[Federal Register Volume 62, Number 143 (Friday, July 25, 1997)]
[Notices]
[Pages 40075-40086]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-19669]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-744; FRL-5726-4]


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-744, must 
be received on or before August 25, 1997.

ADDRESSES: By mail submit written comments to: Public Information and 
Records Integrity Branch, Information Resources andServices Division 
(7506C), 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    
------------------------------------------------------------------------
Mary Waller (PM 21)...........  Rm. 265, CM #2, 703-    1921 Jefferson  
                                 308-9354, e-            Davis Hwy,     
                                 mail:waller.mary@epam   Arlington, VA  
                                 ail.epa.gov.                           
Cynthia Giles-Parker (PM 22)..  Rm. 247, CM #2, 703-    Do.             
                                 305-7740, e-                           
                                 mail:giles-
parker.cynthia@epamai
l.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 raw 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 grantinig of 
the petition. Additional data may be needed before EPA rules on the 
petition.
    The official record for this notice, as well as the public version, 
has been established for this notice of filing under docket control 
number PF-744

[[Page 40076]]

(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''.
    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 control number (insert docket number) and 
appropriate petition number. Electronic comments on this notice may be 
filed online at many Federal Depository Libraries.
    Authority: 21 U.S.C. 346a.

List of Subjects

    Environmental protection, Agricultural commodities, Food additives, 
Feed additives, Pesticides and pests, Reporting and recordkeeping 
requirements.

    Dated: July 11, 1997.

James Jones,
Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

    Below summaries of the pesticide petitions are printed. The 
summaries of the petitions were prepared by the petitioners. The 
petition summary announces the availability of a description of the 
analytical methods available to EPA for the detection and measurement 
of the pesticide chemical residues or an explanation of why no such 
method is needed.

1. Bayer

PP 3E2938

    EPA has received a pesticide petition (PP) 3E2938 from Bayer 
Corporation, 8400 Hawthorn Rd., P.O. Box 4913, Kansas City, MO 64120-
0013 proposing to amend 40 CFR 180.410 by establishing tolerances for 
residues of the fungicide triadimefon, 1-(4-Chlorophenoxy)-3,3-
dimethyl-1-(1H-1,2,4-triazol-1-yl)-2-butanone, and its metabolites 
containing chlorophenoxy and triazole moieties expressed as the 
fungicide in or on the raw agricultural commodities coffee beans at 0.1 
ppm. The nature of the residue in plants and livestock is adequately 
understood. The analytical method for determining residues uses gas-
liquid chromatography coupled with a thermionic detector.

A. Residue Chemistry

    1. Plant and livestock metabolism. The nature of the residue in 
plants and animals is adequately understood. The residue of concern is 
triadimefon and its triazole and chlorophenoxy metabolites. Since there 
are no livestock feedstuffs derived from coffee, the nature of the 
residue in poultry and ruminants is not of concern here.
    2. Analytical method. Adequate analytical methods are available for 
analysis of triadimefon and its triazole and chlorophenoxy metabolites 
in or on coffee. These methods are available in PAM II as Method I.
    3. Magnitude of residue. Fifteen separate residue trials have been 
conducted and submitted to the EPA with triadimefon on coffee. These 
trials were conducted in Brazil (4 trials), Mexico (4 trials), Costa 
Rica (2 trials), El Salvador (2 trials), Guatemala (1 trial) and 
Columbia (2 trials). The EPA has determined that these data show that 
residues of triadimefon and its metabolites containing chlorophenoxy 
and triazole moieties (expressed as the fungicide) in the raw 
agricultural commodity coffee beans will not exceed the proposed 
tolerance of 0.1 ppm. Although no data on roasted beans or instant 
coffee were submitted, the EPA has concluded that food additive 
tolerances are not required. There are no livestock feed stuffs from 
coffee and therefore, secondary residues in meat, milk, poultry and 
eggs are not expected. Since this is an import tolerance petition and 
since coffee is not normally rotated, the nature of residue in 
rotational crops is not of concern.

