Imazapyr - Pesticide Tolerances 4/97
Imazapyr; Pesticide Tolerances
AGENCY: Environmental Protection Agency (EPA).
ACTION: Final Rule.
SUMMARY: This document establishes tolerances for the residues of the
herbicide imazapyr, [2-[4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo- 1H-
imidazol-2-yl]-3-pyridinecarboxylic acid], applied as the acid, in or on field
corn. American Cyanamid submitted a petition to EPA under the Federal Food,
Drug and Cosmetic Act as amended by the Food Quality Protection Act of 1996
requesting the tolerances.
DATES: This rule becomes effective April 9, 1997. Written objections must be
submitted by June 9, 1997.
ADDRESSES: Written objections and hearing requests, identified by the docket
control number, [OPP-300471], may be submitted to: Hearing Clerk (1900),
Environmental Protection Agency, Rm. M3708, 401 M St., SW., Washington, DC
20460. A copy of any objections and hearing requests filed with the Hearing
Clerk should be identified by the docket control number and submitted to:
Public Response and Program Resources Branch, Field Operations Division
(7506C), Office of Pesticide Programs, Environmental Protection Agency, 401 M.
St., SW., Washington, DC 20460. In person, bring copy of objections and
hearing requests to: Rm. 1132, CM #2, 1921 Jefferson Davis Highway, Arlington,
VA 22202. Fees accompanying objections and hearing requests shall be labeled
"Tolerance Petition Fees" and forwarded to: EPA Headquarters Accounting
Operations Branch, OPP (Tolerance Fees), P.O. Box 360277M, Pittsburgh, PA
A copy of objections and hearing requests filed with the Hearing Clerk may
also be submitted electronically by sending electronic mail (e-mail) to : opp-
email@example.com. Copies of objections and hearing requests must be
submitted as an ASCII file avoiding the use of special characters and any form
of encryption. Copies of objections and hearing requests will also be accepted
on disks in WordPerfect in 5.1 file format or ASCII file format. All copies of
objections and hearing requests in electronic form must be identified by the
docket number [OPP-300471]. No Confidential Business Information (CBI) should
be submitted through e-mail. Electronic copies of objections and hearing
requests on this rule may be filed online at many Federal Depository
Libraries. Additional information on electronic submissions can be found in
Unit IX of this document.
FOR FURTHER INFORMATION CONTACT: By Mail: Philip V. Errico, Product Manager
(PM) 25, Registration Division (7505C), Office of Pesticide Programs,
Environmental Protection Agency, 401 M St., SW., Washington, DC 20460. Office
location, telephone number and e-mail address: Rm. 241, CM #2, 1921 Jefferson
Davis Highway, Arlington, VA 22202. (703) 305-6027; e-mail:
SUPPLEMENTARY INFORMATION: In the Federal Register of December 12, 1996 (61 FR
66658)(FRL-5576-9) EPA issued a notice announcing that American Cyanamid, P.O.
Box 400, Princeton, NJ 08543 had submitted pesticide petition 6F4641 which
requested that the Administrator, pursuant to section 408 of the Federal Food,
Drug and Cosmetic Act (FFDCA), and in conformity with the Food Quality
Protection Act (FQPA) of 1996, amend 40 CFR part 180 to establish tolerances
for residues of imazapyr [2- [4,5-dihydro-4-methyl-4(1-methylethyl)-5-oxo-1H-
imidazol-2-yl]-3- pyridinecarboxylic acid], applied as the acid in or on field
corn grain, fodder, and forage at 0.05 ppm. The notice contained a summary of
the petition prepared by the petitioner, American Cyanamid, including
information and arguments to support their conclusion that the petition
complied with FQPA. It was stated in the notice that the conclusions and
arguments were not EPA's.
There were no comments received in response to the notices of filing.
The data submitted in the petition and other relevant material have been
evaluated. The toxicological data listed below were considered in support of
I. Toxicology Profile
1. A battery of acute toxicity studies placing technical imazapyr in toxicity
category I for eye irritation, category IV for oral LD50 and primary dermal
irritation, category III for dermal and inhalation LD50.
