Tebuconazole - Pesticide Tolerance Petition 3/97
Notice of Filing of Pesticide Petitions
AGENCY: Environmental Protection Agency (EPA).
SUMMARY: This notice announces the initial filing of pesticide petitions
proposing the establishment of regulations for residues of certain pesticide
chemicals in or on various agricultural commodities. DATES: Comments,
identified by the docket control number PF-723, must be received on or before
May 2, 1997.
ADDRESSES: By mail submit written comments to: Public Response and Program
Resources Branch, Field Operations Divison (7505C), Office of Pesticides
Programs, Environmental Protection Agency, 401 M St., SW., Washington, DC
20460. In person bring comments to: Rm. 1132, CM #2, 1921 Jefferson Davis
Highway, Arlington, VA.
Comments and data may also be submitted electronically by following the
instructions under "SUPPLEMENTARY INFORMATION." No confidential business
information should be submitted through e-mail.
Information submitted as a comment 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 p.m., Monday through Friday,
excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: The product manager listed in the table
Product Manager telephone number Address
Connie Welch (PM 21) 703-305-6226 Rm. 227, CM #2,
e-mail: 1921 Jefferson
email@example.com Davis Hwy,
Cynthia Giles-Parker (PM 22) Rm. 229, CM #2,
SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as follows
proposing the establishment and/or amendment of regulations for residues of
certain pesticide chemicals in or on various raw agricultural commodities
under section 408 of the Federal Food, Drug, and Comestic Act (FFDCA), 21
U.S.C. 346a. EPA has determined that these petitions contain data or
information regarding the elements set forth in section 408(d)(2); however,
EPA has not fully evaluated the sufficiency of the submitted data at this time
or whether the data supports grantinig of the petition. Additional data may be
needed before EPA rules on the petition.
The official record for this notice of filing, as well as the public version,
has been established for this notice of filing under docket control number PF-
723 (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 p.m., Monday through Friday,
excluding legal holidays. The official record is located at the address in
"ADDRESSES" at the beginning of this document.
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. Comment 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
(insert docket number) and appropriate petition number. Electronic comments on
this proposed rule may be filed online at many Federal Depository Libraries.
List of Subjects
Environmental protection, Agricultural commodities, Food additives, Feed
additives, Pesticides and pests, Reporting and recordkeeping requirements.
Dated: March 24, 1997.
Stephen L. Johnson,
Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
Below summaries of the pesticide petitions are printed. The summaries of the
petitions were prepared by the petitioners. The petition summary announces the
availability of a description of the analytical methods available to EPA for
the detection and measurement of the pesticide chemical residues or an
explanation of why no such method is needed.
EPA has received a pesticide petition (PP) 5F4577 from Bayer Corporation, 8400
Hawthorn Rd., P.O. Box 4913, 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 raw agricultural commodities grass
forage at 8.0 ppm and grass hay at 25.0 ppm and tolerances for residues of the
fungicide tebuconazole in or on the raw agricultural commodities cattle liver
at 0.2 ppm, cattle kidney at 0.2 ppm, cattle meat byproducts at 0.2 ppm, and
milk at 0.1 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. (PM 21)
Tebuconazole is a sterol demethylation inhibitor (DMI) fungicide. It is
systemic and shows activity against rusts (Puccinia spp.) and powdery mildew
infecting grasses grown for seed. Tebuconazole provides protective activity by
preventing completion of the infection process. It is rapidly absorbed by
plants and is translocated systemically in the young growing tissues.
A. Residue Chemistry
1. Plant and livestock metabolism. 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. Bayer has submitted 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 grasses grown for seed. 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. Nine separate residue trials have been conducted and
submitted to the EPA with tebuconazole on grasses grown for seed. The EPA has
determined that these data show that residues of tebuconazole,alpha-[2-(4-
Chlorophenyl)ethyl]-alpha-(1,1- dimethylethyl)-H-1,2,4-triazole-1-eth anol,
are not expected to exceed 8 ppm in grass forage and 25 ppm in grass hay as a
result of the proposed use. In addition, the EPA has determined that
tolerances are needed for the following animal commodities: cattle liver,
kidney and meat byproducts at 0.2 ppm and milk at 0.1 ppm. The tolerance
expression for the animal commodities will include the HWG 2061
dimethyl)ethyl]-1H-1,2,4triazole-1-ethanol, in addition to the parent.