B. Toxicological Profile

    1. Acute toxicity. Rat acute oral study with an LD50 of 
568 + 61 mg/kg (male) and 363 + 41 mg/kg (female). Rabbit acute dermal 
study with a LD50 of >2000 mg/kg. Rat acute inhalation study 
with a LC50 of > 3.570 mg/l. Primary eye irritation study in 
the rabbit which showed practically no irritation. Primary dermal 
irritation study which showed practically no irritation. Primary dermal 
sensitization study which indicated that triadimefon is a skin 
sensitizer.
    2. Genotoxicity. Triadimefon has been found to be negative in the 
Ames reverse mutation test and in the Structural Chromosome Aberration 
Test
    3. Reproductive and developmental toxicity. A rat developmental 
toxicity study showed a maternal systemic NOEL of 30 mg/kg/day and the 
LOEL 90 mg/kg/day. The NOEL for developmental toxicity was 30 mg/kg/day 
and the LOEL was 90 mg/kg/day. In the developmental toxicity study in 
rabbits, the maternal systemic NOEL was 50 mg/kg/day and the LOEL 120 
mg/kg/day. The NOEL for developmental toxicity was 20 mg/kg/day and the 
LOEL was 50 mg/kg/day. Effects seen at the developmental LEL in the 
rabbit study were irregular spinous process and ossification of various 
bones. A 3-generation rat reproduction study showed decreases in 
maternal body weight gain, fertility, and in litter size, pups survival 
during the lactation phase, and pups weights. The maternal NOEL was 300 
ppm and the reproductive NOEL was 50 ppm. A 2-generation rat 
reproductive study showed reductions in litter size, pups viability, 
birth and lactational weights. The reproductive NOEL was 50 ppm.
    4. Subchronic toxicity. A 3-month feeding study in the rat with a 
NOEL of 2,000 ppm based on decreased body weight gain and food 
consumption attributed to palatability. A rat 30-day feeding study with 
a NOEL of 10 mg/kg. A thirteen-week dog-feeding study with a NOEL of 
2,400 ppm based on decreased body weight gain and food consumption due 
to palatability. There was also a decreased hematocrit, RBC count, 
hemoglobin volume and microsomal induction. A 28-day rabbit dermal 
study with a NOEL >250 mg/kg. A rat 21-day inhalation study with a NOEL 
= 78.7 mg/m3/6 hrs. per day/ 15 exposures.
    5. Chronic toxicity. A 2-year rat chronic feeding study defined a 
NOEL for systemic effect as 300 ppm (males = 16.4 mg/kg/day; females = 
22.5 mg/kg/day). The systemic LOEL was 1,800 ppm (males = 114.0 mg/kg/
day; females = 199.0 mg/kg/day) based on neoplastic and systemic 
effects. A dog feeding study showed only minimal toxic effects 
(decrease in body weight, increase in liver weight and in hepatic N-
demethylase activity, and an increase in serum alkaline phosphatase 
activity. The NOEL was established at 100 ppm. A mouse oncogenicity 
study showed hepatocellular adenomas in both sexes of NMRI mice. The 
NOEL was established for males at 50 ppm. No NOEL was reached for 
females. A mouse oncogenicity study using CF1-W74 mice was negative for 
oncogenicity.
    6. Animal metabolism. In a general rat metabolism study triadimefon 
was initially converted to triadimefon. This conversion was more rapid 
in males.

[[Page 40077]]

The major metabolites were the acid and alcohol of triadimefon. In 
males radioactivity was found mainly in feces, whereas, in females, 
radioactivity was equally distributed between urine and feces. No 
radioactivity was recovered in the expired air. Peak tissue levels were 
found in 2 to 4 hours and were highest in fat, liver and kidney.
    7. Endocrine effects. No special studies investigating potential 
estrogenic or endocrine effects of triadimefon have been conducted. 
However, the standard battery of required studies has been completed. 
These studies include an evaluation of the potential effects on 
reproduction and development, and an evaluation of the pathology of the 
endocrine organs following repeated or long-term exposure. These 
studies are generally considered to be sufficient to detect any 
endocrine effects, but no such effects were noted in any of the studies 
with either triadimefon or its metabolites.
    8. Carcinogenicity. Using its Guidelines for Carcinogen Risk 
Assessment published in the Federal Register of September 24, 1986 (51 
FR 33992), EPA has classified triadimefon as Group ``C'' for 
carcinogenicity (possible human carcinogen) based on the results of 
carcinogenicity studies in 2 species. The classification as Group C was 
based on borderline statistically significant increases in thyroid 
adenomas in male rats, and increases in liver adenomas in both sexes of 
mice. Because the tumors were benign, and there were no apparent 
genotoxicity concerns, the Cancer Peer Review Committee recommended the 
RfD approach for quantitation of human risk.

