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Imazapyr - Tolerance Petition Filing 12/96

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ENVIRONMENTAL PROTECTION AGENCY
American Cyanamid Company; Pesticide Tolerance Petition Filing
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice of filing.
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SUMMARY: This notice is a summary of a pesticide petition proposing the
establishment of a regulation for residues of imazapyr (AC 243997) [2- [4,5-
dihydro-4-methylethyl)-5-oxo-1H-imidazol-2-yl]-3- pyridinecarboxylic acid],
applied as the acid or ammonium salt, in or on field corn. This summary was
prepared by the petitioner. DATES: Comments, identified by the docket number
[PF-682], must be received on or before, January 17, 1997.

ADDRESSES: By mail, submit written comments to Public Response and Program
Resources Branch, Field Operations Division (7506C), Office of Pesticide
Programs, Environmental Protection Agency, 401 M St. SW., Washington, DC20460.
In person, bring comments to RM 1132, CM #2, 1921 Jefferson Davis Highway,
Arlington, VA 22202. Comments and data may also be submitted electronically by
sending electronic mail (e-mail) to: opp-docket@epamail.epa.gov.
Electronic
comments on this notice may be filed online at many Federal Depository
Libraries.

Information submitted as comments concerning this document may be claimed
confidential by marking any part or all of that information as "Confidential
Business Information" (CBI). CBI should not be submitted through e-mail.
Information marked as CBI will not be disclosed except in accordance with
procedures set forth in 40 CFR part 2. A copy of the comment that does not
contain CBI must be submitted for inclusion in the public record. Information
not marked confidential may be disclosed publicly by EPA without prior notice.
All written comments will be available for public inspection in Rm. 1132 at
the address given above, from 8:30 a.m. to 4:00 p.m., Monday through Friday,
excluding legal holidays.

Comments and data may also be submitted electronically by sending electronic
mail (e-mail) to: opp-docket@epamail.epa.gov. Electronic comments must
be submitted as an ASCII file avoiding the use of special characters and any form
of encryption. Comments and data will also be accepted on disks in WordPerfect
5.1 file format or ASCII file format. All comments and data in electronic form
must be identified by the docket number [PF-682]. No CBI should be submitted
through e-mail. Electronic comments on this proposed rule may be filed online
at many Federal Depository Libraries. Additional information on electronic
submissions can be found below in this document.

FOR FURTHER INFORMATION CONTACT: By mail: Robert J. Taylor, Product Manager
(PM) 23, Registration Division, (7505C), Office of Pesticide Programs,
Environmental Protection Agency, 401 M St., SW., Washington, DC 20460. Office
location and telephone number: Rm. 241, CM #2, 1921 Jefferson Davis Highway,
Arlington, VA 22202, 703-305-6027, e-mail: taylor.robert@epamail.epa.gov.

SUPPLEMENTARY INFORMATION: EPA has received a pesticide petition (PP 6F4641)
from American Cyanamid Company, P.O. Box 400, Princeton, NJ 08543, proposing
pursuant to section 408(d) of the Federal Food, Drug and Cosmetic Act, 21
U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a tolerance for
residues of the herbicide imazapyr in or on the raw agricultural commodities
field corn grain, fodder, and forage each at 0.05 ppm. The proposed analytical
method is Capillary Electrophoresis Method 2657. Pursuant to section
408(d)(2)(A)(i) of the FFDCA, as amended, American Cyanamid Company has
submitted the following summary of information, data and arguments in support
of their pesticide petition. This summary was prepared by American Cyanamid
Company and EPA has not fully evaluated the merits of the petition. EPA edited
the summary to clarify that the conclusions and arguments were the
petitioner's and not necessarily EPA's and to remove certain extraneous
material.

I. Petition Summary for Imazapyr on Field Corn

On November 9, 1995, American Cyanamid Company petitioned the EPA for a
permanent tolerance for the residues of imazapyr on or in field corn grain,
forage, and fodder. Imazapyr is currently registered for weed control in non-
crop sites. This is the first registration application for a food use in the
United States. Section 408(b)(2)(A) of the amended Federal Food, Drug, and
Cosmetic Act allows the EPA to establish a tolerance only if the Administrator
determines that there is a "reasonable certainty that no harm will result
from the aggregate exposure to the pesticide chemical residue, including all
anticipated dietary exposures and all other exposures for which there is
reliable information." All of the studies required for the proposed use
pattern have been completed and submitted to EPA for review. The available
information indicates there is a reasonable certainty that no harm will result
from various types of exposure. The following is a summary of the information
submitted to the EPA to support the establishment, under section 408(b)(2)(D)
of the amended FFDCA, of a tolerance for imazapyr on field corn.

