[Federal Register Volume 63, Number 224 (Friday, November 20, 1998)]
[Notices]
[Pages 64498-64502]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-31069]
[[Page 64498]]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-842; FRL-6042-1]
Notice of Filing of Pesticide Tolerance 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-842, must
be received on or before December 21, 1998.
ADDRESSES: By mail submit written comments to: Information and Records
Integrity Branch, Public Information and Services Divison (7502C),
Office of Pesticides Programs, Environmental Protection Agency, 401 M
St., SW., Washington, DC 20460. In person bring comments to: Rm. 119,
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. 119 at the
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: Mary L. Waller, Registration Support
Branch, Registration Division (7505W), Office of Pesticide Programs,
Environmental Protection Agency, 401 M St., SW, Washington, DC 20460.
Office location, telephone number, and e-mail address: Rm. 247, Crystal
Mall #2, 1921 Jefferson Davis Highway, Arlington, VA 22202, (703) 308-
9354; e-mail: waller.mary@epamail.epa.gov.
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 Cosmetic
Act (FFDCA), 21 U.S.C. 346a. EPA has determined that this 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.
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-842] (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 5.1/6.1 file format or
ASCII file format. All comments and data in electronic form must be
identified by the docket control number (PF-842) 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: November 10, 1998.
James Jones,
Director, Registration Division, Office of Pesticide Programs.
Summary of Petition
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 summaries announce 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. Novartis Crop Protection, Inc.
PP 8F3654 PP 8F3674
EPA has received two pesticide petitions (PP 8F3654 & PP 8F3674)
from Novartis Crop Protection, Inc., P.O. Box 18300, Greensboro, NC
27419, 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 tolerances for residues of propiconazole (1-[2-(2,4-
dichlorophenyl)-4-propyl-1,3-dioxolan-2-yl]methyl-1H-1,2,4-triazole) in
or on the raw agricultural commodities corn, fodder (12.0 parts per
million (ppm)); corn, forage (12.0 ppm); corn, grain (0.1 ppm); corn,
sweet (0.1 ppm); pineapples (0.1 ppm); pineapples, fodder (0.1 ppm) (PP
8F3674); peanuts (0.2 ppm); peanuts, hay (20 ppm); and peanuts, hulls
(1.0 ppm) (PP 8F3654). 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/animal metabolism. Novartis believes the studies
supporting propiconazole adequately characterize metabolism in plants
and animals. The metabolism profile supports the use of an analytical
enforcement method that accounts for combined residues of propiconazole
and its metabolites which contain the 2,4-dichlorobenzoic acid (DCBA)
moiety.
2. Analytical method. Novartis has submitted a practical analytical
method involving extraction, filtration, conversion, partition,
derivitization, and solid phase cleanup with analysis by confirmatory
gas chromatography using electron capture detection (ECD). The total
residue method is used for determination of propiconazole and its
metabolites. The limit of quantitation (LOQ) for the method is 0.05
ppm.
3. Magnitude of residues. Field residue trials have been conducted
at various rates, timing intervals, and applications methods to
represent the use patterns which would most likely
[[Page 64499]]
result in the highest residues. For all samples, the total residue
method was used for determination of the combined residues of parent
and its metabolites which contain the DCBA moiety.
B. Toxicological Profile
1. Acute toxicity--Propiconazole exhibits low toxicity. Data
indicated the following: a rat acute oral LD50 of 1,517
milligrams/kilograms (mg/kg); a rabbit acute dermal LD50 >
6,000 mg/kg; a rat inhalation LC50 > 5.8 mg/liter air;
minimal skin and slight eye irritation; and nonsensitization.
2. Genotoxicty. Propiconazole exhibits no mutagenic potential based
on the following data: In vitro gene mutation test (Ames assay, rat
hepatocyte DNA repair test, (human fibroblast DNA repair test), In
vitro chromosome test, (human lymphocyte cytogenetic test), In vivo
mutagenicity test, (Chinese hamster bone marrow cell nucleus anomaly
test, Chinese hamster bone marrow cell micronucleus test, mouse
dominant lethal test), and other mutagenicity test (BALB/3T3 cell
transformation assay).
