[Federal Register Volume 62, Number 154 (Monday, August 11, 1997)]
[Notices]
[Pages 42980-42986]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-21147]
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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:
[email protected]
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:
[email protected]
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 (LD50s >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)
2. DowElanco
PP 5E4571
EPA has received a pesticide petition (PP 5E4571) from DowElanco,
9330 Zionsville Road, Indianapolis, IN 46268-1054, 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 a tolerance for
residues of the herbicide, tebuthiuron and its related metabolites in
or on the food commodities refined sugar and molasses at 0.05 parts per
million (ppm) from treatment of sugarcane outside of the United States
with tebuthiuron. The proposed analytical method involves
homogenization, filtration, partition and cleanup with analysis by gas
liquid chromatography using flame photometric detection. 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. The metabolism of tebuthiuron has been
investigated in grasses. The residues of concern are the parent
compound and its metabolites 103 (OH) N-[5-(2-hydroxy-1,1-
dimethylethyl)-1,3,4-thiazol-2-yl]-N,N'dimethylurea, 104 N-[5-(1,1-
dimethylethyl)-1,3,4-thiazol-2-yl]-N-methylurea, and 109 N-[5-(1,1-
dimethylethyl)-1,3,4-thiazol-2-yl]-N'-hydroxymethyl-N-methylurea.
Tebuthiuron and its metabolites 104 and 109 have been identified in
sugarcane.
2. Analytical method. The method for enforcement of plant
commodities tolerances is a GLC method with flame photometric
detection. The stated detection limit for the parent compound and
metabolites 103 (OH), 104 and 109 is 0.01 ppm.
Enforcement methods for milk and meat have been developed by
DowElanco and have been submitted to the Agency as part of
reregistration. An adequate method (GC/flame photometric detection)
exists to determine tebuthiuron and some metabolites (104, 106, and
109) in milk and ruminant tissue. The new enforcement method is needed
to determine additional metabolites of toxicological concern.
3. Magnitude of residues. Commercial sugarcane samples were
collected from two major Brazilian sugarcane growing regions.
Tebuthiuron had been applied at rates ranging from 750 to 1,500 g ai/
ha. Most of the samples were collected approximately 12 months after
treatment. Analysis for tebuthiuron and metabolites 104 and 109
occurred within 60 days of sample collection. No residues of
tebuthiuron were found above the LOQ (0.01 ppm). In many samples there
was no detection of metabolites. In samples at one site treated with
1,250 g ai/ha, however, there were residues of the combined metabolites
at the LOQ.
B. Toxicological Profile
1. Acute toxicity. Tebuthiuron is classified as a Moderate
(Category II) acute toxicant based upon the acute oral LD50
value in the rat (387-477 mg/kg) and rabbit (286 mg/kg. The
LD50 for the dermal toxicity in the rabbit was greater than
the limit dose of 5,000 mg/kg. The acute inhalation LC50 in
the rabbit was greater than 3.696 mg/L. Tebuthiuron produced slight
irritation (slight conjunctival hyperemia at 1 hour post-treatment;
Category IV) and was not a dermal irritant (Category IV) or dermal
sensitizer. The following table summarizes the acute toxicity profile
of tebuthiuron.
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Test Species Category
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Oral Mouse III
Rat, Rabbit II
Dermal Rabbit IV
Inhalation Rat III
Eye Irritation Rabbit IV
Dermal Irritation Rabbit IV
Dermal Sensitization Guinea Pig none
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[[Page 42984]]
2. Genotoxicity. Results from a battery of assays in vitro indicate
that tebuthiuron is not genotoxic. It was inactive in the Ames S.
typhimurium reverse gene mutation assay with or without metabolic
activation. In the mouse lymphoma assay, tebuthiuron was negative
without metabolic activation and slightly positive (mutation index of
2) with metabolic activation at doses 700 mg/mL. In this assay,
cytotoxicity was observed at doses 200 mg/mL. In Chinese Hamster Ovary
cells, there were chromosomal aberrations and cytotoxicity at the
highest doses tested with (1,550 mg/mL) and without (1,950 mg/mL)
metabolic activation. There was no Unscheduled DNA Synthesis in primary
rat hepatocytes at 800 mg/mL, while cytotoxicity was observed at 900
mg/mL.