2. A 90-day rat feeding study at doses of 0, 15,000, or 20,000 ppm (males= 0,
1,248, or 1,695 milligrams per kilogram per day (mg/kg/day); females 0, 1,423,
or 1,784 mg/kg/day) with a no-observed-effect level (NOEL) of 1,695 mg/kg/day
the highest dose tested (HDT).
3. A 21-day rabbit dermal toxicity study at doses of 0, 100, 200, or 400
mg/kg/day which showed occasional statistically significant findings but these
had no consistent pattern of toxicity. The NOEL was determined to be 400
4. A 1-year dog chronic toxicity study at doses of 0, 25, 125, or 250
mg/kg/day. The NOEL was 250 mg/kg/day HDT.
5. A 2-year rat chronic/carcinogenicity study at doses of 0, 1,000, 5,000, or
10,000 ppm (males= 0, 49.9, 252.6, or 503 mg/kg/day; females= 0, 64.2, 317.6,
or 638.6 mg/kg/day) with a NOEL of 503 mg/kg/day HDT.
6. An 18-month mouse carcinogenicity study at doses of 0, 1,000, 5,000, or
10,000 ppm (males= 0, 126, 674, or 1,301 mg/kg/day; females= 0, 151, 776, or
1,639 mg/kg/day) with a NOEL of 1,301 mg/kg/day HDT.
7. A rat developmental toxicity study at doses of 0, 100, 300, or 1,000
mg/kg/day. At 1,000 mg/kg/day, the only clinical sign of toxicity in gravid
dams was salivation. The NOEL for maternal toxicity is 300 mg/kg/day. There
were no developmental findings in this study up to the limit dose of 1,000
8. A rabbit developmental toxicity study at doses of 0, 25, 100, or 400
mg/kg/day with a maternal and developmental NOEL of 400 mg/kg/day HDT.
9. A rat two--generation reproduction study at dietary concentrations of 0,
1,000, 5,000, or 10,000 ppm (males= 0, 74.2, 380.5, or 738 mg/kg/day; females=
0, 94.3, 471.2, or 933.3 mg/kg/day) with a NOEL of 10,000 ppm HDT.
10. A metabolism study in rats indicated that imazapyr was rapidly absorbed
and excreted by 7 days post-dosing, with the majority of the administered 14C-
label (90%) eliminated in the urine within 48 hours. Metabolite
characterization studies showed that essentially all the test material was
excreted unchanged. Two minor metabolites, CL 252,974 and CL 60,032, were
detected in the urine or feces of treated rats; however, their contribution
combined was less than or equal to 0.5% of the administered dose. An
additional 12 unidentified metabolites were isolated, but they contributed
less than 3% of the total dose.
11. Acceptable studies on gene mutation and other genotoxic effects: Ames
Salmonella Assay; CHO/HGPRT Point Mutation Assay; In vitro CHO cell chromosome
aberration assay; Dominant lethal assay; and Unscheduled DNA synthesis (UDS)
yielded negative results.
II. Dose Response Assessment
1. Reference dose. The Reference Dose (RfD) represents the level at or below
which daily aggregate dietary exposure over a lifetime will not pose
appreciable risks to human health. The RfD is determined by using the
toxicological end-point or the NOEL for the most sensitive mammalian
toxicological study. To assure the adequacy of the RfD, the Agency uses an
uncertainty factor in deriving it. The factor is usually 100 to account for
both interspecies extrapolation and intraspecies variability represented by
the toxicological data. The EPA has established an RfD of 2.5 mg/kg/day based
on a NOEL of 250 mg/kg/day from a 1-year chronic dog feeding study.
2. Carcinogenicity classification. Using the Guidelines for Carcinogenic Risk
Assessment published September 24, 1986 (51 FR 33992), the EPA has classified
imazapyr as Group "E", not a likely human carcinogen.
