[Federal Register Volume 62, Number 43 (Wednesday, March 5, 1997)]
[Notices]
[Pages 10047-10050]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-5200]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-705; FRL-5585-6]
Bayer Corporation; Pesticide Tolerance Petition Filing
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice of Filing.
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SUMMARY: This notice announces the filing of a pesticide petition
proposing the establishment of a tolerance for residues of tebuconazole
in or on grapes. This notice contains a summary of the petition that
was prepared by the petitioner, Bayer Corporation.
DATES: Comments, identified by the docket control number PF-705 must be
received on or before April 4, 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, DC 20460. In person, bring comments to: Rm. 1132, Crystal
Mall #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 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 control number PF-705. Electronic comments on this notice may be
filed online at many Federal Depository Libraries. Additional
information on electronic submissions can be found below in this
document.
Information submitted as a comment concerning this notice may be
claimed confidential by marking any part or all of that information as
``Confidential Business Information'' (CBI). No CBI should 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 p.m., Monday through Friday, excluding legal
holidays.
FOR FURTHER INFORMATION CONTACT: Connie B. Welch, Product Manager (PM)
21, 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. 227, CM #2,
1921 Jefferson Davis Highway, Arlington, VA, (703) 305-6226; e-mail:
welch.connie@epamail.epa.gov.
SUPPLEMENTARY INFORMATION: EPA has received a pesticide petition (PP)
6F4669 from Bayer Corp., P.O. Box 4913, 8400 Hawthorne Road, Kansas
City, MO 64120-0013, proposing pursuant to section 408(d) of the
Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a, to amend
40 CFR 180.474 by establishing tolerances for residues of the fungicide
tebuconazole in or on the agricultural commodity grapes at 5.0 ppm. The
proposed analytical method for determining residues uses gas-liquid
chromatography coupled with a thermionic detector. EPA has determined
that the petition contains 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.
As required by section 408(d) of the FFDCA, as recently amended by
the Food Quality Protection Act, (Pub. L. 104-170), Bayer included in
the petition a summary of the petition and authorization for the
summary to be published in the Federal Register in a notice of receipt
of the petition. The summary represents the views of Bayer; EPA is in
the process of evaluating the petition. As required by section
408(d)(3) EPA is including the summary as a part of this notice of
filing. EPA may have made minor edits to the summary for the purpose of
clarity.
I. Petition Summary
A. Residue Chemistry
1. Nature of residue. Bayer believes the nature of the residue in
plants and animals is adequately understood. The residue of concern is
the parent compound only, as specified in 40 CFR 180.474.
2. Analytical method. An enforcement method for plant commodities
has been validated on various commodities. It has undergone successful
EPA validation and has been submitted for inclusion in PAM II. The
method should be adequate for grapes. The animal method has also been
approved as an adequate enforcement method and will be submitted to FDA
for inclusion in PAM II.
3. Magnitude of residue. Fifteen separate residue trials have been
conducted and submitted to the EPA with tebuconazole on grapes. The EPA
has determined that these data show that residues of tebuconazole,
-[2-(4 -Chlorophenyl)ethyl]--(1,1-dimethylethyl)-H-
1,2,4-triazole-1-ethanol, are not expected to exceed 5 ppm in grapes as
a result of the proposed use. Processing data show that residue of
tebuconazole do not concentrate in grape juice and that a tolerance is
not required in or on raisins. In addition, since grapes are not
normally rotated, the nature of residue in rotational crops is not of
concern.
B. Toxicological Profile
The following mammalian toxicity studies have been conducted to
support the tolerances of tebuconazole:
1. Acute toxicity. i. Rat acute oral study with an LD50 of
>5,000 milligrams/kilogram (mg)/(kg) (male) and 3,933 mg/kg (female).
ii. Rabbit acute dermal of LD50 of >5,000 mg/kg.
iii. Rat acute inhalation of LC50 of >0.371 mg/liter(l).
iv. Primary eye irritation study in the rabbit which showed mild
irritation reversible by day 7.
v. Primary dermal irritation study which showed no skin irritation.
vi. Primary dermal sensitization study which showed no
sensitization.