3. Reproductive and developmental toxicity. In an oral teratology
study in the rabbit, a maternal no observed adverse effect level
(NOAEL) of 30 mg/kg was based on reduced food intake but without any
fetotoxicity even at the top dose of 180 mg/kg. In an oral teratology
study in the rabbit, a maternal NOAEL of 100 mg/kg was based on
reductions in body weight gain and food consumption and a fetal NOAEL
of 250 mg/kg was based on increased skeletal variations at 400 mg/kg.
In an oral teratology study in the rat, a maternal and fetal NOAEL of
100 mg/kg was based on decreased survival, body weight gain, and food
consumption in the dams and delayed ossification in the fetuses at 300
mg/kg. In a second teratology study in the rat, a maternal and fetal
NOAEL of 30 mg/kg was based on reductions in body weight gain and food
consumption in the dams and delayed development in the fetuses at 90
and 360/300 mg/kg. A supplemental teratology study in the rat involving
eight times as many animals per group as usually required showed no
teratogenic potential for the compound. A 2-generation reproduction
study in the rat showed excessive toxicity at 5,000 ppm without any
teratogenic effects. A 2-generation reproduction study in the rat
showed no effects on reproductive or fetal parameters at any dose
level. Postnatal growth and survival were affected at the top dose of
2,500 ppm, and parental toxicity was also evident. The NOAEL for
development toxicity is 500 ppm.
4. Subchronic toxicity. In a 21 day dermal study in the rabbit, a
NOAEL of 200 mg/kg was based on clinical signs of systemic toxicity. In
a 28 day oral toxicity study in the rat, a NOAEL of 50 mg/kg was based
on increased liver weight. In a subchronic feeding study in the mouse,
a NOAEL of 20 ppm (3 mg/kg) was based on liver pathologic changes. In a
13 week feeding study in the male mouse, a NOAEL of 20 ppm (3 mg/kg)
was based on liver pathologic changes. In a 90 day feeding study in
rats, the NOAEL was 240 ppm (24 mg/kg) based on a reduction in body
weight gain. In a 90 day feeding study in dogs, the NOAEL was 250 ppm
(6.25 mg/kg) based on reduced food intake and stomach histologic
changes.
5. Chronic toxicity. In a 12 month feeding study in the dog, a
NOAEL of 50 ppm (1.25 mg/kg) was based on stomach histologic changes.
In a 24 month oncogenicity feeding study in the mouse, the NOAEL was
100 ppm (15 mg/kg). The MTD was exceeded at 2,500 ppm in males based on
decreased survival and body weight. Increased incidence of liver tumor
was seen in these males but no evidence of carcinogenicity was seen at
the next lower dose of 500 ppm in either sex. In a 24 month chronic
feeding/oncogenicity study in the rat, a NOAEL of 100 ppm (5 mg/kg) was
based on body weight and blood chemistry. The MTD was 2,500 ppm based
on reduction in body weight gain and no evidence of oncogenicity was
seen. Based on the available chronic toxicity data, Novartis believes
the Reference dose (RfD) for propiconazole is 0.0125 mg/kg/day. This
RfD is based on a 1 year feeding study in dogs with a NOAEL of 1.25 mg/
kg/day (50 ppm) and an uncertainly factor of 100. No additional
modifying factor for the nature of effects was judged to be necessary
as stomach mucosa hyperemia was the most sensitive indicator of
toxicity in that study.