3. Developmental toxicant determination. The acceptable developmental studies
(two-generation reproduction study in rats and prenatal developmental toxicity
studies in rats and rabbits) provided no indication of increased sensitivity
of rats or rabbits to in utero and/or postnatal exposure to imazapyr.
III. Non-dietary (Residential and Occupational) Exposure Assessment
Imazapyr products marketed for residential use include total vegetation
control products that are used for plot 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, for these limited
residential uses, the potential for exposure is minimal, and is expected to be
non-chronic. These products are in Toxicity Categories II for eye irritation.
Under the protective clothing requirements of the Worker Protection Standards
(WPS), handlers of these products are expected to be adequately protected.
Imazapyr is also registered for use on non-food sites including 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. These low rate uses
entail minimal exposure potential for the general population. Use of
protective clothing also reduces exposure.
Since imazapyr is a group E chemical (evidence of non- carcinogenicity for
humans); the 21 day dermal study lacked any significant observable effects at
the limit dose, and no adverse effects were observed in developmental toxicity
studies in rats up to 1,000 mg/kg/day and rabbits up to 400 mg/kg/day, no
toxicological endpoints for non-chronic residential exposures were identified.
Therefore, non-chronic risk assessments are not required for occupational or
non-occupational residential uses.
IV. Dietary Exposure Assessment
Use of a agricultural pesticide may result, directly or indirectly, in
pesticide residues in food. Primary residues or indirect/inadvertent residues
in agricultural commodities are determined by chemical analysis. To account
for the diversity of growing conditions, cultural practices, soil types,
climates, crop varieties and methods of application of the pesticide, data
from studies that represent the commodities are collected and evaluated to
determine an appropriate level of residue that would not be exceeded if the
pesticide is used as represented in the studies.
1. Plant/animal metabolism and magnitude of the residue. The nature
(metabolism) of imazapyr in plants and animals is adequately understood for
the purposes of these tolerances. There are no Codex maximum residue levels
established for residues of imazapyr on corn or the rotational crops. In all
the plant and animal (poultry and ruminants) metabolism studies submitted, the
residue of concern was the parent per se, imazapyr.
2. Residue analytical methods. The analytical method proposed as an
enforcement method for field corn commodities is GS/MS Method M 2468.02. The
method is suitable for detecting residues of the parent compound, imazapyr, in
field corn forage, silage, grain, fodder, meal and oil. Tolerances for meat,
milk, poultry, and eggs, are not required for this petition, therefore, an
analytical method for the enforcement of animal tolerances is not needed.
V. Aggregate Exposure Assessment
In examining aggregate exposure, FQPA directs EPA to consider available
information concerning exposures from pesticide residue in food, including
water, and all other non-occupational exposures. The aggregate sources of
exposure the Agency looks at includes food, drinking water or groundwater, and
exposure from pesticide use in gardens, lawns, or buildings (residential and
other indoor uses).
1. Acute dietary. As part of the hazard assessment process, the Agency reviews
the available toxicology database to determine the endpoints of concern. For
imazapyr, the Agency does not have a concern for an acute dietary assessment
since the available data do not indicate any evidence of significant toxicity
from a 1 day or single event exposure by the oral route. Therefore, an acute
dietary risk assessment was not required.
2. Chronic dietary. Using the Dietary Risk Evaluation System (DRES), a chronic
exposure analysis was performed using tolerance level residues and 100 percent
crop treated to estimate the Theoretical Maximum Residue Contribution (TMRC)
for the general population and 22 subgroups. This exposure analysis showed
that exposure from residues in/on corn for the U.S. population and all
subgroups would be less than 1% of the RfD.
3. Drinking water. To determine the exposure from drinking water, the Agency
applied modeling procedures. Using the estimated chronic drinking water values
of 1 mg/L for surface water and 3 mg/L for ground water, the exposure to
imazapyr from drinking water was calculated to be 3 x 10 to the minus 5
milligrams per kilogram of body weight per day (mg/kg bw/day) for the U.S
population (surface water), 1 x 10 to the minus 4 mg/kg bw/day for children
(surface water), 7 x 10 to the minus 5 mg/kg bw/day for U.S. population
(ground water), and 3 x 10 to the minus 4 mg/kg bw/day for children (ground
water). The calculations are included in the docket for this rulemaking.