No processed commodities are associated with the proposed use on grasses grown
for seed. In addition, due to the nature of the crop, rotational crops will
not be an issue.
B. Toxicological Profile of Tebuconazole
1. Acute toxicity.
i. Rat acute oral study with an LD50 of > 5,000 mg/kg (male) and 3,933 mg/kg
ii. Rabbit acute dermal of LD50 of > 5,000 mg/kg
iii. Rat acute inhalation of LC50 of > 0.371 mg/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
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 mg/mL without activation or 15 to 120 mg/mL
iv. An unscheduled DNA synthesis (UDS) study was negative for UDS in rat
3. Reproductive and developmental toxicity.
i. A rat oral developmental toxicity study with a maternal NOEL of 30
milligrams per kilogram of body weight per day (mg/kg bwtt/day) and an LEL of
60 mg/kg bwtt/day based on elevation of absolute and relative liver weights.
For developmental toxicity, a NOEL of 30 mg/kg bwtt/day and an LEL of 60 mg/kg
bwtt/day was determined, based on delayed ossification of thoracic, cervical
and sacral vertebrae, sternum, fore and hind limbs and increase in
ii. A rabbit oral developmental toxicity study with a maternal NOEL of 30
mg/kg bwt/day and an LEL of 100 mg/kg bwt/day based on depression of body
weight gains and food consumption. A developmental NOEL of 30 mg/kg bwt/day
and an LEL of 100 mg/kg bwt/day were based on increased post-implantation
losses, from both early and late resorptions and frank malformations in eight
fetuses of five litters.
iii. A mouse oral developmental toxicity study with a maternal NOEL of 10
mg/kg bwt/day and an LEL of 20 mg/kg bwt/day based on a supplementary study
indicating reduction in hematocrit and histological changes in liver. A
developmental NOEL of 10 mg/kg bwt/day and an LEL of 30 mg/kg bwt/day based on
dose-dependent increases in runts/dam at 30 and 100 mg/kg bwt/day.
iv. A mouse dermal developmental toxicity study with a maternal NOEL of 30
mg/kg bwt/day and an LEL of 60 mg/kg bwt/day based on a supplementary study
indicating increased liver microsomal enzymes and histological changes in
liver. The NOEL for developmental toxicity in the dermal study in the mouse is
1,000 mg/kg bwt/day, the highest dose tested (HDT).
v. A two-generation rat reproduction study with a dietary maternal NOEL of 15
mg/kg bwt/day (300 ppm) and an LEL of 50 mg/kg bwt/day (1,000 ppm) based on
depressed body weights, increased spleen hemosiderosis, and decreased liver
and kidney weights. A reproductive NOEL of 15 mg/kg bwt/day (300 ppm) and an
LEL of 50 mg/kg bwt/day (1,000 ppm) were based on neonatal birth weight
4. Subchronic toxicity.
i. 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
ii. A 90-day rat feeding study with a no-observed-effect level (NOEL) of 34.8
(mg/kg bwt/day) (400 ppm) and a lowest-effect-level (LEL) of 171.7 mg/kg
bwt/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
bwt/day (100 ppm) and the LEL was 46.5 mg/kg bwt/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 bwt/day in
males and 73.4 mg/kg bwt/day in females) and an LEL of 1,000 ppm (368.3 mg/kg
bwt/day in males and 351.8 mg/kg bwt/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 bwt/day (100
ppm) and an LEL of 22.8 mg/kg bwt/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 bwt/day (40 ppm) and an
LEL of 5 mg/kg bwt/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%
excreted by the feces and urine and 0.0304% 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, alpha-
[2-(4 -Chlorophenyl)-ethyl]-alpha-[(2- hydroxy-1,1-dimethyl)ethyl]-1H-
1,2,4triazole-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 highest dose tested.