Using the Guidelines for Carcinogenic Risk Assessment published on
September 24, 1986 (51 FR 33992), the USEPA has classified
propiconazole in group C for carcinogenicity (evidence of possible
carcinogenicity for humans). The compound was tested in 24 month
studies with both rats and mice. The only evidence of carcinogenicity
was an increase in liver tumor incidence in male mice at a dose level
that exceeded the maximum tolerated dose (MTD). Dosage levels in the
rat study were appropriate for identifying a cancer risk. The Cancer
Peer Review Committee recommended the RfD approach for quantitation of
human risk. Therefore, the RfD is deemed protective of all chronic
human health effects, including cancer.
C. Aggregate Exposure
1. Dietary exposure. The RfD for propiconazole is 0.0125 mg/kg/day
and is based on a 1 year feeding study in dogs with a NOAEL of 1.25 mg/
kg/day (50 ppm) and an uncertainly factor of 100.
2. Food--i. Acute risk. The risk from acute dietary exposure to
propiconazole is considered to be very low. The lowest NOAEL in a short
term exposure scenario, identified as 30 mg/kg in the rat teratology
study, is 24-fold higher than the chronic NOAEL. Based on worst-case
assumptions, the chronic exposure assessment did not result in any
margin of exposure (MOE) less than 150 for even the most impacted
population subgroup. Novartis believes that the MOE for acute exposure
would be more than 100 for any population groups; MOE of 100 or more
are considered satisfactory.
ii. Chronic risk. For the purposes of assessing the potential
dietary exposure under the existing, pending, and proposed tolerances
for the residue of propiconazole and its metabolites determined as 2,4-
dichlorobenzoic acid, Novartis has estimated aggregate exposure based
upon the Theoretical Maximum Residue Concentration (TMRC). The TMRC is
a ``worst case'' estimate of dietary exposure since it assumes 100% of
all crops for which tolerances are established are treated and that
pesticide residues are at the tolerance levels, resulting in an
overestimate of human exposure.
Currently established tolerances range from 0.05 ppm in milk to 60
ppm in grass seed screenings and include: apricots (1.0 ppm); bananas
(0.2 ppm); barley grain (0.1 ppm); barley straw (1.5 ppm); cattle
kidney and liver (2.0 ppm); cattle meat, fat, and meat by products
except kidney and liver (0.1 ppm); celery (5.0 ppm); corn forage and
fodder (12.0 ppm); corn grain and sweet (0.1); eggs (0.1 ppm); goat
kidney and liver (2.0 ppm); goat meat, fat, and meat by products except
kidney and liver (0.1 ppm); grass forage (0.5 ppm); grass hay/straw
(40.0 ppm); grass seed screenings (60.0 ppm); hogs kidney and liver
(2.0 ppm); hog meat, fat, and meat by products except kidney and liver
(0.1 ppm); horses kidney and liver (2.0 ppm); horse meat, fat, and meat
by products except kidney and liver (0.1 ppm); milk (0.05 ppm); mint
tops (0.3 ppm - regional tolerance west of Cascade Mountains);
mushrooms (0.1 ppm); nectarines (1.0 ppm); oat forage (10.0 ppm); oat
grain (0.1 ppm); oat hay (30.0 ppm); oat straw (1.0 ppm); peaches
[[Page 64500]]
(1.0 ppm); peanut hay (20.0 ppm); peanut hulls (1.0 ppm); peanuts (0.2
ppm);, pecans (0.1 ppm); pineapple (0.1 ppm); pineapple fodder (0.1
ppm); plums (1.0 ppm); poultry liver and kidney (0.2 ppm); poultry
meat, fat, and meat by products except kidney and liver (0.1 ppm);
prunes, fresh (1.0 ppm); rice grain (0.1 ppm); rice straw (3.0 ppm);
wild rice (0.5 ppm regional tolerance Minnesota); rye grain (0.1 ppm);
rye straw (1.5 ppm); sheep kidney and liver (2.0 ppm); sheep meat, fat,
and meat by products except kidney and liver (0.1 ppm); stone fruit
crop group 12 (1.0 ppm); wheat grain (0.1 ppm); and wheat straw (1.5
ppm). In addition, time-limited regional tolerances for sorghum grain
and stover at 0.1 ppm and 1.5 ppm, respectively were established to
support a Section 18 Crisis exemption in Texas (expiration date October
31, 1998).