A. Residue Chemistry

1. Plant metabolism. The qualitative nature of the residues of imazapyr in
corn is adequately understood. In corn forage, fodder and grain samples, the
only significant component is parent compound. A modified processing study,
utilizing corn treated at exaggerated rates, indicates that the low levels of
residue in grain did not concentrate in corn oil and concentrated only
slightly (≤ 1.2x) in corn meal.

2. Analytical method. A practical analytical method (Capillary
Electrophoresis Method 2657) for detecting and measuring levels of imazapyr in
corn has been submitted to

[[Page 66659]]

EPA. This method is appropriate for enforcement purposes.

3. Magnitude of residues. In field corn residue studies conducted at a
slightly exaggerated use rate, no residues were detected at levels above 0.05
ppm (the limit of quantitation for the analytical method). These field studies
clearly support the proposed tolerance of 0.05 ppm.

B. Toxicological Profile

A complete battery of mammalian toxicology studies supports the tolerance for
imazapyr on field corn. The database is complete, valid and reliable, and all
studies have been accepted by EPA and found to meet EPA requirements.

1. Acute toxicity. Imazapyr technical is relatively non-toxic via the oral
route of exposure, and only slightly toxic via the dermal and inhalation
routes of exposure.
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Acute oral toxicity in rats............... LD50 > 5,000 mg/kg
Acute dermal toxicity in rabbits.......... LD50 > 2,000 mg/kg
Acute inhalation toxicity in rats......... LC50 > 1.3 mg/l
Primary eye irritation in rabbits......... Irreversible irritation Primary
Dermal irritation in rabbits.............. Slightly irritating 
Dermal sensitization in guinea pigs....... Non-sensitizer
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2. Genotoxicity. Imazapyr has shown no genotoxic activity in in vitro tests,
indicating that this compound is not a mutagen.

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Ames...................................... Non-mutagenic Chromosomal
aberrations................... Non-genotoxic Mammalian gene mutation
(CHO/HGPRT)....... Non-mutagenic Unscheduled DNA synthesis.................
Non-genotoxic
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3. Reproductive and developmental toxicity. Results indicate that imazapyr is
not a reproductive toxicant, a developmental toxicant, or a teratogen.

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Teratology in rats........................ NOEL (maternal) = 300 mg/kg/day
NOEL (developmental) = 1,000 mg/kg/day*
Teratology in rabbits..................... NOEL (maternal) = 400 mg/kg/day*
NOEL (developmental) = 400 mg/kg/day*
2-Generation reproduction in rats......... NOEL (parental reproductive)
= 10,000 ppm* (– 800 mg/kg/day in males) (– 980 mg/kg/day in females)
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* Highest dose

tested.

4. Subchronic toxicity. No treatment-related adverse effects were noted in
subchronic toxicity studies at the highest doses tested.

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13-Week oral feeding in rats.............. NOEL ≥ 20,000 ppm*(– 1,740 mg/kg/day)
21-Day dermal in rabbits.................. NOEL = 400 mg/kg/day*
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* Highest dose

tested.

5. Chronic toxicity. The EPA Carcinogenicity Peer Review Committee, on April
26, 1995, assigned imazapyr to Group E for carcinogenic potential since there
is "no evidence of carcinogenicity in at least two adequate animal tests in
different species. "No treatment related effects were observed, and no
increase in tumors was observed at any dose level.

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1-Year chronic toxicity in dogs........... NOEL = 10,000 ppm*(– 250 mg/kg/day)
18-Month chronic toxicity & oncogenicity NOEL = 10,000 ppm* in mice.(– 1500 mg/kg/day)
24-Month chronic toxicity & oncogenicity NOEL = 10,000 ppm* in rats.
(– 500 mg/kg/day in males) (– 640 mg/kg/day in females)
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* Highest dose tested

6. Animal metabolism. The qualitative nature of the residues of imazapyr in
animals is adequately understood. Based on metabolism studies with goats, hens
and rats, there is no reasonable expectation that measurable imazapyr-related
residues will occur in meat, milk, poultry or eggs from the proposed use.

7. Metabolite toxicology. No significant metabolites were detected in plant
or animal metabolism studies. Therefore, toxicology studies with metabolites
are not required.

