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Tolylfluanid (Bayer). August 11, 1997. Petition to Establish Import Tolerances for residues of the fungicide in or on apples and grapes at 5.0 ppm, hops at 30 ppm and tomatoes at 1.0 ppm. Federal Register.
http://www.epa.gov/fedrgstr/EPA-PEST/1997/August/Day-11/p21147.htm
[Federal Register: August 11, 1997 (Volume 62, Number 154)]
[Notices]
[Page 42980-42986]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr11au97-65]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-755; FRL-5736-1]
Notice of Filing of Pesticide Petitions
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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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 food commodities.
DATES: Comments, identified by the docket control number PF-755, must
be received on or before September 10, 1997.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch (7506C), Information Resources and Services
Division, 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 below:
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Office location/
Product Manager telephone number Address
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George LaRocca (PM 13)........ Rm. 204, CM #2, 703- 1921 Jefferson
305-6100, e-mail: Davis Hwy,
larocca.george@epamai Arlington, VA
l.epa.gov.
Mary Waller, Acting (PM 21)... Rm. 265, CM #2, 703- Do.
308-9354, e-mail:
waller.mary@epamail.e
pa.gov.
[[Page 42981]]
James Tompkins, Acting (PM 25) Rm. 239, CM #2, 703- Do.
305-5697, e-mail:
tompkins.jim@epamail.
epa.gov.
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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 food
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 granting 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-755] (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:
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. 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 [PF-755] and appropriate petition
number. Electronic comments on this notice 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: August 1, 1997.
Peter Caulkins,
Acting Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
Petitioner summaries of the pesticide petitions are printed below
as required by section 408(d)(3) of the FFDCA. The summaries of the
petitions were prepared by the petitioners and represent the views of
the petitioners. EPA is publishing the petition summaries verbatim
without editing them in any way. 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.
1. Bayer Corporation
PP 7E4825
EPA has received a pesticide petition (PP 7E4825) from Bayer
Corporation, 8400 Hawthorn Road, Kansas City, MO 64120, proposing
pursuant to section 408(d) of the Federal Food, Drug and Cosmetic Act,
21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing import
tolerances for residues of the fungicide Tolylfluanid in or on the raw
agricultural commodities apples and grapes at 5.0 parts per million
(ppm), hops at 30 ppm and tomatoes at 1.0 ppm. EPA has determined that
the petition contains data or information regarding the elements set
forth in section 408(d)(2) of the FFDCA; 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.
A. Residue Chemistry
1. Plant metabolism. Plant metabolism studies were conducted using
radiolabeled tolylfluanid applied to apples, grapes, and strawberries.
Unchanged parent tolylfluanid was the major metabolite identified in
these studies.
2. Analytical method. Bayer has developed an analytical method for
the determination of tolylfluanid residues in raw agricultural and
processed commodities of apples, grapes, tomatoes, and hops. Samples
are analyzed by gas chromatography using thermionic nitrogen-phosphorus
detector or flame photometric detector following extraction,
filtration, and cleanup procedures. The limit of quantitation is 0.02
mg/kg for all matrices, except it is 0.05 mg/kg for raisins and wet
apple pomace, 0.5 mg/kg for green hop cones, and 1.0 mg/kg for dried
hop cones.
3. Magnitude of residues. Bayer has conducted over 90 residue field
trials in seven countries on apples, grapes, tomatoes, and hops.
Residues of tolylfluanid in or on grapes harvested 14, 21 or 35 days
following treatment according to recommended practices ranged from 0.03
mg/kg to 3.45 mg/kg, except residues of tolylfluanid were 5.08 mg/kg in
one sample from a trial conducted in Spain. Residues of tolylfluanid
ranged from 0.03 mg/kg to 0.66 mg/kg in tomatoes harvested 3 or 7 days
following multiple applications with tolylfluanid. Residues of
tolylfluanid ranged from 0.14 to 2.31 mg/kg in or on apples harvested 7
days after multiple applications with tolylfluanid. Residues of
tolylfluanid in or on hops harvested 14 days following multiple
applications ranged from 3.31 mg/kg to 27.0 mg/kg (dried cone) and
ranged from 3.8 mg/kg to 17.6 mg/kg (green cone).
Studies have also been conducted to evaluate the potential for
concentration of tolylfluanid residues during the processing of apples,
grapes, and tomatoes. Tolylfluanid does not have the potential to
concentrate in the EPA required processed commodities consumed by
humans for apples, grapes and tomatoes. Residues of tolylfluanid may
have the potential to concentrate in wet apple pomace, an animal feed
item.