Additional uses of propiconazole have been requested in several
pending petitions. Proposed tolerances include: PP 5F4424 for use of
propiconazole on drybean and soybean - dry bean forage (8.0 ppm); dry
bean hay (8.0 ppm); dry bean vines (0.5 ppm); dry bean (0.5 ppm),
soybeans (0.5 ppm); soybean fodder (8.0 ppm); soybean forage (8.0 ppm);
soybean hay (25.0 ppm); and soybean straw (0.1 ppm). PP 5F4591 for use
of propiconazole on berries, carrots and onions - berry crop grouping
(1.0 ppm); dry bulb onion (0.3 ppm); green onion (8.0); PP 5F3740 -
tree nut crop grouping (0.1 ppm); PP 5F4498 - inadvertent/rotational
crop tolerances for alfalfa forage (0.1 ppm), alfalfa hay (0.1 ppm),
grain sorghum fodder (0.3 ppm), grain sorghum forage (0.3 ppm) and
grain sorghum grain (0.2 ppm).
3. Drinking water. Other potential sources of exposure of the
general population to residues of propiconazole are residues in
drinking water and exposure from non-occupational sources. Review of
environmental fate data by the Environmental Fate and Effects Division
of USEPA indicates that propiconazole is persistent and moderately
mobile to relatively immobile in most soil and aqueous environments. No
Maximum Concentration Level (MCL) currently exists for residues of
propiconazole in drinking water and no drinking water health advisory
levels have been established for propiconazole.
The degradation of propiconazole is microbially mediated with an
aerobic soil metabolism half-life of 70 days. While propiconazole is
hydrolytically and photochemically stable (T1/2 >100 days),
it binds very rapidly and tightly to soil particles following
application. Adsorption/desorption and aged leaching data indicate that
propiconazole and its degradates will primarily remain in the top 0-6
inches of the soil. It has been determined that under field conditions
propiconazole will degrade with a half-life of approximately 100 days.
4. Non-dietary exposure. Propiconazole is registered for
residential use as a preservative treatment for wood and for lawn and
ornamental uses. At this time, no reliable data exist which would allow
quantitative incorporation of risk from these uses into a human health
risk assessment. The exposure to propiconazole from contacting treated
wood products is anticipated to be very low since the surface of wood
is usually coated with paint or sealant when used in or around the
house. The non-occupational exposure from lawn and ornamental
applications is also considered to be minor. It is estimated that less
than 0.01% of all households nationally use propiconazole in a
residential setting.
D. Cumulative Effects
Consideration of a common mechanism of toxicity is not appropriate
at this time since there is no reliable information to indicate that
toxic effects produced by propiconazole would be cumulative with those
of any other types of chemicals. While other triazoles are available on
the commercial or consumer market, sufficient structural differences
exist among these compounds to preclude any categorical grouping for
cumulative toxicity. Consequently, Novartis is considering only the
potential risks of propiconazole in its aggregate exposure assessment.
E. Safety Determination
1. U.S. population--Reference dose. Using the conservative exposure
assumptions described above (100% stone fruit acres treated and
tolerance level residues) and based on the completeness and reliability
of the toxicity data base for propiconazole, Novartis has calculated
aggregate exposure levels for this chemical. The calculation shows that
only 16% of the RfD will be utilized for the U.S. population based on
chronic toxicity endpoints. EPA generally has no concern for exposures
below 100% of the RfD because the RfD represents the level at or below
which daily aggregate dietary exposure over a lifetime will not pose
appreciable risks to human health. Novartis concludes that there is a
reasonable certainty that no harm will result from aggregate exposure
to propiconazole residues.
