
is 26 mg/kg/day, the NOAEL for nasal tumors in the rat. Comparison of
the aggregate exposure estimate of 1.29 x 10-5 mg/kg/day to
the 26 mg/kg/day cancer endpoint gives a MOE (relative to this minimum
NOAEL) of 2,015,504. The margins of safety for short-term exposure,
chronic exposure and carcinogenicity are all adequate and support the
conclusion that there is a reasonable certainty of no harm resulting
from the established and proposed uses of acetochlor.
ii. U.S. general population--acetamides common nasal mechanism. The
Aggregate Exposure (chronic) estimate for acetochlor is given above as
1.29 x 10-5 mg/kg/day. Using Aggregate Exposure estimates
and ED10 derived by Monsanto for alachlor, butachlor and
metolachlor, and this refined Aggregate Exposure estimate for
acetochlor, the Common Mechanism MOE for all four pesticides was
Because some of these active ingredients have more than one chronic
rat study, MOE ED10 was calculated using the lowest or worst
case ED10's. (The lowest ED10's were 8.5 mg/kg/
day for alachlor, 40.7 mg/kg/day for acetochlor and 85.1 mg/kg/day for
butachlor. For metolachlor there were insufficient data to estimate an
ED10 and a worst-case value of 150 mg/kg/day was used. The
aggregate exposure estimates used for alachlor, butachlor, and
metolachlor were 1.7 x 10-5, 5.2 x 10-7, and 2.1
x 10-4 mg/kg/day, respectively.) The Combined Mechanism MOE
relative to the ED10 was 268596. This MOE is sufficiently
large to demonstrate that there is a reasonable certainty of no harm
from cumulative exposure to these chloroacetamides even if they are
considered to share a common toxic mechanism.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of acetochlor, EPA
considers data from developmental studies in the rat and the rabbit and
a 2-generation reproduction study in the rat. The developmental
toxicity studies are designed to evaluate adverse effects on the
developing organism resulting from pesticide exposure to female test
animals. Reproduction studies provide information relating to effects
from exposure to the pesticide on the reproductive capability of mating
animals data on systemic toxicity and the survival, growth and
development of the offspring.
Based on the current toxicological data requirements, the
acetochlor data base is complete and sufficient for assessing prenatal
and postnatal effects on children. There are two developmental studies
with acetochlor in both the rat and the rabbit and there are two
reproduction studies in the rat. In the four developmental studies and
two reproduction studies with acetochlor, the fetal NOAEL's were either
equal to or higher than the maternal (systemic) NOAEL's, indicating
that there is no increased sensitivity for offspring. The NOAEL of 2
mg/kg/day in the dog study which was used to establish the RfD is lower
than the lowest developmental NOAEL by a factor of 75, and lower than
the lowest reproductive NOAEL by a factor of 10, suggesting that the
RfD is appropriate for assessing aggregate risk to infants and
children. The results of the acetochlor testing establishes that there
is reasonable certainty of no harm to infants and children from the
proposed uses of acetochlor.
The upper bound Aggregate Exposure for infants or children is 2.27
x 10-4 mg/kg/day, representing the combination of dietary
exposure for non-nursing infants less than 1 year old (the most highly
exposed subgroup) with potential short-term exposure to drinking water
containing 2.0 ppb acetochlor. This potential short-term exposure
provides a margin of safety of 660,793 when compared to the
toxicological reference point of 150 mg/kg/day for acute dietary
exposures. Chronic exposure at this level would utilize only 1.1% of
the RfD. EPA generally has no concern about chronic exposures that
utilize less than 100% of the RfD. Cancer risk assessment for children
is considered to be included in the adult assessment because of the
long induction period for carcinogenic effects. The cumulative risk
assessment for chloroacetamides is based on the proposed common
mechanism for induction of nasal tumors, a process requiring a long
dosing period. Therefore, the data presented support the conclusion
that there is a reasonable certainty of no harm to infants or children
will result from the established and proposed uses for acetochlor.
F. International Tolerances
There are no Codex Alimentarius Commission (CODEX) Maximum Residue
Levels established for residues of acetochlor on agricultural
II. Interregional Research Project Number 4
EPA has received a pesticide petition (9E6025) from the
Interregional Project Number 4 (IR-4), New Jersey
Agricultural Experiment Station, Rutgers University, New Brunswick, New
Jersey 08903 proposing, pursuant to section 408(d) of the FFDCA, 21
U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a tolerance
for residues of pyridate, 0-(6-chloro-3-phenyl-4-pyridazinyl)-S-octyl
carbonothioate and its metabolite 6-chloro-3-phenyl-pyridazine-4-ol
(known as SAN 1367), and conjugates of SAN 1367 in or on the raw
agricultural commodities peppermint tops and spearmint tops at 0.20
parts per million (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
support granting of the petition. Additional data may be needed before
EPA rules on the petition. This summary was prepared by Novartis Crop
Protection, Inc., Greensboro, NC, 27419.