8. Endocrine effects. Collective organ weights and histopathological findings
from the two-generation rat reproductive study, as well as from the subchronic
and chronic toxicity studies in two or more animal species, demonstrate no
apparent estrogenic effects or effects on the endocrine system. There is no
information available which suggests that imazapyr would be associated with
endocrine effects.

C. Aggregate Exposure

1. Dietary exposure-- i. Food. The Theoretical Maximum Residue Concentrations
(TMRC) of imazapyr on or in field corn are:
• 0.000070 mg/kg b.w./day for the general U.S. population
• 0.000142 mg/kg b.w./day for non-nursing infants
• 0.000165 mg/kg b.w./day for children 1 to 6 years of age
• 0.000123 mg/kg b.w./day for children 7 to 12 years of age.

These values are calculated from the proposed 0.05 ppm tolerance of imazapyr
on corn using a "worse case" estimate of dietary exposure. This conservative
estimate assumes that 100 percent of all field corn is treated with imazapyr
and that the residues of imazapyr on corn are at the tolerance level (0.05
ppm). In reality, field trials with sampling at least 30 days after treatment
resulted in no residues above the analytical method limit of quantitation
(0.05 ppm).

Dietary exposure to residues of imazapyr in or on food will be limited to
residues on corn. Field corn grain, forage, fodder and milled byproducts could
be fed to animals. However, there is no reasonable expectation that measurable
residues of imazapyr will occur in meat, milk, poultry or eggs from the
proposed use. There are no other established tolerances for imazapyr, and
there are no other registered uses for imazapyr on food or feed crops in the
United States.

With a Reference Dose (RfD) of 2.50 mg/kg b.w./day, the dietary exposure for
this proposed use will utilize only 0.0028 percent of the RfD for the general
U.S. population.

ii. Drinking water. There is no available information about imazapyr exposure
via levels in drinking water. Imazapyr has been registered for non-crop uses
for 12 years and there are no confirmed findings in either ground or surface
water from these uses. Low initial soil residue levels due to low application
rates (0.014 lb. ae/acre) contribute to the minimal risk of exposure to
imazapyr in drinking water from this use.

[[Page 66660]]

EPA has not established a Maximum Concentration Level for residues of
imazapyr in drinking water under the Safe Drinking Water Act, because imazapyr
is unlikely to be found in groundwater.The low level of mammalian toxicity
further supports the lack of real risk of imazapyr to humans. A Lifetime
Health Advisory level for imazapyr in drinking water calculated by EPA
procedures would be 17.5 mg/liter, assuming a 20 percent relative contribution
from water. There is a reasonable certainty that no harm will result from
dietary exposure to imazapyr, because dietary exposure to residues on food
will use only a small fraction of the Reference Dose (including exposure of
sensitive populations), and exposure through drinking water is expected to be
insignificant.

2. Non-dietary exposure. There is no available information quantifying non-
dietary exposure to imazapyr. However, based on physical and chemical
characteristics of the compound, the use patterns, and available information
concerning its environmental fate, non-dietary exposure is expected to be
negligible.

Currently, registrations for imazapyr limit use to non-crop sites. Labeled
use sites for one group of imazapyr products include railroad, utility,
pipeline, and highway rights-of-way, utility plant sites, petroleum tank
farms, pumping installations, fence rows, storage areas, non-irrigation
ditchbanks, under asphalt, under pond liners, wildlife management areas,
forestry site preparation, and other non-crop areas. Imazapyr products for the
above uses are clearly not intended for use in residential or recreational
areas that have a high potential of exposure for the general population. The
labels state that these imazapyr products are not for use on lawns, walks,
driveways, tennis courts or similar areas.

Other imazapyr products are labeled as plant growth regulators for
applications to limited care-low maintenance areas, such as roadsides,
airports, fairgrounds, and golf course roughs, and to limited wear areas such
as industrial, institutional, and cemetery grounds. These low rate uses entail
minimal exposure potential for the general population. The product labeling
does not allow use on turf that is being grown for sale or other commercial
use, such as sod.

There are imazapyr products marketed for residential use. These total
vegetation control products are used for spot treatments or bare ground
applications. These products are to be applied only where no plant growth is
desired and are not to be used on lawns. Therefore, even for the limited
residential uses, the potential for exposure is minimal.