2. Infants and children. Developmental toxicity (e.g., reduced pup
weight and ossification) was observed in the rat teratology studies and
2-generation rat reproduction studies at maternally toxic doses. Some
of these findings are judged to be nonspecific, secondary effects of
maternal toxicity. The lowest NOAEL for developmental toxicity was
established in the rat teratology study at 30 mg/kg, a level 24-fold
higher than the NOAEL of 1.25 mg/kg on which the RfD is based.
3. Reference dose. Using the same conservative exposure assumptions
as employed for the determination in the general population, Novartis
has calculated that the percent of the RfD that will be utilized by
aggregate exposure to residues of propiconazole is 26% for nursing
infants less than 1 year old, 65% for non-nursing infants less than 1
year old, 35% for children 1-6 years old, and 23% for children 7-12
years old. Therefore, based on the completeness and reliability of the
toxicity data base and the conservative exposure assessment, Novartis
concludes that there is a reasonable certainty that no harm will result
to infants and children from aggregate exposure to propiconazole
residues.
F. International Tolerances
International CODEX values are established for almond, animal
products, bananas, barley, coffee, eggs, grapes, mango, meat, milk,
oat, peanut-whole, peanut grains, pecans, rape, rye, stone fruit, sugar
cane, sugar beets, sugar beet tops, and wheat. The U.S. residue
definition includes both propiconazole and metabolites determined as
2,4-dichlorobenzoic acid (DCBA), while the CODEX definition is for
propiconazole, per se, i.e. parent only. This difference results in
unique tolerance expressions with the U.S. definition resulting in the
higher tolerance levels.
2. Tomen Agro, Inc. and Bayer Corporation, Agriculture Division
PP 7F4890
EPA has received a pesticide petition (PP 7F4890) from the TM-402
Fungicide Task Force comprised of Tomen Agro, Inc., 100 First Street,
Suite 1610, San Francisco, CA 94105 and Bayer Corporation, Agriculture
Division, 8400 Hawthorn Road, P.O. Box 4913, Kansas City, MO 64120-
0013, 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 N-(2,3-dichloro-4-
hydroxyphenyl)-1-
[[Page 64501]]
methyl-cyclohexanecarboxamide (TM-402 or Fenhexamid) in or on the raw
agricultural commodities grapes and strawberries at 3.0 parts per
million (ppm) and in raisens at 6.0 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. Analytical method. An adequate method for purposes of
enforcement of the proposed TM-402 tolerances in plant commodities is
available. Bayer AG Analytical Method No. 00362 was used by Bayer AG to
determine magnitude of TM-402 residues in fresh and processed grapes.
This method has been independently validated. The limits of
quantitation (LOQ) were determined to be 0.02 ppm for grapes, wine, and
juice, and 0.05 ppm for strawberries, and raisins.
2. Magnitude of residues. The maximum TM-402 residues in fresh
grapes, grape juice, raisins or wine permitted by the proposed label is
2.9 ppm. The maximum TM-402 calculated residue for grape juice is 1.7
ppm. For raisins the calculated residue value is 5.2 ppm, and for wine
the value is 1.2 ppm. The maximum TM-402 residue for fresh strawberries
permitted by the proposed label is 2.3 ppm. The average TM-402 residues
for fresh grapes, grape juice, raisins and wine resulting from the
treatment of grapes permitted by the proposed label are 1.3 ppm. The
average TM-402 calculated residue for grape juice is 0.8 ppm. For
raisins the average calculated residue value was 2.3 ppm, and for wine
the values are 0.52 ppm. The average TM-402 residue for fresh
strawberries permitted by the proposed label is 1.2 ppm. Since
strawberries, grapes and processed grape commodities are not
significant livestock feeds, a nature-of-the-residue discussion in
livestock is not required. Additionally, since no aquatic uses are
proposed, magnitude of the residue data in fish and irrigated crops are
not required.
