[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: [email protected].
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:
    [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 5.1/6.1 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

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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