3. Reproductive and developmental toxicity. In a 3-generation
reproduction study in which rats were fed 28 or 56 mg tebuthiuron/kg/
day, F1b weanling pups had reduced mean body weight gains.
No reproductive no observed effect level (NOEL) could be determined
from this study.
In a 2-generation reproduction study, rats were fed tebuthiuron at
dietary levels of 100, 200 or 400 ppm (7, 14, 28 mg/kg/day). There was
a reduced rate of body weight gain in the F1 females during
the premating period at the 14 and 28 mg/kg/day dose levels. The
systemic NOEL of this study was 7 mg/kg/day and the reproductive NOEL
was the highest dose tested (28 mg/kg/day). The RfD for tebuthiuron was
determined to be 0.07 mg/kg/day based upon the systemic NOEL of this 2-
generation reproduction study with a Safety Factor of 100.
In a developmental toxicity study in which rats were fed 0, 15, 30,
or 45 mg tebuthiuron/kg/day, the maternal NOEL was 30 mg/kg/day based
upon reduced body weight gain and food consumption. There were no
adverse developmental effects observed in this study. The developmental
NOEL was the highest dose tested (45 mg/kg/day).
Rabbits were administered 0, 10, or 25 mg tebuthiuron/kg/day by
oral gavage on gestation days 6-18. The maternal toxicity NOEL was the
highest dose tested (25 mg/kg/day). Although there was an apparent
decrease in fetal weights at the highest dose, this was probably the
result of an increased number of fetuses per litter in the highest dose
group (5.7 fetuses/litter versus 4.4 fetuses/litter in controls).
Therefore, no treatment-related adverse affects were attributed to
tebuthiuron.
These studies indicate that tebuthiuron is not a developmental or
reproductive toxicant.
4. Subchronic toxicity. Rats were exposed to tebuthiuron in the
diet at the exposure levels of 0, 20, 50, or 125 mg/kg/day for 90 days.
The NOEL was determined to be 50 mg/kg/day based upon reduced body
weight, increased relative liver, kidney, and gonad weights, and slight
vacuolization of pancreatic acinar cells at 125 mg/kg/day. In addition,
males also had increased relative spleen and prostate gland weights at
the highest dose.
Dogs were exposed to tebuthiuron in the diet for 90 days at 0, 500,
1,000, or 2,500 ppm. The NOEL was determined to be 500 ppm (12.5 mg/kg/
day) based upon anorexia, weight loss, increases in blood urea nitrogen
and alkaline phosphatase activity, and increases in spleen and thyroid
gland weights at the LOEL value of 1,000 ppm (25 mg/kg/day).
Rabbits were exposed dermally to 1,000 mg tebuthiuron/kg/day for 6
hours a day for 21 days. Slight erythema occurred in these rabbits and
resolved by day 7. The NOEL was less than 1,000 mg/kg/day.
5. Chronic toxicity. Dogs were fed tebuthiuron in capsules at doses
of 0, 12.5, 25, or 50 mg/kg/day for 1-year. The NOEL was determined to
be 25 mg/kg/day based upon the clinical signs of anorexia, diarrhea,
and emesis as well as increased thrombocyte count, alanine transferase,
and alkaline phosphatase activity, and increased liver, kidney, and
thyroid weights at the LOEL value of 50 mg/kg/day.
Tebuthiuron was fed to 40 Harlan (Wistar) rats/sex/group at
concentrations 400, 800, or 1,600 ppm (20, 40, or 80 mg/kg/day) for 2
years. There were 60 control rats/sex. The systemic NOEL value was 40
mg/kg/day and the lowest observed effect level (LOEL) value was 80 mg/
kg/day based upon a reduction in weight gain and elevated kidney
weights. There were no treatment-related carcinogenic effects.