B. Toxicological Profile
1. Acute toxicity. Data from a complete battery of acute toxicity
studies for TM-402 technical are available. The acute oral toxicity
study resulted in an LD50 of >5,000 milligrams/kilogram (mg/
kg) for both sexes. The acute dermal toxicity in rats resulted in an
LD50 of > 5,000 mg/kg for both sexes. The acute inhalation
was investigated in two studies in rats. Inhalation by aerosol at the
maximum technically possible concentration of 0.322 mg/l resulted in no
deaths or symptoms (LC50 >0.322 mg/l). A dust inhalation
study resulted in an LC50 >5.057 mg/l. TM-402 was not
irritating to the skin or eyes after a 4 hour exposure period. The
Buehler dermal sensitization study in guinea pigs indicated that TM-402
is not a sensitizer. Based on these results TM-402 technical is placed
in toxicity Category IV and does not pose any acute dietary risks.
2. Genotoxicty. The potential for genetic toxicity of TM-402 was
evaluated in six assays including two Ames tests, an HGPRT forward
mutation assay, a UDS assay, an in vitro chromosomal aberration assay
in CHO cells, and a micronucleus test in mice. The compound was found
to be devoid of any mutagenic activity in each of these assays
including those tests that investigated the absence or presence of
metabolic activating systems. The weight of evidence indicates that TM-
402 technical does not pose a risk of mutagenicity or genotoxicity.
3. Reproductive and developmental toxicity. TM-402 has been tested
for reproductive toxicity in rats and developmental toxicity in both
rats and rabbits.
i. In a 2-generation reproduction study (one mating per
generation), 30 Sprague-Dawley rats per sex per dose were administered
0, 100, 500, 5,000, or 20,000 ppm of TM-402 in the diet. The
reproductive toxicity no observed adverse effect level (NOAEL) was
20,000 ppm. The neonatal NOAEL was 500 ppm, and the lowest abserved
effect level (LOAEL) was 5,000 ppm based on decreased pup body weight.
The parental toxicity NOAEL was 500 ppm based on lower adult pre-mating
body weights at 5,000 and 20,000 ppm, lower gestation body weights at
20,000 ppm, lower lactation body weights at 5,000 and 20,000 ppm, and
statistically significant changes in clinical chemistry parameters,
terminal body weights, and organ weights at 5,000 and 20,000 ppm. Based
on this study, it is clear that the only toxic effects in the neonates
occurred at parentally toxic doses.
ii. In rats. TM-402 was administered by gavage at doses of 0 or
1,000 mg/kg for gestation days 6-15. No maternal toxicity,
embryotoxicity, fetotoxicity, or teratogenic effects were observed at
the limit dose of 1,000 mg/kg/day. Therefore, the NOAEL for maternal
and developmental toxicity was 1,000 mg/kg/day.
iii. In rabbits. TM-402 was administered by gavage at doses of 0,
100, 300, and 1,000 mg/kg for gestation days 6-18. Body weight gain and
feed consumption of the dams were reduced at the two top doses. One
abortion occurred in each of the top two dose groups and two total
resorptions occurred in the top dose group. The placental weights were
slightly decreased at 300 mg/kg/day and above. In the 1,000 mg/kg/day
group slightly decreased fetal weights and a slightly retarded skeletal
ossification were observed. All other parameters investigated in the
study were unaffected. Therefore, the NOAELs for maternal and
developmental toxicity were 100 mg/kg/day in this study.
Based on the 2-generation reproduction study in rats, TM-402 is not
considered a reproductive toxicant and shows no evidence of endocrine
effects. The data from the developmental toxicity studies on TM-402
show no evidence of a potential for developmental effects
(malformations or variations) at doses that are not maternally toxic.
The NOAEL for both maternal and developmental toxicity in rats was
1,000 mg/kg/day and for rabbits the NOAEL for both maternal and
developmental toxicity was 100 mg/kg/day.