C. Aggregate Exposure

    1. Dietary (food) exposure--a. Chronic. For purposes of assessing 
the potential dietary exposure from food under the proposed tolerances, 
Bayer has estimated exposure based on the Theoretical Maximum Residue 
Contribution (TMRC) derived from the previously established tolerances 
for triadimefon as well as the proposed tolerance for triadimefon on 
coffee beans at 0.1 ppm. The TMRC is obtained by using a model which 
multiplies the tolerance level residue for each commodity by 
consumption data which estimate the amount of each commodity and 
products derived from the commodities that are eaten by the U.S. 
population and various population subgroups. In conducting this 
exposure assessment, very conservative assumptions--100% of all 
commodities will contain triadimefon residues, and those residues would 
be at the level of the tolerance--which result in a large overestimate 
of human exposure. Thus, in making a safety determination for these 
tolerances, Bayer took into account this very conservative exposure 
assessment.
    b. Acute. EPA has not estimated non-occupational exposures other 
than dietary for triadimefon. Acceptable, reliable data are not 
currently available with which to assess acute risk. Triadimefon is 
registered for outdoor residential use (lawn use). While dietary and 
residential scenarios could possibly occur in a single day, triadimefon 
would rarely be present on both the food eaten and the lawn on that 
single day. Even assuming this were the case, it is yet more unlikely 
that residues would be present at tolerance level on all food eaten 
that day for which triadimefon tolerances exist, as is assumed in the 
acute dietary risk analysis, and on the lawn that same day. Because the 
acute dietary exposure estimate assumes tolerance level residues and 
100% crop treated for all crops evaluated, it is a large over-estimate 
of exposure and is considered to be protective of any acute exposure 
scenario.
    2. Drinking water exposure. Based on the available studies used in 
EPA's assessment of environmental risk, triadimefon and its metabolites 
are mobile and persistent and have the potential to leach into 
groundwater. There is no established Maximum Concentration Level for 
residues of triadimefon in drinking water. No drinking water health 
advisory levels have been issued for triadimefon or its metabolite 
triadimenol. The ``Pesticides in Groundwater Database'' (EPA 734-12-92-
001, September 1992) indicated that triadimefon was monitored for in 14 
wells in California from 1984 to 1989. There were no detectable 
residues (limit of detection was not stated). Although the Agency does 
not have available data to perform a quantitative drinking water risk 
assessment for triadimefon at this time, Bayer is currently conducting 
2 prospective groundwater monitoring studies. Previous experience with 
more persistent and mobile pesticides for which there have been 
available data to perform quantitative risk assessments have 
demonstrated that drinking water exposure is typically a small 
percentage of the total exposure when compared to the total dietary 
exposure. This observation holds even for pesticides detected in wells 
and drinking water at levels nearing or exceeding established MCLs. 
Based on this experience and the Agency's best scientific judgement, 
EPA concludes that it is not likely that the potential exposure from 
residues of triadimefon in drinking water added to the current dietary 
exposure will result in an exposure which exceeds the RfD.
    3. Non-occupational exposure. Triadimefon is currently registered 
for use on turf and ornamentals. Bayer has conducted and submitted to 
the EPA an exposure study designed to measure the upper bound acute 
exposure potential of adults and children from contact with triadimefon 
treated turf. The population considered to have the greatest potential 
exposure from contact with pesticide treated turf soon after pesticides 
are applied are young children. The estimated safe residue levels for 
triadimefon on treated turf for 10-year-old children ranged from 1.3 - 
6.4 g/cm2 and for 5-year-old children from 1.1 - 
5.6 g/cm2. This compares with the average 
triadimefon transferable residue level of 1.0 g/cm2 
present immediately after the sprays have dried. These data indicate 
that children can safely contact triadimefon-treated turf as soon after 
application as the spray has dried.

D. Cumulative Effects

    At this time, the Agency has not made a determination that 
triadimefon and other substances that may have a common mode of 
toxicity would have cumulative effects. For purposes of this tolerance, 
only the potential risks of triadimefon in its aggregate exposure are 
being considered.

E. Safety Determination

    1. U.S. population.--a. Chronic risk. Based on the available 
chronic toxicity data, EPA has established the RfD for triadimefon at 
0.04 milligrams(mg)/kilogram(kg)/day. This RfD is based on a 2-year dog 
feeding study with a NOEL of 11.4 mg/kg/day and an uncertainty factor 
of 300. An uncertainty factor of 300 was applied to account for inter-
species extrapolation (10), intra-species variability (10), and the 
lack of an adequate reproduction study (3). Decreased food intake, 
depression in weight gain, and significantly (p <0.05) increased 
alkaline phosphatase activity in both sexes were the effects observed 
at the lowest effect level (LEL). Using the conservative exposure 
assumptions described above, Bayer has determined that aggregate 
dietary exposure to triadimefon from the previously established and the 
proposed tolerance on coffee will utilize 12.32% of the RfD for the 
U.S. population (48 states). There is generally no concern for 
exposures below 100 percent of the RfD because the RfD represents the 
level at or below which daily aggregate exposure over a lifetime will 
not pose appreciable risks to human health. Acceptable, reliable data 
are not available to quantitatively assess risk from drinking water or 
from