B. Toxicological Profile
1. Acute toxicity. Tolylfluanid exhibits low acute oral, dermal,
and inhalation toxicity (LD<INF>50s</INF> >5,000 mg/kg b.w.). An acute
neurotoxicity study showed no specific evidence of neurotoxicity; non-
specific signs of toxicity were observed in this study (in females
only) at doses at and greater than 150 mg/kg b.w. Tolylfluanid is a
severe dermal irritant, moderately irritating to the eye, and a skin
sensitizer. Tolylfluanid showed no systemic toxicity following subacute
dermal administration, but did cause dermal irritation. Effects seen in
the acute as well as subacute inhalation
[[Page 42982]]
study indicate tolylfluanid is a strong respiratory irritant.
2. Genotoxicity. The genotoxic potential of tolylfluanid was
assessed in several in vivo and in vitro studies. The weight-of-the-
evidence indicates that tolylfluanid is not genotoxic.
3. Reproductive and developmental toxicity. Tolylfluanid showed no
evidence of developmental toxicity based on two rat developmental
toxicity studies. Tolylfluanid showed evidence of developmental effects
in rabbits but only at a maternally toxic dose level.
Two complete 2-generation reproductive toxicity studies in rats and
one supplementary 2-generation reproductive toxicity rat study have
been conducted on tolylfluanid. Reproductive toxicity (decreased body
weight development in pups and decreased number of pups born, birth
weight, litter size, and lactation index) was noted only in the
presence of parental toxicity (decreased body weight gain, organ weight
changes, and hyperostosis of the crania).
4. Subchronic toxicity. Subchronic toxicity studies have been done
with tolylfluanid in rats and dogs. Decreased body weight gain,
decreased liver enzymes, slightly increased relative liver weights, and
thyroid toxicity were noted in a subchronic rat dietary study (no
correlating histopathological findings). Decreased body weight gain,
increased liver enzyme activity, slightly increased relative liver
weights, and increased PAS staining in the liver occurred in a
subchronic dietary dog study. A subchronic neurotoxicity study in rats
showed no evidence of neurotoxicity.
5. Chronic toxicity. Chronic toxicity studies on tolylfluanid were
done in the rat, mouse and dog. Tolylfluanid was tested in two rat
chronic dietary studies. Increased growth of the incisors of the upper
jaw and skeletal changes (hyperostosis in the skull and ribs) resulted
from the high fluorine content of the compound. Hepatotoxicity and
renal toxicity were seen in rats, mice, and dogs. Hepatotoxicity was
evidenced by hepatocellular cytoplasmic changes, vacuolation, and focal
fatty changes in rats, hepatocellular hypertrophy and single cell
necrosis in mice, decreased liver enzymes in rats, and increased liver
enzymes in mice and dogs. Renal toxicity (microscopic kidney lesions,
increased relative kidney weights, effects on urinalysis parameters)
was probably attributable to the effects of fluoride on renal tubules.
A second chronic toxicity study in dogs is currently ongoing (results
not yet available).
6. Oncogenicity. Tolylfluanid showed no evidence of direct
oncogenic activity in rats or mice. In rats tolylfluanid altered
thyroid hormone levels and an increased incidence of hyperplastic and
neoplastic lesions of the thyroid (primarily adenomas) in rats was
observed. The thyroid neoplasia is considered to be a secondary
(thresholdable) effect to altered thyroidal iodine metabolism and does
not suggest a direct oncogenic effect. No treatment-related neoplasms
were seen in the mouse oncogenicity study.
Based on the chronic toxicity data, Bayer believes the RfD for
tolylfluanid is 0.08 mg/kg, based on the no observed adverse effect
level (NOAEL) of 8 mg/kg b.w./day for parental and reproductive
toxicity identified in the second 2-generation rat reproductive
toxicity study (Pinckel and Ricke, 1995) and an uncertainty factor of
100. No unique concern for toxicity to infants and children was
identified, therefore an additional safety factor is not warranted.
(Note there is a seven-fold difference between the NOAEL and lowest
effect level (LEL).
Using the Guidelines for Carcinogenic Risk Assessment published in
September 1986, we believe the Agency will classify tolylfluanid as a
Group C carcinogen (possible human carcinogen) based on benign thyroid
tumors seen in the chronic rat studies). Mechanistic studies with
tolylfluanid have shown that these tumors are induced through a
nonlinear threshold mechanism similar to that discussed in EPA's
thyroid policy document. Therefore, tolylfluanid should be regulated
using the margin of exposure approach.
7. Animal metabolism. Metabolism studies were conducted using hens
and goats. No residues of parent tolylfluanid were detected in any
tissues, organs, milk, or eggs. Tolylfluanid is metabolized and
excreted rapidly and efficiently in mammals.
C. Aggregate Exposure
1. Dietary exposure. Food and drinking water/non-dietary exposure.
2. Food. A chronic dietary exposure analysis was conducted for
tolylfluanid. The reference dose (RfD) was 0.08 mg/kg/day based on a
NOEL of 8 mg/kg/day and an uncertainty factor of 100. The no observed
effect level (NOEL) was obtained from the rat reproduction study and
the effect was decreased pup viability and decreased body weights.