4. Subchronic toxicity. The subchronic toxicity of TM-402 has been
evaluated in rats, mice, and dogs.
i. TM-402 was administered in the diet to rats for 13 weeks at
doses of 0, 2,500, 5,000, 10,000 and 20,000 ppm. The NOAEL was 5,000
ppm (415 mg/kg/day in males and 549 mg/kg/day in females). Reversible
liver effects were observed at 10,000 ppm.
ii. TM-402 was administered in the diet to mice for approximately
14 weeks at doses of 0, 100, 1,000 and 10,000 ppm. The NOAEL was 1,000
ppm (266.6 mg/kg/day in males and 453.9 mg/kg/day in females).
Increased feed and water consumption and kidney and liver effects were
observed at 10,000 ppm.
iii. TM-402 was administered in the diet to beagle dogs for 13
weeks at doses of 0, 1,000, 7,000 and 50,000 ppm. The NOAEL was 1,000
ppm (33.9 mg/kg/day in males and 37.0 mg/kg/day in females. Increased
Heinz bodies were observed at 7,000 ppm.
5. Chronic toxicity. The chronic toxicity of TM-402 has been
evaluated in a 1 year dog study and a 2 year chronic toxicity/
oncogenicity study in rats.
i. TM-402 was administered in the feed at doses of 0, 500, 3,500,
or 25,000 ppm to 4 male and 4 female beagle dogs per group for 52
weeks. A systemic
[[Page 64502]]
NOAEL of 500 ppm (an average dose of 17.4 mg/kg/day over the course of
the study) was observed based on decreased food consumption and
decreased body weight gain at 25,000 ppm, decreased erythrocyte,
hemoglobin and hematocrit values at 25,000 ppm, increased Heinz bodies
at 3,500 ppm and above, and a dose-dependent increase of alkaline
phosphatase at 3,500 ppm and above. There were no treatment related
effects on either macroscopic or histologic pathology.
ii. A combined chronic/oncogenicity study was performed in Wistar
rats. Fifty animals/sex/dose were administered doses of 0, 500, 5,000,
or 20,000 ppm for 24 months in the feed. A further 10 animals/sex/group
received the same doses and were sacrificed after 52 weeks. The doses
administered relative to body weight were 0, 28, 292, or 1,280 mg/kg/
day for males and 0, 40, 415, or 2067 mg/kg/day for females. The NOAEL
in the study was 500 ppm (28 mg/kg/day for males and 40 mg/kg/day for
females) based on body weight decreases in females at 5,000 ppm and
above, changes in biochemical liver parameters in the absence of
morphological changes in both sexes at 5,000 ppm and above, and caecal
mucosal hyperplasia evident at 5,000 ppm and above.
The NOAEL in the chronic dog study was 17.4 mg/kg/day based on body
weight, hematology and clinical chemistry effects. The lowest NOAEL in
the 2 year rat study was determined to be 28 mg/kg/day based on body
weight, clinical chemistry parameters in the liver, and caecal mucosal
hyperplasia.
6. Oncogenicity. The oncogenic potential of TM-402 has been in a 2
year oncogenicity study in mice and a 2 year chronic toxicity/
oncogenicity study in rats.
i. Mouse. TM-402 was administered to 50 B6C3F1 mice/sex/group in
their feed at concentrations of 0, 800 ,2,400 , or 7,000 ppm for 24
months. These concentrations resulted in a compound intake of
247.4,807.4 or 2354.8 mg,kg,day in males and 364.5, 1054.5 and 3178.2
mg/kg/day in females. A further 10 mice/sex/group received the same
concentrations and were sacrificed after 12 months. There was no
treatment effect on mortality, feed consumption,the hematological
system or on the liver. Water consumption was increased in both sexes,
and body weights were 8% lower in males at the highest dose of 7,000
ppm. At 7,000 ppm, elevated plasma creatinine concentrations, decreased
kidney weights, and an increased occurrence of morphological lesions
indicated a nephrotoxic effect of the compound. There was no shift in
the tumor spectrum with treatment, and therefore, TM-402 was not
oncogenic in this study.
ii. Rat. In the 2 year rat chronic/oncogenicity study described
above, there was no indication of an oncogenic response. There was no
indication of an oncogenic response in the 2 year rat and mouse studies
on TM-402.