[[Page 40078]]

residential uses. However, there is a reasonable certainty that no harm 
will result from aggregate exposure to triadimefon residues.
    b. Acute risk. The EPA has recommended that the developmental NOEL 
from the rabbit developmental toxicity study (20 mg/kg/day) be used for 
acute dietary risk calculations. Based on the NFCS 1989-92 data base, 
the population of concern for this risk assessment is children 1-6 
years old. The calculated Margin Of Exposure (MOE) value is 531. This 
MOE does not exceed the Agency's level of concern for acute dietary 
exposure.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of triadimefon, the 
data from developmental studies in both rat and rabbit and a 2-
generation reproduction study in the rat should be considered. The 
developmental toxicity studies evaluate any potential adverse effects 
on the developing animal resulting from pesticide exposure of the 
mother during prenatal development. The reproduction study evaluates 
any effects from exposure to the pesticide on the reproductive 
capability of mating animals through 2-generations, as well as any 
observed systemic toxicity. A rat and rabbit developmental toxicity 
studies and a 2-generation and 3-generation rat reproduction studies 
have been conducted with triadimefon as described above under 
Toxicology Profile. Maternal and developmental toxicity NOELs of 30 mg/
kg/day were determined in the rat developmental toxicity studies. In 
the rabbit developmental toxicity study, the maternal NOEL was 50 mg/kg 
bwt/day and the developmental NOEL was 20 mg/kg bwt/day. Although EPA 
has accepted the rat and rabbit developmental toxicity studies, they 
have determined that the rat reproduction studies are not acceptable 
and question whether another study would adequately answer the question 
about the potential reproductive toxicity of triadimefon. The EPA 
believes that the additional information my be collected from the 90-
day neurotoxicity study which was submitted to the EPA on October 30, 
1996.
    a. Chronic risk. FFDCA Section 408 provides that EPA may apply an 
additional safety factor for infants and children in the case of 
threshold effects to account for pre- and post-natal effects and the 
completeness of the toxicity database. Therefore, EPA has incorporated 
an additional 3-fold uncertainty factor into the calculation of the RfD 
because of the absence of an acceptable reproduction study. The Agency 
notes that there is approximately a 2-fold difference between the 
developmental NOEL of 20 mg/kg/day from the rabbit developmental 
toxicity study and the NOEL of 11.4 mg/kg/day from the 2-year dog 
feeding study which was the basis of the RfD. It is further noted that 
in the rabbit developmental toxicity study, the developmental NOEL of 
20 mg/kg/day is lower than the maternal systemic NOEL of 50 mg/kg/day, 
suggesting the possibility of increased sensitivity for the pre-natal 
child. The TMRC value for the most highly exposed infant and children 
subgroup (non-nursing infants <1 year old) occupies 35.1% of the RfD. 
However, this calculation also assumes 100% crop treated and uses 
tolerance level residues for all commodities. Refinement of the dietary 
risk assessment by using percent of crop treated and anticipated 
residue data would likely greatly reduce the dietary exposure estimate 
and result in an anticipated residue contribution (ARC) which would 
occupy a percent of the RfD that is substantially lower than the 
currently calculated TMRC value. Should an additional uncertainty 
factor be deemed appropriate, when considered in conjunction with a 
refined exposure estimate, it is unlikely that the dietary risk will 
exceed 100 percent of the RfD. Therefore, taking into account the 
completeness and reliability of the toxicity data and the conservative 
exposure assessment, there is a reasonable certainty that no harm will 
result to infants and children from aggregate exposure to triadimefon 
residues.
    b. Acute risk. The EPA has recommended that the developmental NOEL 
from the rabbit developmental toxicity study (20 mg/kg/day) be used for 
acute dietary risk calculations. Based on the NFCS 1989-92 data base, 
the population of concern for this risk assessment is children 1-6 
years old. The calculated Margin Of Exposure (MOE) value is 531. This 
MOE does not exceed the Agency's level of concern for acute dietary 
exposure.

F. International Issues

    A Codex Maximum Residue Level (MRL) of 0.1 ppm has been established 
for residues of triadimefon and triadimenol.