In another study, tebuthiuron was fed to 40 Harlan (ICR) mice/sex/
group at 400, 800, or 1,600 ppm (57, 144, or 228 mg/kg/day) for 2
years. There were 60 control mice/sex. The systemic NOEL value was the
highest dose tested (228 mg/kg/day). Although there were no compound-
related carcinogenic effects, the dose levels were judged to be
inadequate for carcinogenic testing. This study was considered to be
supplemental to the rat study by the Health Effects Division (HED) and
the Reference Dose (RfD) Committee, and that no additional study would
be required. The HED RfD Committee has classified tebuthiuron as a
Group D carcinogen (not classifiable as to human carcinogenicity).
6. Animal metabolism. The metabolism of tebuthiuron has been
investigated in ruminants. The residues of concern in milk and meat are
the parent compound and its metabolites 104, 106 N-[5-(1,1-
dimethylethyl)-1,3,4-thiazol-2-yl]-urea, 108 [2-dimethylethyl)-5-amino-
1,3,4-thiadiazole], and 109.
The metabolism of radiolabelled tebuthiuron was conducted in four
laboratory species (rats, rabbits, dogs, and mice) using a single
administration by gavage of 10 or 160 mg/kg. In all four species,
tebuthiuron was readily absorbed, metabolized, and excreted. In rats,
rabbits and dogs, elimination in the urine accounted for 84% to 95% of
the administered dose (the parent compound accounting for 0.4% to 0.7%
of the dose). Biliary excretion was demonstrated in the rat. Mice
excreted less radioactivity in the urine (66%; with 23% as unchanged
parent compound) and more in the feces (31%) as compared with the other
species examined. At least seven major metabolites were excreted in the
urine, and there was no unusual tissue distribution of metabolites.
C. Aggregate Exposure
Tebuthiuron currently is registered for treatment of forage grasses
and hay, therefore, potential dietary exposure to humans is from
secondary residues in milk and meat from livestock which have consumed
treated grasses. A chronic dietary exposure analysis was conducted for
tebuthiuron using the existing tolerances of 0.3 ppm in milk and 2.0
ppm in meat and the proposed tolerance of 0.05 ppm in cane sugar and
molasses. The exposure assessment included the worst-case assumptions
that all ruminants and horses were fed treated grasses, and sugar and
molasses available to consumers came from treated sugarcane. As
tebuthiuron was detected in ground water at 23 ppb in a small scale
monitoring study under a high exposure scenario, this value was used in
all water in the consumption survey. In this estimation, exposure to
the U.S. population from water sources represented 1.1% of the RfD
(about 24% of total exposure to tebuthiuron). The following table
summarizes the results from the chronic aggregate exposure analysis.
[[Page 42985]]
------------------------------------------------------------------------
Dietary Exposure
(mg/kg BW/day) % of Rfd
------------------------------------------------------------------------
All Infants 0.004971 7.1%
Nurs. Infants < 1 yr 0.001859 2.7%
Non-nurs. Inf. < 1 yr 0.006429 9.2%
Children 1-6 yrs 0.005732 8.2%
Children 7-12 yrs 0.004376 6.3%
Females 13-50 yrs 0.002394 3.4%
------------------------------------------------------------------------
As the RfD was based upon decreased body weight gains in the
reproduction toxicity study, the subpopulations shown above represent
the groups with the highest potential impact from this endpoint. This
is a worst-case estimate based upon tolerance values and the assumption
that all water sources will have the residue concentration that was
found in the monitoring study. Even with these worst-case estimations,
aggregate exposure levels were less than 10% of the RfD for any
subpopulation.
D. Cumulative Effects
The potential for cumulative effects of tebuthiuron and other
substances that have a common mechanism of toxicity was considered. The
mammalian toxicity of tebuthiuron is well defined. However, the
biochemical mechanism of toxicity of this compound is not well known.