7. Neurotoxicity. The possibility for acute neurotoxicity of TM-402
was investigated. TM-402 was administered by gavage ina single dose to
12 Wistar rats/sex/group at doses of 0, 200, 630, 2,000 mg/kg. There
was no evidence of neurotoxicity at any level tested.
8. Endocrine disruption. TM-402 has no endocrine-modulation
characteristics as demonstrated by the lack of endocrine effects in
developmental, reproductive, subchronic, and chronic studies.
C. Aggregate Exposure
1. Dietary exposure. Sources of dietary exposure to TM-402 are
limited to the crops in the current submission. The following are the
proposed tolerances: grapes - 3.0 ppm and strawberries - 3.0 ppm. A
food additive tolerance of 6.0 ppm in raisins is also being proposed.
2. Drinking water. Review of the environmental fate data indicates
the TM-402 is relatively immobile and rapidly degrades in the soil and
water. TM-402 dissipates in the environment via several processes.
Therefore, a significant contribution to aggregate risk from drinking
water is unlikely.
3. Non-dietary exposure. There is no significant potential for non-
occupational exposure to the general public. The proposed uses are
limited to agricultural and horticultural use.
D. Cumulative Effects
Consideration of a common mechanism of toxicity is not appropriate
at this time since there is no significant toxicity observed for TM-
402. Even at toxicology limit doses, only minimal toxicity is observed
for TM-402. Therefore, only the potential risks of TM-402 are
considered in the exposure assessment.
E. Safety Determination
1. U.S. population. Based on the most sensitive species, Tomen Agro
has calculated an appropriate Reference Dose (RfD) for TM-402. Using
the NOAEL of 17.4 mg/kg/day in the 1 year dog study and an uncertainty
factor (UF) of 100 to account for inter- and intra-species variability,
an RfD of 0.177 mg/kg/day is recommended.
A chronic dietary risk assessment which included all proposed
tolerances was conducted on TM-402 using U.S. EPA's Dietary Risk
Evaluation System (DRES). The theoretical maximum residue contribution
(TMRC) for the U.S. population (48 States) is 0.00125 mg/kg/day and
this represents 0.71% of the propoed RfD. The most highly exposed
subgroup was children (1- 6 years old) where the TMRC was 0.00382 mg/
kg/day, representing only 2.15% of the proposed RfD. For non-nursing
infants (>1 year old) the TMRC was 0.00101 mg/kg/day (0.57% of the RfD)
and for children 7-12 years old the TMRC is 0.00156 mg/kg/day (0.88% of
the RfD). If these calculations consider the average of anticipated
residue values instead of assuming ``tolerance level'' residues, the
values are reduced to approximately one-third of those listed above.
Even under the most conservative assumptions, the estimates of dietary
exposure clearly demonstrate adequate safety margins of all segments of
the population.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of TM-402, the
available developmental toxicity and reproductive toxicity studies and
the potential for endocrine modulation by TM-402 were considered.
Developmental toxicity studies in two species indicate that TM-402 does
not impose additional risks to developing fetuses and is not a
teratogen. The 2-generation reproduction study in rats demonstrated
that there were no adverse effects on reproductive performance,
fertility, fecundity, pup survival, or pup development at non-
maternally toxic levels. Maternal and developmental NOAELs and LOAELs
were comparable, indicating no increase in susceptibility of developing
organisms. No evidence of endocrine effects were noted in any study. It
is therefore concluded that TM-402 poses no additional risk for infants
and children and no additional uncertainty factor is warranted.
[FR Doc. 98-31069 Filed 11-19-98; 8:45 am]
BILLING CODE 6560-50-F