G. Mode of Action

     Triadimefon is a sterol demethylation inhibitor (DMI) fungicide. 
It is systemic and shows activity against rust infecting coffee. 
Triadimefon provides protective activity by preventing completion of 
the infection process by direct inhibition of sterol synthesis. It is 
rapidly absorbed by plants and translocated systemically in the young 
growing tissues.   (PM 22)

2. E.I. duPont de Nemours & Co. (DuPont)

PP 7F4805

    EPA has received a pesticide petition (PP) 7F4805 from E.I. duPont 
de Nemours & Co. (DuPont), P.O. Box 80038, Wilmington, DE 19880-0038 
proposing, pursuant to section 408(d) of the Federal Food, Drug and 
Cosmetic Act (FFDCA), 21 U.S.C. Section 346a, to amend 40 CFR 180.474 
by establishing tolerances for residues of the fungicide cymoxanil: 2-
cyano-N-[(ethylamino)carbonyl]-2-(methoxyimino)acetamide in or on the 
raw agricultural commodity potatoes at 0.1 ppm. The proposed analytical 
method for determining residues is high performance liquid 
chromatography.

A. Residue Chemistry

    1. Plant metabolism. The metabolism of cymoxanil in plants is 
adequately understood for the purposes of this tolerance. Cymoxanil 
degrades rapidly and extensively in potatoes to natural products. The 
primary metabolite is glycine (a natural amino acid), which is 
reincorporated into other naturally occurring products.
    2. Animal metabolism. The metabolism of cymoxanil in animals is 
adequately understood. Cymoxanil degrades rapidly and extensively in 
ruminants to natural products, including fatty acids, glycerol, glycine 
and other amino acids, lactose, and acid hydrolyzable formyl and acetyl 
groups.
    3. Analytical method. The proposed practical analytical method 
utilizes high performance liquid chromatography for detecting and 
measuring levels of cymoxanil in or on potatoes with a general limit of 
quantitation of 0.05 ppm. This method allows monitoring of food with 
residues at or above the levels proposed in this tolerance. This method 
has been validated by an independent laboratory.
    4. Magnitude of the residue in plants. Field residue trials were 
conducted with cymoxanil on potatoes at 19 test sites in the U.S. at 
rates equal to or higher than (up to 5 x ) the proposed maximum use 
rate with pre-harvest intervals as short as 0 days. No detectable 
cymoxanil residue (detection limit = 0.02 ppm) was found in any sample 
at any of the tested sites or rates.
    5. Magnitude of the residue in processed commodities. Because there 
were no detectable residues present in potato samples treated at highly 
exaggerated rates, no detectable residues are expected in processed 
potatoes at

[[Page 40079]]

rates which would appear on the product label.
    6. Magnitude of the residue in animals. Based on a ruminant 
metabolism study, no secondary tolerances in animal commodities are 
necessary.