2. Genotoxicity. i. An Ames mutagenesis study in Salmonella showed
no mutagenicity with or without metabolic activation.
ii. A micronucleus mutagenesis assay study in mice showed no
genotoxicity.
iii. A sister chromatid exchange mutagenesis study using CHO cells
was negative at dose levels 4 to 30 micrograms/milliliter (g/
mL) without activation or 15 to 120 g/mL with activation.
iv. An unscheduled DNA synthesis (UDS) study was negative for UDS
in rat hepatocytes.
3. Reproductive and developmental toxicity. i. A rat oral
developmental toxicity study with a maternal no
[[Page 10048]]
observed effect level (NOEL) of 30 milligrams per kilogram of body
weight per day (mg/kg bw/day) and an lowest effect level (LEL) of 60
mg/kg bw/day based on elevation of absolute and relative liver weights.
For developmental toxicity, a NOEL of 30 mg/kg bw/day and an LEL of 60
mg/kg bw/day was determined, based on delayed ossification of thoracic,
cervical and sacral vertebrae, sternum, fore and hind limbs and
increase in supernumerary ribs.
ii. A rabbit oral developmental toxicity study with a maternal NOEL
of 30 mg/kg bw/day and an LEL of 100 mg/kg bw/day based on depression
of body weight gains and food consumption.
iii. A developmental NOEL of 30 mg/kg bw/day and an LEL of 100 mg/
kg bw/day were based on increased post-implantation losses, from both
early and late resorptions and frank malformations in eight fetuses of
five litters.
iv. A mouse oral developmental toxicity study with a maternal NOEL
of 10 mg/kg bw/day and an LEL of 20 mg/kg bw/day based on a
supplementary study indicating reduction in hematocrit and histological
changes in liver.
v. A developmental NOEL of 10 mg/kg bw/day and an LEL of 30 mg/kg
bw/day based on dose-dependent increases in runts/dam at 30 and 100 mg/
kg bw/day.
vi. A mouse dermal developmental toxicity study with a maternal
NOEL of 30 mg/kg bw/day and an LEL of 60 mg/kg bw/day based on a
supplementary study indicating increased liver microsomal enzymes and
histological changes in liver.
vii. The NOEL for developmental toxicity in the dermal study in the
mouse is 1,000 mg/kg bw/day, the highest dose tested (HDT).
viii. A 2-generation rat reproduction study with a dietary maternal
NOEL of 15 mg/kg bw/day (300 ppm) and an LEL of 50 mg/kg bw/day (1,000
ppm) based on depressed body weights, increased spleen hemosiderosis,
and decreased liver and kidney weights.
ix. A reproductive NOEL of 15 mg/kg bw/day (300 ppm) and an LEL of
50 mg/kg bw/day (1,000 ppm) were based on neonatal birth weight
depression.
4. Subchronic toxicity. i. A 28-day feeding study in the rat with a
NOEL of 30 mg/kg/day and a LEL of 100 mg/kg/day based on changes in
hematology and clinical chemistry parameters.
ii. A 90-day rat feeding study with a NOEL of 34.8 mg/kg bw/day
(400 ppm) and an LEL of 171.7 mg/kg bw/day (1,600 ppm) in males, based
on decreased body weight gains and histological changes in the
adrenals. For females, the NOEL was 10.8 mg/kg bw/day (100 ppm) and the
LEL was 46.5 mg/kg bw/day (400 ppm) based on decreased body weights,
decreased body weight gains, and histological changes in the adrenals.
iii. A 90-day dog-feeding study with a NOEL of 200 ppm (73.7 mg/kg
bw/day in males and 73.4 mg/kg bw/day in females) and an LEL of 1,000
ppm (368.3 mg/kg bw/day in males and 351.8 mg/kg bw/day in females).