A. Residue Chemistry
1. Plant metabolism. The metabolism of pyridate in plants is well
understood based on studies with broccoli, corn, and peanut. Pyridate
is rapidly broken down by hydrolysis to its major degraded, SAN 1367.
The SAN 1367 metabolite is further conjugated to glucoside and
2. Analytical method. The proposed analytical method is ``Method of
Analysis of Determination of Residues of Pyridate and its Metabolites
CL 9673 and Conjugated CL 9673 in Plant Materials.''
B. Toxicological Profile
1. Acute toxicity. Results of a rat acute oral study showed a
lethal dose (LD)50 of 4,690 mg/body weight (bwt)/day (5,993
mg/kg in males and 3,544 mg/kg in females).
In a rat acute dermal study, the LD50 was shown to be >
2,000 mg/kg. A rat acute inhalation study yielded a LD50 >
4.37 mg/milliliter (ml).
Results of a primary eye irritation study in the rabbit indicated
that pyridate is a mild irritant.
A primary dermal irritation study showed pyridate to be a moderate
skin irritant, whereas, a dermal sensitization study indicated it is a
2. Genotoxicity. Pyridate was tested in the Ames test, mouse
micronucleus assay, chromosome aberration assay with Chinese hamster
ovary cells (CHO), the REC assay, and rat hepatocyte unscheduled DNA
synthesis assay. Results were negative for mutagenicity and chromosome
3. Reproductive and developmental toxicity. A developmental
toxicity study in the rat dosed at 0, 55, 165, 400, or 495 mg/kg/day
showed a maternal no observed adverse effect level (NOAEL) of 165 mg/
kg/day, and a developmental NOAEL > 495 mg/kg/day.
A developmental toxicity study in the rabbit with doses of 0, 150,
300, or 600 mg/kg/day showed a maternal NOAEL of 300 mg/kg/day and a
developmental NOAEL > 600 mg/kg/day.
Results of a multi-generational reproduction study with rats dosed
at 0, 2.2, 10.8, or 67.5 mg/kg/day showed a NOAEL of 10.8 mg/kg/day for
maternal and developmental toxicity.
4. Subchronic toxicity. Results of a 21-day dermal study showed a
NOAEL > 1,000 mg/kg. A 90-day feeding study in rats dosed at 0, 62.5,
177, and 500 mg/kg/day showed a NOAEL of 62.5 mg/kg/day. No
neuropathological effects were found.
A 90-day feeding study in dogs with doses of 0, 20, 60, or 200 mg/
kg/day showed a NOAEL of 20 mg/kg/day. Slight degenerative myelopathy
in the peripheral nerves was observed at the highest dose level, which
is much higher than the NOAEL and the expected exposure from field use.
5. Chronic toxicity. A 1-year feeding study in dogs was conducted
with doses of 0, 5, 20 or 60 mg/kg/day for 34 weeks. After week 34, the
doses were increased to 30, 100, or 150 mg/kg/day because no toxic
effects were evident at the lower doses. The final results showed a
systemic NOAEL of 20 mg/kg/day.
A lifespan (121 week) chronic/carcinogenicity study in rats treated
with analytical levels of 0, 2.2, 10.8, or 67.5 mg/kg/day (equivalent
to 0, 48, 240, or 1,500 ppm) showed a systemic NOAEL of 10.8 mg/kg/day
(240 ppm) based on body weight depression. No carcinogenic potential
In an 18-month carcinogenicity study, mice were fed doses of 0,
400, 800, 1,600 or 7,000 ppm of pyridate. In males, dose levels were
approximately 0, 47.7; 97.1; 169.5, and 882.6 mg/kg bwt/day; in
females, dose levels were approximately 0, 54.5, 114.6, 204.3, and
1,044.6 mg/kg bwt/day with a NOAEL at 800 ppm (97.1 mg/kg in males and
114.6 mg/kg in females). Results showed no evidence of carcinogenicity.
Carcinogenicity. Existing data demonstrate that there is no
evidence of carcinogenicity in rats at 1,500 ppm (67.5 mg/kg/day) or
mice at 7,000 ppm (883 mg/kg bwt/day in males, and 1,044.6 mg/kg bwt/
day in females). These data have been obtained at dosing in excess of
any dietary exposure.
6. Animal metabolism. Pyridate has been tested in rats, dogs,
cattle, goats, and hens. In every study, pyridate was hydrolyzed to SAN
1367 and rapidly excreted, primarily through the urine as SAN 1367 or
its glucoside or glucuronide conjugates. Pyridate and its metabolites
are not persistent and do not accumulate in animal systems.