B. Toxicological Profile of Cymoxanil

    1. Acute toxicity. Technical cymoxanil has low acute toxicity. The 
acute oral LD50 is 960 mg/kg in rats. The acute dermal 
LD50 is >2000 mg/kg in rabbits. The 4-hour rat inhalation 
LC50 is >5.06 mg/L. Minimal transient irritation of the skin 
and eyes was observed in rabbits. Cymoxanil did not cause skin 
sensitization in guinea pigs. Cymoxanil should be classified as 
Toxicity Category III for oral and dermal toxicity and Toxicity 
Category IV for inhalation toxicity and skin and eye irritation 
potential.
    2. Genotoxicity. A battery of in vitro and in vivo tests were 
conducted to determine the genotoxic potential of cymoxanil. Cymoxanil 
was negative for mutagenicity in in vitro bacterial (Salmonella 
typhimurium or Escherichia coli tester strains) and mammalian cell 
assays (Chinese hamster ovary (CHO) cells) and is therefore considered 
not mutagenic. Cymoxanil was positive for induction of chromosome 
aberrations in in vitro assays (CHO cells and human lymphocytes), but 
negative in 2 species of in vivo assays (rat clastogenicity and mouse 
micronucleus). The weight-of-evidence indicates that cymoxanil is not 
clastogenic. Cymoxanil was negative for induction of unscheduled DNA 
synthesis (UDS) in 1 in vitro assay but positive in another; however, 
it was negative for induction of UDS in both hepatocytes and 
spermatocytes when evaluated in in vivo assays.
    Therefore, Dupont believes that the weight-of-evidence indicates 
that cymoxanil does not produce DNA damage. In summary, cymoxanil is 
not considered genotoxic, nor does it have the potential to induce 
heritable effects.
    3. Reproductive and developmental toxicity. A 2-generation 
reproduction study in rats fed diets containing 0, 100, 500, or 1,500 
ppm resulted in no-observed-adverse-effects-level (NOAELs) of 100 ppm 
for both parental rats (equivalent to 6.50 and 7.85 mg/kg/day for P1 
males and females, respectively) and offspring (equivalent to 7.39 and 
8.85 mg/kg/day for F1 males and females, respectively). The NOAELs were 
based on alterations in body weight parameters, food consumption and 
food efficiency in the parents at 500 ppm, and decreases in pup weights 
and viability in the offspring at 500 ppm. Based on these results, 
cymoxanil is not a reproductive toxin.
    A developmental toxicity study was conducted with cymoxanil in rats 
at 0, 10, 25, 75, or 150 mg/kg/day on days 7-16 of gestation. The no-
observable-effect levels (NOELs) for maternal and developmental effects 
were considered to be 10 mg/kg/day for both maternal toxicity (based on 
reduced weight gain and food consumption at 25 ppm and above) and 
developmental toxicity (based on effects that included fetal variations 
in ossification at 25 ppm and above).
    A developmental toxicity study was conducted in rabbits at dose 
levels of 0, 4, 8 and 16 mg/kg/day. Cymoxanil was not considered 
maternally or fetally toxic at any dose level. A second rabbit study at 
0, 8, 16 and 32 mg/kg/day demonstrated toxicity to the doe at 16 mg/kg/
day. Changes in axial skeleton of the fetus were observed at all dose 
levels, but without direct relation to dosage. A third rabbit study was 
conducted at 0, 1, 4, 8, and 32 mg/kg/day. Maternal toxicity was 
observed at 8 mg/kg/day. Although skeletal variations were seen in some 
fetal groups, they were not considered related to cymoxanil since they 
were not statistically increased or dose related. A reevaluation of the 
combined results of all three rabbit studies using current statistical 
methods demonstrated NOAELs of 8 mg/kg/day for the doe and 4 mg/kg/day 
for the fetus.
    In the absence of significant differences between maternal and 
fetal effect levels (revealed in both the rat and combined rabbit 
studies), cymoxanil is not considered a developmental toxin.
    4. Subchronic toxicity. A 90-day feeding study was conducted in 
rats at dietary levels of 0, 100, 750, 1,500 or 3,000 ppm. Body weight 
effects, increased food consumption, decreased food efficiency, 
increased mean relative organ weights, and testicular (elongate 
spermatid degeneration) and epididymal histopathologic effects were 
observed at 1,500 and 3,000 ppm. The NOEL was 750 ppm (47.6 mg/kg/day 
males; 59.9 mg/kg/day females).
    The potential neurotoxicity of cymoxanil was evaluated in rats as 
part of the 90-day feeding study at dietary levels of 0, 100, 750, 
1,500 or 3,000 ppm. The NOEL for neurotoxicity was the highest dietary 
level tested, 3,000 ppm for male (224 mg/kg/day) and female (333 mg/kg/
day) rats. Cymoxanil is judged not to be a neurotoxicant.
    A 90-day feeding study was conducted in mice at dietary levels of 
0, 50, 500 and 1,750, 3,500 or 7,000 ppm. The highest dietary level was 
terminated by the third week of the study due to severe toxicity. The 
NOEL was established at 50 ppm for female mice (11.3 mg/kg/day) based 
on body weight effects at 500 ppm; no NOEL was established for male 
mice due to body weight effects and increased liver weights at all 
dietary levels. Liver weight increases were observed in female mice at 
1,750 and 3,500 ppm. No histopathologic alterations were found in male 
or female mice at levels up to 3,500 ppm.
    A 90-day feeding study was conducted in dogs at dietary levels of 
0, 100, 200 or 250/500 ppm (250 ppm for weeks 1 and 2; 500 ppm for the 
remainder of the study). No NOEL was established for female dogs due to 
lower body weight gain, food consumption and food efficiency at all 
dietary levels. The NOEL in males was 100 ppm (3 mg/kg/day) based on 
decreased body weight gain.
    A 28-day repeated dose dermal study was conducted with rats at 
dosages of 50, 500 or 1,000 mg/kg with daily 6-hour exposures. No 
toxicologically significant effects were observed in any treatment 
group. The NOEL is considered to be 1,000 mg/kg/day.
    5. Chronic toxicity/oncogenicity. A 12-month chronic feeding study 
was conducted in male dogs at dietary levels of 0, 50, 100 and 200 ppm 
and in female dogs at 0, 25, 50 and 100 ppm. The NOAELs for chronic 
toxicity were 100 ppm in male dogs (3.0 mg/kg/day) and 50 ppm in female 
dogs (1.6 mg/kg/day), based on body weight and food consumption effects 
in both sexes and decreased red cell parameters in males. No gross or 
histopathological effects were observed.
    An 18-month oncogenicity study was conducted in mice at dietary 
levels of 0, 30, 300, 1,500 or 3,000 ppm. The NOEL was 30 ppm (4.19 and 
5.83 mg/kg/day for males and females, respectively) based on 
histopathological effects in testis and liver for males and the mucosal 
lining of the gastrointestinal tract for females at 300 ppm. Cymoxanil 
is not considered oncogenic.
    A 2-year combined chronic toxicity/oncogenicity study was conducted 
in rats at dietary levels of 0, 50, 100, 700 or 2,000 ppm. The NOEL for 
chronic effects was 100 ppm (4.08 and 5.36 mg/kg/day for male and 
female rats, respectively), based on decreased mean body weights, mean 
body weight gains, food consumption, and food efficiency; and gross 
and/or histopathological alterations of the retina, lymph nodes, lung, 
intestine, testes, and sciatic nerve at 700 ppm. Cymoxanil is not 
considered oncogenic.