The LEL was based on decreases in mean body weights, body weight gains,
and food consumption, and an increase in liver N-demethylase activity.
5. Chronic toxicity. i. A 2-year rat chronic feeding study defined
a NOEL of 7.4 mg/kg bw/day (100 ppm) and an LEL of 22.8 mg/kg bw/day
(300 ppm) based on body weight depression, decreased hemoglobin,
hematocrit, MCV and MCHC, and increased liver microsomal enzymes in
females. Tebuconazole was not oncogenic at the dose levels tested (0,
100, 300, and 1,000 ppm).
ii. A 1-year dog feeding study with a NOEL of 1 mg/kg bw/day (40
ppm) and an LEL of 5 mg/kg bw/day (200 ppm), based on lenticular and
corneal opacity and hepatic toxicity in either sex (the current
Reference Dose was determined based on this study). A subsequent 1-year
dog feeding study, using lower doses to further define the NOEL for
tebuconazole, defines a systemic LOEL of 150 ppm (based on adrenal
effects in both sexes) and a systemic NOEL of 100 ppm.
iii. A mouse oncogenicity study at dietary levels of 0, 20, 60, and
80 ppm for 21 months did not reveal any oncogenic effect for
tebuconazole at any dose tested. Because the maximum-tolerated-dose
(MTD) was not reached in this study, the study was classified as
supplementary. A follow-up mouse study at higher doses (0, 500, and
1,500 ppm in the diet), with an MTD at 500 ppm, revealed statistically
significant incidences of hepatocellular adenomas and carcinomas in
males and carcinomas in females. The initial and follow-up studies,
together with supplementary data were classified as core minimum.
6. Animal metabolism. A general rat metabolism study at dietary
levels of 2 and 20 mg/kg showed rapid elimination from the rat in 3
days (some 99 percent excreted by the feces and urine and 0.0304
percent in expired air). Increased concentrations of radioactivity from
the active ingredient and metabolites were found only in the liver. The
bones and the brain were among the tissues showing the least amount of
radioactivity.
7. Metabolite toxicity. The residue of concern in plants is the
parent compound, tebuconazole, only. For animal commodities, the EPA
has determined that the tolerance expression should include the HWG
2061 metabolite, -[2-(4 -Chlorophenyl)-ethyl]--[(2-
hydroxy-1,1-dimethyl)ethyl]-1H-1,2,4-triazole-1-ethanol. An acute oral
toxicity study has been submitted to the EPA on this metabolite. This
study shows an oral LD50 of >5,000 for female rats. This value
indicates that the HWG 2061 metabolite is relatively innocuous and less
acutely toxic than tebuconazole.
8. Endocrine effects. No special studies investigating potential
estrogenic or endocrine effects of tebuconazole have been conducted.
However, the standard battery of required studies has been completed.
These studies include an evaluation of the potential effects on
reproduction and development, and an evaluation of the pathology of the
endocrine organs following repeated or long-term exposure. These
studies are generally considered to be sufficient to detect any
endocrine effects but no such effects were noted in any of the studies
with either tebuconazole or its metabolites.
9. Carcinogenicity. EPA's Carcinogenicity Peer Review Committee
(CPRC) has classified tebuconazole as a Group C carcinogen (possible
human carcinogen). This classification is based on the Agency's
``Guidelines for Carcinogen Risk Assessment'' published in the Federal
Register of September 24, 1986 (51 FR 33992). The Agency has chosen to
use the reference dose calculations to estimate human dietary risk from
tebuconazole residues. The decision supporting classification of
tebuconazole as a possible human carcinogen (Group C) was primarily
based on the statistically significant increase in the incidence of
hepatocellular adenomas, carcinomas, and combined adenomas/carcinomas
in both sexes of NMRI mice both by positive trend and pairwise
comparison at the HDT.