C. Aggregate Exposure
1. Dietary (food) exposure. For purposes of assessing the potential dietary
exposure from food under the proposed tolerances, Bayer has been advised that
the EPA 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 milk at 0.1 ppm and
cattle liver, kidney and meat byproducts at 0.2 ppm. The TMRC is obtained by
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, the EPA has made
very conservative assumptions--100% 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, the Agency 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
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, Bayer concludes that tebuconazole bears no apparent risk to ground
water under most circumstances.
3. Non-dietary exposure. Although current registrations and the proposed use
for grasses grown for seed 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 (MOE) of 1,518 - 8,561 for 10-year-old children
and 1,364 - 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 - 27.3 mg/ cm2 and for 5-year-old children from 4.4 -
24.0 mg/ cm2. This compares with the average tebuconazole transferable residue
level of 0.319 mg/cm2 present immediately after the sprays have dried. Bayer
concludes that 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, Bayer has considered only the
potential risks of tebuconazole in its aggregate exposure.
E. Safety Determination
1. U.S. population. Chronic Dietary Exposure: 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 been advised that the EPA has concluded that
aggregate dietary exposure to tebuconazole from the previously established and
the proposed tolerances will utilize 5.1 % of the RfD for the U.S. population
(48 states) and 30.7% of the RfD for the most highly exposed population
subgroup (non-nursing infants, <1 year old). There is generally no concern for
exposures below 100 % 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, Bayer concludes that there is a reasonable
certainty that no harm will result from aggregate exposure to tebuconazole.
2. Acute dietary exposure. EPA recently proposed a tiered approach to estimate
acute dietary exposure. The methods proposed by the EPA were reviewed and
supported by the FIFRA Scientific Advisory Panel (SAP, 1995). EPA's Tier 1
method is based on the assumption that residue concentrations do not vary. The
analysis assumes that all residues have the same magnitude, typically the
highest field trial residue or tolerance value. This value is assumed for all
points along the consumption distribution, resulting in a distribution of
dietary exposure. Bayer has been advised that the EPA conducted an acute
dietary analysis using the NOEL of 10 mg/kg/day for developmental toxicity in
the mouse. The EPA has calculated a high end Margin of Exposure (MOE) value of
1,000 for the population subgroup of concern (females 13+). In addition, Bayer
has calculated 95th percentile MOE for the following population groups:
overall U.S. population (MOE = 2,528), infants (MOE = 711), children 1 to 6
years of age (MOE = 1,145), females 13 years and older (MOE = 4,285), and
males 13 years and older (MOE = 3,685). Therefore, since EPA considers values
of 100 or more satisfactory, there is no concern from acute dietary exposure.
3. 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 rat and rabbit and a two-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. 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/bwtt 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 bwt/day) and rabbits (30 mg/kg
bwt/day) by a factor of 10 times. Since a hundredfold 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/bwtt/day is
appropriate for assessing aggregate risk to infants and children. Using the
conservative exposure assumptions, Bayer has concluded from the EPA's recent
chronic dietary analysis that the percent of the RfD utilized by aggregate
exposure to residues of tebuconazole ranges from 14.2% for children 1 to 6
years old up to 30.7% for non-nursing infants. EPA generally has no concern
for exposure below 100 % 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-
F. International Issues
No CODEX Maximum Residue Levels (MRLs) have been established for residues of
tebuconazole on any crops at this time. Data have not been submitted to the
Joint Meeting of the Food and Agriculture Organization Panel of Experts on
Pesticide Residues in Food and the Environment and the World Health
Organization Expert Group on Pesticide Residues (JMPR) to establish Codex MRLs
for grasses grown for seed.
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 rusts
(Puccinia spp.) and powdery mildew infecting grasses grown for seed.
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.
[FR Doc. 97-8397 Filed 4-1-97; 8:45 am]