[[Page 40080]]

    6. Animal metabolism. An oral dose of radiolabelled cymoxanil was 
extensively metabolized and rapidly eliminated in the rat. More than 
85% of the dosed radioactivity is eliminated in the excreta, mostly in 
the urine, within 48 hours. After 96 hours, less than 1% of the 
administered dose remained in the tissues. The major excretory products 
were polar metabolites such as 2-cyano-2-methoxyimino acetic acid, 
glycine and other amino acid conjugates. These metabolites are rapidly 
metabolized to other natural products. A minor metabolite, 1-ethyl-5,6-
di-2,4(1H,3H)pyridinedione, was also identified and is postulated as an 
intermediate metabolite.
    7. Metabolite toxicology. Cymoxanil breaks down rapidly in plants 
and animals into naturally occurring compounds. Because of this, no 
significant risk is expected from exposure to potatoes or other crops 
treated with cymoxanil.
    8. Endocrine effects. No evidence of endocrine effects were 
observed upon comprehensive evaluation of data from the standard 
battery of EPA required toxicology studies. These animal studies were 
conducted at exposure levels that far exceed those likely to be 
experienced by a human. Thus, adverse endocrine effects are not 
expected to occur in humans (general population or sub-groups, 
including nursing infants and children).
    This battery of tests included, but is not limited to, the 
following studies: reproductive, developmental, subchronic, chronic/
oncogenicity and metabolism. Most of these studies included gross and 
histopathologic assessment of the endocrine organs (e.g., thyroid, 
mammary glands, and testes).

C. Aggregate Exposure

    Cymoxanil is a fungicide used on crops including potatoes, 
tomatoes, and grapes. Cymoxanil is not registered for non-crop use in 
any country. Although cymoxanil is not registered in the U.S., DuPont's 
request for import tolerances on grapes and tomatoes is pending review 
at EPA.
    No aggregate exposure considerations are required for cymoxanil 
because no residues are anticipated to occur in drinking water or from 
other non-occupational exposures. Human exposure to residues in food is 
the primary exposure consideration when calculating risk. Total chronic 
dietary exposure to the most sensitive sub-population (children 1-6 
yrs.) is determined to be less than 3% of the Reference Dose (RfD). 
Details are given below:
    1. Dietary (Food) Exposure. A complete and reliable database is 
available for the assessment of threshold effects of cymoxanil. 
Comparison of no effect levels (NOEL) for subchronic and chronic 
studies found that the dog was the most sensitive species with a NOEL 
of 1.6 mg/kg/day in the 1year study. The endpoint effects noted in this 
study were reduced body weight gain, food consumption, and food 
efficiency in females.
    Applying a 100-fold safety factor, 0.016 mg/kg/day was selected as 
the reference dose (RfD) in the dietary risk evaluation system (DRES) 
analysis. No additional safety factor was used for infants or children 
since they are not more sensitive to cymoxanil toxicity as discussed in 
section E.2 of this document.
    The ``worst-case'' DRES analysis included total potential dietary 
intake of cymoxanil residues from potatoes, grapes, and tomatoes. It 
was also assumed that 100% of these crops were treated with cymoxanil 
and that all commodities contained residues at the proposed tolerance 
levels (0.1 ppm). Analyses of actual field samples have detected no 
residues of cymoxanil above the limit of detection (0.02 ppm). Potato 
cells and processed potato waste may be fed to livestock. However, the 
lack of detectable cymoxanil residues in any feed item and the lack of 
transfer of cymoxanil to meat or milk in a ruminant metabolism study 
indicate there is no reasonable expectation of cymoxanil residue in 
meat and milk. Potatoes do not serve as a source of poultry feed, thus 
no residues are expected in poultry or eggs.
    Using this conservative exposure scenario, the DRES estimates a 
theoretical maximum daily intake of 0.000216 mg/kg/day or 1.35% of the 
RfD for the general U.S. population. Since cymoxanil is unlikely to 
occur in drinking water, water was not included in this assessment (see 
Section D.2 of this document). The most sensitive sub-population is 
children (1-6 yrs.) with a predicted intake of 2.63% of the RfD. Using 
the conservative exposure assumptions described above, it is estimated 
that the cymoxanil exposure for infants and children ranges from 0.29% 
of the RfD for nursing infants to 2.63% for children 1-6 years old.
    An acute dietary risk exposure analysis for cymoxanil was not 
performed. Since potatoes are the only commodity for which registration 
of cymoxanil is being sought, significant dietary impact to any U.S. 
population is not anticipated. Cymoxanil is not registered on grapes in 
Chile or tomatoes in Mexico, the major countries that import these 
commodities to the U.S. Therefore, exposure to cymoxanil from grapes 
and tomatoes imported into the United States would not be expected to 
contribute significantly to the U.S. diet. In addition, exposure to 
cymoxanil through drinking water is unlikely since cymoxanil degrades 
rapidly in soil and water as discussed in section D.2 of this document.
    2. Dietary (Drinking Water) Exposure. It is unlikely that there 
will be exposure to significant residues of cymoxanil through drinking 
water supplies. Cymoxanil degrades rapidly in the environment. Studies 
to satisfy the environmental fate data requirements are included with 
this submission. Evaluation of these studies indicates the potential 
for cymoxanil residues to be detected in drinking water supplies at 
significant levels is minimal. Degradation from photolysis and both 
anaerobic and aerobic metabolism in soils occur rapidly. Degradation 
products also decline rapidly. The half-life of cymoxanil in soil under 
field conditions was 1 to 9 days. Although cymoxanil and its degradates 
are weakly adsorbed to the soil, they degrade so rapidly that movement 
into groundwater is unlikely. Should movement into surface or ground 
water occur, degradation will be very rapid. In water the photolytic 
half-life of cymoxanil is less than 2-days at neutral and acidic 
conditions, and its hydrolytic half-life at pH 9 is less than 1 hour.
    3. Non-dietary exposure. Since cymoxanil is to be used on food 
crops only there will be no non-dietary non-occupational exposure.