No reliable information exists to indicate that toxic effects produced
by tebuthiuron would be cumulative with those of any other chemical
compounds. Therefore, consideration of a common mechanism of toxicity
with other compounds is not appropriate. Thus only the potential risks
of tebuthiuron are considered in the aggregate exposure assessment.
E. Safety Determination
1. U.S. population. Based upon maximum expected residues in meat,
milk, and refined sugar and molasses from sugarcane, DowElanco
concludes that there is a reasonable certainty of no harm resulting
from aggregate exposure of tebuthiuron to the general population.
2. Infants and children. The toxicological data indicate that
tebuthiuron is not a developmental or reproductive toxicant, and that
infants and children are not sensitive subpopulations. There is a
reasonable certainty that no harm will result from aggregate exposure
of tebuthiuron to infants and children.
F. International Tolerances
No Codex MRLs have been established or proposed for residues of
tebuthiuron.
G. Endocrine Effects
An evaluation of the potential effects on the endocrine systems of
mammals has not been determined; However, no evidence of such effects
were reported in the chronic or reproductive toxicology studies
described above. There was no observed pathology of the endocrine
organs in these studies. There is no evidence at this time that
tebuthiuron causes endocrine effects. (James Tompkins)
3. Merck Research Laboratories
PP 7F4844
EPA has received a pesticide petition (PP 7F4844) from Merck
Research Laboratories, P.O. Box 450, Hillsborough Road, Three Bridges,
NJ. The petition proposes, pursuant to section 408 of the Federal Food,
Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d). that EPA amend 40
CFR part 180 to establish tolerances for pesticide chemical residues
consisting of the insecticide abamectin (avermectin B1) and/
or its delat 8,9- isomers in or on the following food items: grapes,
raisins, and other grape-derived food items at 0.02 parts per million
(ppm) and chili peppers at 0.01 ppm. Abamectin has been approved by EPA
for use on many other food crops, including various tree fruits, nuts,
and vegetables (including bell peppers), as well as hops and cotton.
Tolerances corresponding to these uses are in effect for abamectin
residues (including a tolerance for bell peppers at 0.01 ppm); the most
recent rule, reissuing tolerances for abamectin on citrus and cotton
under the FFDCA as amended by the Food Quality Protection Act (FQPA),
was published in the Federal Register on March 24, 1997 (62 FR 13833).
A notice of filing with regard to that rulemaking had earlier been
published on December 10, 1996 (61 FR 65043). The proposed analytical
method involves homogenization, filtration, partition and cleanup with
analysis by high performance liquid chromatography using UV detection.
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. The metabolism of abamectin in plants is
adequately understood and the residues of concern include the parent
insecticide, abamectin or avermectin B1 (which is a mixture
of a minimum of 80% avermectin B1a and a maximum of 20%
avermectin B1b) and the delta 8,9- isomer of the
B1a and of the B1b components of the parent
insecticide. Animal metabolism also has been studied but is not
relevant to this petition, since the crops involved are not significant
animal feed items.
2. Analytical method. Practicable analytical methods (HPLC-
fluorescence methods) are available to detect residues that would
exceed the proposed tolerances, and for enforcement. The methods are
sufficiently sensitive to detect residues at or above the tolerances
proposed. All methods have undergone independent laboratory validation
as required by PR Notice 88-5.
3. Magnitude of residues. In residue field trials on grapes, the
highest residue combined values in day 28 (or later) samples was 6.7
ppb for abamectin B1a plus its delta 8,9- photoisomer; there
were no detectable levels of abamectin b1b residues in any
of the day 28 (or later) samples. In the two raisin samples the levels
for abamectin B1a ranged from 8.6 to 11.8 ppb. The residues
did not concentrate in grape juice. These data support the proposed
tolerance of 0.02 ppm for total toxic residues of abamectin on the RACs
grapes, grape juice, and raisins and the proposed 28-day PHI.