The RfD could change based on the NOEL from a repeat chronic dog
toxicity study which is currently ongoing (doses tested: 5, 20, and 80
mg/kg/day). The final report for this study is expected to be completed
in the second part of 1997. If necessary, revising the RfD will be
addressed at that time.
Tolylfluanid does not have the potential to concentrate in
processed commodities consumed by humans. The proposed MRLs for the
respective crops were used for the raw agricultural and processed
commodities for grapes (5 mg/kg), tomatoes, (1 mg/kg), and hops (30 mg/
kg). The anticipated residue level for fresh apples and apple juice was
calculated by adjusting the proposed MRL for apples (5 mg/kg) for the
percentage of fresh apples (4.8%) and apple juice (59.7%) consumed in
the U.S. that are imported. No adjustments were made for the
anticipated residue levels for grapes, tomatoes and hops.
The results of the chronic dietary exposure analysis for the
overall U.S. population and the three most highly exposed population
subgroups are summarized as follows.. The exposure estimate was
compared against the RfD of 0.08 mg/kg. The theoretical maximum residue
contribution (TMRC) as percentage of the RfD, was 9.53% for the U.S.
population, 53.36% for non-nursing infants, 38.02% for nursing infants
(0-1 yr old), and 26.16% for children (1-6 yrs old). The anticipated
residue contribution (ARC) as percentage of the RfD was 5.97% for the
U.S. population, 23.29% for non-nursing infants, 15.41% for nursing
infants and 15.10% for children. As seen above, chronic dietary
exposure to tolylfluanid is less than 24% of the RfD for even the most
highly exposed subgroup. In addition, these exposure estimates greatly
over estimate the anticipated risk for the following reasons: (1) a
relatively small percentage of these crops will be treated with
tolylfluanid; (2) a small percentage of the treated crops are imported
to the U.S.; (3) a small percentage of the total U.S. consumption of
these crops are imported products; and (4) the actual residues in the
imported commodities will likely be below the proposed MRLs.
3. Drinking water. Tolylfluanid residue levels in tap water, non-
tap water, and water in commercially prepared food were assumed to be
zero because tolylfluanid is not registered for use in the United
States and therefore, the only exposure is from the importation of
tolylfluanid-treated commodities.
4. Non-dietary exposure. Tolylfluanid is not registered in the
United States, therefore there is no non-occupational, structural or
residential exposure.
D. Cumulative Effects
Tolylfluanid is a fungicide that is somewhat structurally similar
to
[[Page 42983]]
Captan, and appears to share a common mechanism of fungicidal action
with this product. However, tolylfluanid does not show a similar
mammalian toxicity profile to Captan, which has been reported to
produce mouse gastrointestinal tumors and male rat kidney tumors. No
significant cumulative toxicity to mammals based on a common mechanism
of action to that of Captan is anticipated for tolylfluanid.
Tolylfluanid alters the thyroid hormone balance, but: (1) no data
exist showing specifically how tolylfluanid causes thyroid changes; (2)
tolylfluanid is not known to be structurally similar to other thyroid
tumorigens; (3) no common mechanism has been established or proposed
and (4) even if it is eventually determined that the mechanism for
thyroid tumorigenesis may be similar to other classes of pesticides,
this endpoint is seen with tolylfluanid only at very high exposure
levels. If an RfD for tolylfluanid were based on dose levels at which
thyroid hormone levels were altered, a very low impact on a cumulative
risk cup would be anticipated because the potency of tolylfluanid is
very low.
Endocrine effects. Endocrine-related effects of tolylfluanid
exposure appear to be limited to the thyroid. No evidence of estrogenic
or anti-estrogenic activity was present in the available animal
studies. The developmental toxicity and reproductive toxicity studies
showed no effects suggesting endocrine disruption, (e.g., change in
fetal sex ratios, change in estrous cycles or mating performance,
change in fertility, or malformed or altered reproductive organ
development).
E. Safety Determination
1. U.S. population. A chronic dietary exposure analysis was
conducted for tolylfluanid. The chronic dietary exposure to
tolylfluanid is 5.97% of the RfD for the U.S. population, using the
ARC.
2. Infants and children. A chronic dietary exposure analysis was
conducted for tolylfluanid. The chronic dietary exposure to
tolylfluanid is 23.29% of the RfD for non-nursing infants, the most
highly exposed group, using the ARC.
F. International Tolerances
The current Codex tolerances for tolylfluanid are based on residues
of parent only. The Codex tolerances are: 5 mg/kg for currents (black,
red, and white), 2 mg/kg for Gherkins, 1 mg/kg for head lettuce, 5 mg/
kg for pome fruits, 3 mg/kg for strawberries, and 2 mg/kg for tomatoes.
(Mary Waller)