4. Non-dietary (residential and non-occupational) exposure. Imazapyr is
registered for residential and non-occupational uses. As part of the hazard
assessment process, the Agency reviews the available toxicological database to
determine the endpoints of concern. For imazapyr, the Agency does not have a
concern for acute, short-term, or intermediate-term occupational or
residential risk assessment since the available data do not indicate any
evidence of significant toxicity by the dermal or inhalation routes, or from a
1 day or single event exposure by the oral route. Therefore, acute, short-term
or intermediate-term non-occupational or residential risk assessment was not
As part of the hazard assessment process it was determined that a chronic
residential assessment was not necessary. The exposures which would result
from the use of imazapyr were determined to be of an intermittent nature. The
frequency and duration of these exposures do not exhibit a chronic exposure
pattern. The exposures do not occur often enough to be considered a chronic
exposure i.e., a continuous exposure that occurs for at least several months.
Therefore, chronic residential exposures were not aggregated with dietary
exposures in estimating chronic risk.
5. Cumulative exposure to substances with common mechanism of toxicity.
Section 408(b)(2)(D)(v) requires that, when considering whether to establish,
modify, or revoke a tolerance, the Agency consider "available information"
concerning the cumulative effects of a particular pesticide's residues and
"other substances that have a common mechanism of toxicity." The Agency
believes that "available information" in this context might include not only
toxicity, chemistry, and exposure data, but also scientific policies and
methodologies for understanding common mechanisms of toxicity and conducting
cumulative risk assessments. For most pesticides, although the Agency has some
information in its files that may be helpful in determining whether a
pesticide shares a common mechanism of toxicity with any other substances, EPA
does not at this time have the methodology to resolve the scientific issues
concerning common mechanism of toxicity in a meaningful way. EPA has begun a
pilot process to study this issue further through examination of particular
classes of pesticides. The Agency hopes that the results of this pilot process
will increase the Agency`s scientific understanding of this question such that
EPA will be able to develop and apply scientific principles for better
determining which chemicals have a common mechanism of toxicity and evaluating
the cumulative effects of such chemicals. The Agency anticipates, however,
that even as its understanding of the science of common mechanisms increases,
decisions on specific classes of chemicals will be heavily dependent on
chemical specific data, much of which may not be presently available.
Although, at present, the Agency does not know how to apply the information in
its files concerning common mechanism issues to most risk assessments, there
are pesticides as to which the common mechanism issues can be resolved. These
pesticides include pesticides that are toxicologically dissimilar to existing
chemical substances (in which the Agency can conclude that it is unlikely that
a pesticide shares a common mechanism of activity with other substances) and
pesticides that produce a common toxic metabolite (in which case common
mechanism of activity will be assumed).
EPA does not have, at this time, available data to determine whether imazapyr
has a common mechanism of toxicity with other substances or how to include
this pesticide in a cumulative risk assessment. Unlike other pesticides for
which EPA has followed a cumulative risk approach, imazapyr does not appear to
produce a toxic metabolite produced by other substances. For the purposes of
this tolerance action, therefore, EPA has not assumed that imazapyr has a
common mechanism of toxicity with other substances. After EPA develops
methodologies for more fully applying common mechanism of toxicity issues to
risk assessments, the Agency will develop a process (either as part of the
periodic review of pesticides or otherwise) to reexamine those tolerance
decisions made earlier.
The registrant must submit, upon EPA's request and according to a schedule
determined by the Agency, such information as the Agency directs to be
submitted in order to evaluate issues related to whether imazapyr shares a
common mechanism of toxicity with any other substance and, if so, whether any
tolerance for imazapyr needs to be modified or revoked.
