[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]


-----------------------------------------------------------------------

ENVIRONMENTAL PROTECTION AGENCY
[PF-705; FRL-5585-6]


Bayer Corporation; Pesticide Tolerance Petition Filing

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice of Filing.

-----------------------------------------------------------------------

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: [email protected]. 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: 
[email protected].
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:
    [email protected]


    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