D. Cumulative effects

Imazapyr belongs to the imidazolinone class of compounds. Other compounds in
this class are registered herbicides. However, the herbicidal activity of the
imidazolinones is due to the inhibition of acetohydroxyacid synthase (AHAS),
an enzyme only found in plants. AHAS is part of the biosynthetic pathway
leading to the formation of branched chain amino acids. Animals lack AHAS and
this biosynthetic pathway. This lack of AHAS contributes to the low toxicity
of the imidazolinone compounds in animals. We are aware of no information to
indicate or suggest that imazapyr has any toxic effects on mammals that would
be cumulative with those of any other chemical.

E. Safety Determination

1. U.S. population. The RfD of 2.50 mg/kg b.w./day, supported by a NOEL of
10,000 ppm or 250 mg/kg b.w./day from the 1-year dog study and a safety
(uncertainty) factor of 100, is the "worst case" estimate of chronic dietary
exposure of imazapyr in corn. This proposed application will utilize only
0.0028 percent of the RfD for the general U.S. population. EPA generally has
no concern for exposures below 100 percent of the RfD which represents the
level at or below which daily aggregate dietary exposure over a lifetime will
not pose appreciable risks to human health. The complete and reliable toxicity
data, indicating low potential mammalian toxicity, and the conservative
chronic exposure assumptions support the conclusion that there is a
"reasonable certainty of no harm" from aggregate exposure to imazapyr
residues.

2. Infants and children. The conservative estimates for dietary exposure to
imazapyr from food, as described above in Unit C of this notice of filing,
indicate that exposure of imazapyr on corn will utilize approximately 0.0057
percent of the RfD for non-nursing infants, approximately 0.0066 percent for
the RfD for children 1 to 6 years of age, and approximately 0.0049 percent of
the RfD for children seven to 12 years of age.

Furthermore, no developmental, reproductive or fetotoxic effects were noted
at the highest doses of imazapyr tested. The only maternal effect in the rat
teratology study was increased salivation in the highest dose group. The NOEL
used to calculate the RfD for the general U.S. population is 250 mg/kg
b.w./day derived from the 1-year chronic toxicity study in dogs. That NOEL is
lower than the developmental NOELs for the teratology studies in rabbits and
rats (1.6 and 4x, respectively), as well as lower than the NOEL for the two-
generation reproduction study in male and female rats (3.2 to 3.9x).

The EPA has found the database relative to pre-and post-natal effects for
children to be complete, valid and reliable. There were no effects observed in
the offspring in the developmental studies in rats and rabbits. In the
reproduction study, the lack of any pup effects observed at 10,000 ppm (the
highest dose tested) in their growth and development from parturition through
adulthood, suggests that there is no additional sensitivity for infants and
children. Therefore, an additional safety (uncertainty) factor is not
warranted and the RfD of 2.50 mg/kg b.w./day, which utilizes a 100-fold safety
factor, is appropriate to assure a reasonable certainty of no harm to infants
and children.

F. International Tolerances

There are no Codex maximum residue levels established for residues of
imazapyr on field corn grain, fodder or forage.

II. Administrative Matters

Interested persons are invited to submit comments on the notice of filing.
Comments must bear a notation indicating the document control number, [PF-
682]. All written comments filed in response to this petition will be
available in the Public Response and Program Resources Branch, at the address
given above from 8:30 a.m. to 4:00 p.m., Monday through Friday, except legal
holidays.

A record has been established for this notice under docket number [PF-682]
including comments and data submitted electronically as described below). A
public version of this record, including printed, paper versions of electronic
comments, which does not include any information claimed as CBI, is available
for inspection from 8:30 a.m. to 4:00 p.m., Monday through Friday, excluding
legal holidays. The public record is located in Room 1132 of the Public
Response and Program Resources Branch, Field Operations Division (7506C),
Office of Pesticide Programs, Environmental Protection Agency, Crystal Mall
#2, 1921 Jefferson Davis Highway, Arlington, VA.

Electronic comments can be sent directly to EPA at:
opp=Docket@epamail.epa.gov.

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Electronic comments must be submitted as an ASCII file avoiding the use of
special characters and any form of encryption. The official record for this
rulemaking, as well as the public version, as described above will be kept in
paper form. Accordingly, EPA will transfer all comments received
electronically into printed, paper form as they are received and will place
the paper copies in the official rulemaking record which will also include all
comments submitted directly in writing. The official rulemaking record is the
paper record maintained at the address in "ADDRESSES" at the beginning of
this document.

List of Subjects

Environmental Protection, Administrative practice and procedure, Agricultural
commodities, Pesticides and pests, Reporting and recordkeeping requirements.

Dated: December 11, 1996.

Stephen L. Johnson,

Director, Registration Division, Office of Pesticide Programs.