For chili peppers the primary B1a component and its
photoisomer, the residues recovered on day 7 were all either
nonquantifiable (less than 5 ng/g, but equal or greater to 2 ng/g) or
nondetectable (less than 2 ng/g). These data support the proposed
tolerance of 0.01 ppm for total toxic residues of
[[Page 42986]]
abamectin on the RAC chili peppers and the proposed 7-day PHI.
B. Toxicological Profile
All the toxicity data on which this petition is based have
previously been submitted to EPA in support of other petitions, and
were summarized in the recent notice of filing (61 FR 65043). In the
recent final rule (62 FR 13833) EPA concluded that acute dietary
exposure risk evaluations should be based on a no observed effect level
(NOEL) of 0.06 mg/kg bw/day (mouse pup NOEL in a developmental toxicity
study using the delta 8,9-isomer of abamectin) and that a margin of
exposure of 300 should be required. EPA determined that chronic dietary
exposure risk evaluations should be based on a reference dose (RfD) of
0.0004 mg/kg bw/day, derived from a 2-generation rat reproduction study
with a NOEL of 0.12 mg/kg/day and an uncertainty factor of 300.
This petition contains a supplemental a document setting forth new
acute exposure and chronic exposure and risk analyses that corrects
previously submitted analyses to reflect newly available residue data
on chili peppers (the previously submitted report used data on bell
peppers only) and to reflect current Agency preferences regarding the
handling of blended foods. The results of the old and new analyses are
substantially similar.
C. Aggregate Exposure
1. Dietary exposure. The March 1997 rule was based on an exposure
analysis submitted by Merck that included exposure attributable to
grapes and peppers. The exposure contribution for chili peppers was
calculated using data on bell peppers. With the present petition, Merck
is submitting new residue data on chili peppers and a revised acute and
chronic risk assessment that incorporates that data; the exposure
levels have not changed significantly. The chronic exposure for the
U.S. population at large is estimated to be 0.000006 mg/kg bw/day, and
for children aged 1-6, the highest exposure group, chronic exposure is
estimated to be 0.000014 mg/kg bw/day. The estimated acute exposure (at
the 99.9th percentile level) is for the U.S. population at large,
0.000025 mg/kg bw/day.
2. Drinking water. In the final rule EPA also concluded that
drinking water exposure assumptions were not of concern.
3. Non-dietary exposure. In the final rule published on March 24,
1997, EPA concluded that there is no likelihood of significant exposure
from the registered residential indoor and outdoor nonfat use of
abamectin. Approval of tolerances for grapes and chili peppers would
not change that conclusion.
D. Cumulative Effects
Abamectin is a member of the avermectin family of natural and semi-
synthetic compounds. Ivermectin, another member of that family, is very
closely similar to abamectin in structural standpoint; it is used as a
human and animal drug. Emamectin, a proposed new pesticide, is made
from abamectin but is less similar to abamectin than is avermectin.
These compounds are all Merck products. Other companies product certain
other drugs have certain structural similarities. Merck in not aware of
any information indicating what, if any, cumulative effect would result
from exposure to two or more of these compounds. The March 1997 rule
discussed cumulative effects and stated that in view of the lack of
information on how to evaluate possible common mechanisms, it would not
assume that abamectin has a common mechanism of toxicity with any other
substance.
E. Safety Determination
In the recently issued final rule (62 FR 13833, March 24, 1997)
EPA discussed analyses of risks from chronic and acute exposure for all
existing or pending tolerances. Those analyses included exposure to
grapes and peppers, among other previously-approved and then-pending
uses. In the final rule, EPA found the risks to be acceptable, with
regard to both the general U.S. population and with regard to infants
and children. As noted earlier, Merck now has submitted specific
residue data on chili peppers, but the exposure analyses are not
significantly affected thereby.
F. International Tolerances
Codex has not issued abamectin tolerances for grapes and chili
peppers. (George LaRocca)
[FR Doc. 97-21147 Filed 8-8-97; 8:45 am]
BILLING CODE 6560-50-F