VI. Determination of Safety for the U.S. Population and Non-Nursing Infants
A. U.S. Population and Non-Nursing Infants
Using the Dietary Risks Evaluation System (DRES) a chronic analysis was
performed based on 100% of the crop treated and all residues at tolerance
levels. Based on the dietary/water risk assessment, the proposed uses utilize
less than 1% of the RfD for the U.S. population; less than 1% of the RfD for
nonnursing infants under 1 year old; less than 1% for nursing infants under 1
year old; less than 1% for children 1 to 6 years old; and less than 1% for
children 7 to 12 years old. The Agency concluded that no harm will occur to
non-nursing infants, or any other members of the U.S. population from
aggregate exposure to imazapyr.
B. Infants and Children
Risk to infants and children was determined by the use of two developmental
toxicity studies in rats and rabbits and the two- generation reproduction
study in rats discussed below. The developmental toxicity studies evaluates
the potential for adverse effects on the developing organism resulting from
exposure during prenatal development. The reproduction study provides
information relating to effects from exposure to the chemical on the
reproductive capability of both (mating) parents and on systemic toxicity.
The toxicological database for evaluating pre- and post-natal toxicity for
imazapyr is considered to be complete at this time. In the rabbits, no
evidence of maternal or developmental toxicity was observed at doses up to 400
mg/kg/day, highest dose tested HDT. In the rat developmental toxicity study,
maternal (systemic) toxicity was noted (indicated by salivation) at 1,000
In the rat two-generation reproduction study, no evidence of toxicity was
noted in either the adults or the offspring at dietary levels at or close to
the limit dose.
FFDCA section 408 provides that the EPA shall apply an additional safety
factor of 10 in the case of threshold effects for infants and children to
account for pre- and post-natal toxicity and the completeness of the database
unless EPA determines, based on reliable data, that a different safety factor
would be appropriate. The Agency believes that an additional safety factor for
infants and children is not warranted. A complete set of developmental and
reproductive studies have been submitted and EPA has found them to be
acceptable. The NOEL used to calculate the RfD for the general U.S. population
is 250 mg/kg bw/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 Agency does not believe the effects seen in the above studies are
of such concern to require an additional safety factor. Accordingly, the
Agency believes the RfD has an adequate margin of protection for infants and
children. The percent RfD utilized by imazapyr is less than 1% for nursing
infants (less than 1 year old), and for non-nursing infants and children 1 to
6 years old. EPA concluded that there is reasonable certainty that no harm
will occur to infants and children from aggregate exposure to imazapyr.
VII. Other Considerations
1. Endocrine effects. No specific tests have been conducted with imazapyr to
determine whether the chemical may have an effect in humans that is similar to
an effect produced by a naturally occuring estrogen or other endocrine
effects. However, there were no significant findings in other relative
toxicity studies, i.e., teratology and multi- generation reproductive studies,
which would suggest that imazapyr produces endocrine related effects.
2. Data Gap. Additional storage stability data are required to support the 18
and 27 month storage stability tabulated data, including storage temperature,
analysis, raw data, representative chromatograms, and quality assurance (good
VIII. Objections and Hearing Requests
The new FFDCA section 408 (g) provides essentially the same process for
persons to "object" to a tolerance regulation issued by EPA under the new
section 408 (e) and (l)(6) as was provided in the old section 408 and section
409. However, the period for filing objections is 60 days rather than 30 days.
EPA currently has procedural regulations which governs the submission of
objections and hearing requests. These regulations will require some
modification to reflect the new law. However, until those modifications can be
made, EPA will continue to use those procedural regulations with appropriate
adjustments to reflect the new law.