C. Aggregate Exposure
1. Dietary (food) exposure. For purposes of assessing the potential
dietary exposure from food under the proposed tolerances, Bayer has
estimated exposure based on the Theoretical Maximum Residue
Contribution (TMRC) derived from the previously established tolerances
for tebuconazole on cherries, peaches, bananas, barley, oats, wheat,
and peanuts as well as the proposed tolerances for tebuconazole on
grapes at 5.0 ppm. The TMRC is obtained by
[[Page 10049]]
using a model which multiplies the tolerance level residue for each
commodity by consumption data which estimate the amount of each
commodity and products derived from the commodities that are eaten by
the U.S. population and various population subgroups. In conducting
this exposure assessment, very conservative assumptions -- 100 percent
of all commodities will contain tebuconazole residues, and those
residues would be at the level of the tolerance -- which result in a
large overestimate of human exposure. Thus, in making a safety
determination for these tolerances, Bayer took into account this very
conservative exposure assessment.
2. Dietary (drinking water) exposure. There is no Maximum
Contaminant Level established for residues of tebuconazole. Bayer was
advised by the EPA's Environmental Fate and Ground Water Branch's
(EFGWB) May 26, 1993 memorandum for our application for use on bananas
and peanuts that all environmental fate data requirements for
tebuconazole were satisfied. The EFGWB had determined that tebuconazole
is resistant to most degradative processes in the environment,
including hydrolysis, photolysis in water and aerobic and anaerobic
metabolism. Only minor degradation occurred in soil photolysis studies.
The photolytic half-life of tebuconazole is 19 days. Laboratory and
field studies have shown that the mobility of tebuconazole in soil is
minimal. Therefore, tebuconazole bears no apparent risk to ground water
under most circumstances.
3. Non-dietary exposure. Although current registrations and the
proposed use on grapes are limited to commercial crop production, Bayer
has submitted an application to register tebuconazole on turf. Bayer
has conducted an exposure study designed to measure the upper bound
acute exposure potential of adults and children from contact with
tebuconazole treated turf. The population considered to have the
greatest potential exposure from contact with pesticide treated turf
soon after pesticides are applied are young children. Margins of
exposure of 1,518 to 8,561 for 10-year-old children and 1,364 to 7,527
for 5-year-old children were estimated by comparing dermal exposure
doses to the tebuconazole no-observable effect level of 1,000 mg/kg/day
established in a subacute dermal toxicity study in rabbits. The
estimated safe residue levels for tebuconazole on treated turf for 10-
year-old children ranged from 4.8 to 27.3 micrograms per square
centimeter (g/cm2) and for 5-year-old children from 4.4
to 24.0 g/cm2. This compares with the average
tebuconazole transferable residue level of 0.319 g/cm2
present immediately after the sprays have dried. These data indicate
that children can safely contact tebuconazole-treated turf as soon
after application as the spray has dried.
D. Cumulative Effects
At this time, the EPA has not made a determination that
tebuconazole and other substances that may have a common mechanism of
toxicity would have cumulative effects. Therefore, for this tolerance,
only the potential risks of tebuconazole in its aggregate exposure are
considered.
E. Safety Determination
1. U.S. population. Based on a complete and reliable toxicity
database, the EPA has adopted an RfD value of 0.03 mg/kg/day. This RfD
is based on a 1-year dog study with a NOEL of 2.96 mg/kg/day and an
uncertainty factor of 100. Using the conservative exposure assumptions
described above, Bayer has determined that aggregate dietary exposure
to tebuconazole from the previously established and the proposed
tolerances will utilize 7.1 percent of the RfD for the U.S. population
(48 states) and 29.5 percent of the RfD for the most highly exposed
population subgroup (children 1 to 6 years old). There is generally no
concern for exposures below 100 percent of the RfD because the RfD
represents the level at or below which daily aggregate exposure over a
lifetime will not pose appreciable risks to human health. Therefore,
there is a reasonable certainty that no harm will result from aggregate
exposure to tebuconazole.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of tebuconazole, the
data from developmental studies in both the rat and rabbit and a 2-
generation reproduction study in the rat should be considered. The
developmental toxicity studies evaluate any potential adverse effects
on the developing animal resulting from pesticide exposure of the
mother during prenatal development. The reproduction study evaluates
any effects from exposure to the pesticide on the reproductive
capability of mating animals through two generations, as well as any
observed systemic toxicity.