C. Aggregate Exposure
1. Dietary exposure. Pyridate is registered for use in corn,
peanut, and cabbage. The pending petition add the use in/on peppermint
tops and spearmint tops. The potential dietary exposure of the
population to residues of pyridate or its metabolites is calculated
based on Theoretical Maximum Residue Contribution (TMRC) for all crops
with pyridate use. The TMRC is a worst case estimate of dietary
exposure since it assumes that 100% of all crops for which tolerances
are established are treated with pyridate, and that pesticide residues
are present at the tolerance levels. Novartis maintains that this
method of calculation result in an overestimation of the exposure and
is considered conservative. Dietary exposure is not expected in meat,
milk, poultry, or eggs, based on cow and hen feeding studies, animal
metabolism studies, and the fact the residue studies indicate that
residues are not present in crops fed to animals above the limit of
i. Chronic effects. The chronic population adjusted dose (cPAD) has
been established based on the chronic toxicity data base. The cPAD =
0.11 mg/kg bwt/day based on the NOAEL of 10.8 from the lifespan rat
carcinogenicity study due to body weight depression in males, and
assuming a safety factor of 100.
ii. Acute effects. Acute dietary analysis compared the daily
dietary exposure to the lowest NOAEL for subchronic studies. EPA's
current policy for Tier I analysis uses the conservation assumption
that all residues are at a high end estimate or maximum, typically
taken as the tolerance value. Acute dietary assessment for pyridate was
generated by comparing the ratio of exposure and the NOAEL from the 90-
day feeding study in dogs of 20 mg/kg bwt/day to determine a margin of
exposure (MOE). The exposure estimate includes all current and pending
tolerances from Sandoz Agro, Inc. and IR-4. A MOE of 100 or more is
considered acceptable. For all subgroups evaluated, the MOE is greater
2. Drinking water. Drinking water is not expected to be a means of
exposure to pyridate. Environmental studies indicate that pyridate
binds to the soil and is rapidly hydrolyzed into its
metabolites. The metabolites are then photolyzed and further degraded
and finally mineralized to CO2. Leaching studies and
lysimeter studies indicate that under typical agricultural conditions,
neither pyridate nor its metabolites were detected below 30
centimeters. Ground water monitoring studies conducted in Europe have
not confirmed any detection of pyridate or metabolites. Therefore,
significant movement of pyridate is not likely and is not a
considerable factor in assessing human health risk.
3. Non-dietary exposure. There are no registered uses for pyridate
on residential or recreational turf. Therefore, non-dietary exposure of
pyridate is not likely and not a factor in assessing human health risk.
D. Cumulative Effects
Pyridate belongs to the pyridazine group of herbicidal compounds
and has a unique mode of action in plants. Sandoz does not have data to
indicate a common mechanism of toxicity to other compounds in humans.
Therefore cumulative effects from common mechanisms of action are
E. Safety Determination
1. U.S. population. The cPAD is calculated to be 0.11 mg/kg bwt/
day. The estimates of exposure are based on conservative assumptions
that all crops with a tolerance for pyridate are treated and that all
residues found are at the maximum or tolerance level. The dietary
exposure to the U.S. population for the current uses plus the corn
grain, peanut butter, and cabbage uses is estimated at most to be 6.0 x
10-5 mg/kg/bwt/day, which is 0.1% of the cPAD. Therefore,
Novartis concludes that there is reasonable certainty of no harm from
aggregate exposure of residues of pyridate or its metabolites including
all dietary and other non-occupational exposures.
2. Infants and children. Pyridate is not a reproductive or
developmental toxicant. Therefore no specific effects on infants and
children are expected. Based on the weight of evidence of the toxicity
studies, an additional safety factor is not warranted.
Using the same assumptions as above, the exposure to infants and
children is presented as a percent of cPAD. The dietary exposure for
the current uses plus the corn grain, peanut butter, and cabbage uses
for non-nursing infants is estimated as 1.25 x 10-4 mg/kg/
bwt/day, which is 0.1% of the cPAD. For children age 1-6, the estimated
exposure is 1.43 x 10-4 mg/kg/day, 0.1% of the cPAD.
Therefore, Sandoz concludes that there is reasonable certainty of no
harm from aggregate exposure of residues of pyridate or its metabolites
including all dietary and other non-occupational exposures.
F. International Tolerances
No international tolerances have been established for pyridate on
peppermint tops and spearmint tops by CODEX Alimentarius Commission.
[FR Doc. 00-1553 Filed 1-21-00; 8:45 am]
BILLING CODE 6560-50-F