Any person may, by June 9, 1997 file written objections to any aspect of this
regulation and may also request a hearing with the Hearing Clerk, at the
address given below (40 CFR 178.20). A copy of the objections and/or hearing
requests filed with the Hearing Clerk should be submitted to the OPP docket
for this rulemaking. The objections submitted must specify the provisions of
the regulation deemed objectionable and the grounds for the objections (40 CFR
178.25). Each objection must be accompanied by the fee prescribed by 40 CFR
180.33(i). If a hearing is requested, the objections must include a statement
of the factual issue(s) on which a hearing is requested, the requestor`s
contentions on each such issue, and a summary of any evidence relied upon by
the objector, (40 CFR 178.27). A request for a hearing will be granted if the
Administrator determines that the material submitted shows the following:
There is a genuine and substantial issue of fact; there is a reasonable
possibility that available evidence identified by the requestor would, if
established, resolve one or more of such issues in favor of the requestor,
taking into account uncontested claims or facts to the contrary; and
resolution of the factual issue(s) in the manner sought by the requestor would
be adequate to justify the action requested (40 CFR 178.32). Information
submitted in connection with an objection or hearing request may be claimed
confidential by marking any part or all of that information as "Confidential
Business Information" (CBI), Information marked as CBI will not be disclosed
except in accordance with procedures set forth in 40 CFR part 2. A copy of the
information 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.
IX. Public Docket
A record has been established for this rulemaking under the docket number
[OPP-300471] (including any comments and data submitted electronically). 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 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 22202.
Electronic comments can be sent directly to EPA at: firstname.lastname@example.org
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 any
copies of objections and hearing requests received electronically into
printed, paper form as they are received and will place the paper copies in
the official rule-making 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.
X. Regulatory Assessment Requirements
Under Executive Order 12866 (58 FR 51735, October 4, 1993), this action is not
a "significant regulatory action" and since this action does not impose any
information collection requirements subject to approval under the Paperwork
Reduction Act, 44 U.S.C. 3501 et seq., it is not subject to review by the
Office of Management and Budget. In addition, this action does not impose any
enforceable duty, or contain any "unfunded mandates" as described in Title II
of the Unfunded Mandates Reform Act of 1995 Pub.L. 104-4), or require prior
consultation as specified by Executive Order 12875 (58 FR 58093, October 28.
1993), or special considerations as required by Executive Order 12898 (59 FR
7629), February 16, 1994).
Because tolerances established on the basis of a petition under section 408(d)
of FFDCA do not require issuance of a proposed rule, the regulatory
flexibility analysis requirements of the Regulatory Flexibility Act (RFA), 5
U.S.C. 604(a), do not apply. Prior to the recent amendment of the FFDCA, EPA
had treated such rulemakings as subject to the RFA; however, the amendments to
the FFDCA clarify that no proposal is required for such rulemakings and hence
that the RFA is inapplicable. Nonetheless, the Agency has previously assessed
whether establishing tolerances or exemptions from tolerance, raising
tolerance levels, or expanding exemptions adversely impact small entities and
concluded, as a generic matter, that there is no adverse impact. (46 FR 24950,
May 4, 1981).
Under 5 U.S.C. 801(a)(1)(A) of the Administrative Procedure Act (APA) as
amended by the Small Business Regulatory Enforcement Fairness Act of 1996
(Title II of Pub. L. 104-121, 110 Stat. 847), EPA submitted a report
containing this rule and other required information to the U.S. Senate, the
U.S. House of Representatives and the Comptroller General of the General
Accounting Office prior to publication of the rule in today's Federal
Register. This rule is not a "major rule" as defined by 5 U.S.C. 804(2) of the
APA, as amended.
List of Subjects in 40 CFR Part 180
Environmental protection, Administrative practice and procedure, Agriculatural
commodities, Pesticides and pest, Reporting and recordkeeping requirements.
Dated: March 31, 1997.
Daniel M. Barolo,
Director, Office of Pesticide Programs.
Therefore, 40 CFR part 180 is amended as follows: 1. The authority citation
for part 180 continues to read as follows:
Authority: 21 U.S.C. 346a. and 371.
2. By adding Sec. 180.500 to read as follows:
Sec. 180.500 Imazapyr; tolerances for residues.
Tolerances are being established for residues of the herbicide imazapyr, [2-
pyridinecarboxylic acid], applied as the acid or ammonium salt, in or on the
following raw agricultural commodities:
Corn, field, forage (silage)............................... 0.05
Corn, field, grain......................................... 0.05
Corn, field, stover........................................ 0.05