A developmental toxicity study in the rat, a developmental toxicity
study in the rabbit, two developmental studies in the mouse and a 2-
generation rat reproduction study have been conducted with
tebuconazole. Maternal and developmental toxicity NOELs of 30 mg/kg/day
were determined in the rat and rabbit studies. An oral mouse
developmental toxicity study had maternal and developmental toxicity
NOELs of 10 mg/kg/day while the mouse dermal developmental study had a
maternal NOEL of 30 mg/kg/day and a developmental toxicity NOEL of
1,000 mg/kg/day. The parental and reproductive NOELs in the 2-
generation rat reproduction study were determined to be 15 mg/kg/day
(300 ppm). In all cases, the reproductive and developmental NOELs were
greater than or equal to the parental NOELs. Bayer concludes that this
indicates that tebuconazole does not pose any increased risk to infants
or children.
FFDCA section 408 provides that EPA may apply an additional safety
factor for infants and children in the case of threshold effects to
account for pre-and post-natal effects and the completeness of the
toxicity database. Based on current toxicological data requirements,
the toxicology database for tebuconazole relative to pre-and post-natal
effects is complete. Further for tebuconazole, the NOEL of 2.96 mg/kg/
bw from the 1-year dog study, which was used to calculate the RfD, is
already lower than the NOELs from the developmental studies in rats (30
mg/kg bw/day) and rabbits (30 mg/kg bw/day) by a factor of 10 times.
Since a 100-fold uncertainty factor is already used to calculate the
RfD, Bayer surmises that an additional uncertainty factor is not
warranted and that the RfD at 0.03 mg/kg/bw/day is appropriate for
assessing aggregate risk to infants and children.
Using the conservative exposure assumptions, Bayer has determined
from a chronic dietary analysis that the percent of the RfD utilized by
aggregate exposure to residues of tebuconazole ranges from 9.2 percent
for children 7 to 12 years old up to 29.5 percent for children 1 to 6
years old. EPA generally has no concern for exposure below 100 percent
of the RfD. Therefore, based on the completeness and reliability of the
toxicity data and the conservative exposure assessment, Bayer concludes
that there is a reasonable certainty that no harm will result to
infants and children from aggregate exposure to the residues of
tebuconazole, including all anticipated dietary exposure and all other
non-occupational exposures.
F. International Issues
No Codex Maximum Residue Level (MRL) have been established for
residues of tebuconazole on any crops at this time. A Codex MRL of 2.0
ppm for residues of tebuconazole on grapes has been proposed. There are
no established tolerances for tebuconazole in or on grapes in Canada
and Mexico.
[[Page 10050]]
G. Mode of Action
Tebuconazole, the active ingredient of Folicur 3.6 F is a sterol
demethylation inhibitor (DMI) fungicide. It is systemic and shows
activity against powdery mildew and black rot infecting grapes.
Tebuconazole provides protective activity by preventing completion of
the infection process by direct inhibition of sterol synthesis. It is
rapidly absorbed by plants and translocated systemically in the young
growing tissues.
II. Public Record
EPA invites interested persons to submit comments on this notice of
filing. Comments must bear a notification indicating the docket control
number PF-705.
A record has been established for this notice docket under docket
control number PF-705 (including any 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 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
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 notice of filing, 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.
Dated: February 19, 1997.
Stephen L. Johnson,
Director, Registration Division, Office of Pesticide Programs.
[FR Doc. 97-5200 Filed 3-4-97; 8:45 am]
BILLING CODE 6560-50-F