D. Cumulative Effects

    Given cymoxanil's unique chemistry, low acute toxicity, the absence 
of genotoxic, oncogenic, developmental, or reproductive effects, and 
low exposure potential (see section C), the expression of cumulative 
human health effects with cymoxanil and other natural or synthetic 
pesticides is not anticipated. The potential for cumulative effects of 
cymoxanil and other substances, that have a common mechanism of 
toxicity, has been considered and is not applicable. Cymoxanil is a 
unique cyanoacetamide and is chemically unrelated to any other 
commercial plant disease control agents. Its biochemical mode of action 
in fungi appears to be unique; it is theorized to act through 
inhibition of multiple cellular processes, but a definitive mechanism 
is not completely elucidated. Similarly, the mechanism of action 
underlying observed toxicological effects in mammals is not fully 
characterized and there is no reliable information to

[[Page 40081]]

suggest that cymoxanil has a mechanism of toxicity in common with any 
other compound.

E. Safety Determination

    1. U.S. population. Dupont believes that the chronic dietary risk 
assessment demonstrates that an adequate margin of safety exists for 
all U.S. sub-populations under DRES consideration.
    A ``worst case'' DRES analysis was performed using proposed 
tolerance levels for potatoes, tomatoes, and grapes and assuming 100% 
of all crops are treated. Using these conservative assumptions, the 
percentage of the RfD utilized by the general U.S. population is 1.35%. 
The most sensitive sub-population, children 1-6 yrs., utilized 2.63% of 
the RfD. These levels are well below those which would cause an 
appreciable risk of harm from aggregate exposure to cymoxanil residues.
    2. Infants and children. Based on the current toxicological 
requirements, a complete and reliable database exists to assess the 
potential for additional sensitivity of infants and children to the 
residues of cymoxanil. Data from developmental and reproductive 
toxicity studies (see section B.3) show that developing and young 
animals are no more susceptible to prenatal and postnatal effects of 
cymoxanil than the adult animals. In addition, the NOAEL from the dog 
study proposed as the basis for the RfD is already more than 3-fold 
lower than the lowest NOAEL observed in immature animals in the 
developmental or reproductive studies. Therefore, Dupont concludes that 
the safety factor used for protection of adults is fully appropriate 
for the protection of infants and children; no additional safety factor 
is necessary.
    Thus toxicity of cymoxanil to developing and young animals is no 
greater than to adults as demonstrated in the developmental and 
reproductive toxicity studies.
    Nonetheless, children 1-6 yrs. are identified as the most sensitive 
sub-population in the chronic dietary risk analysis based on potential 
for exposure (i.e., food consumption patterns). This sub-population 
consumes more potatoes, grapes, and tomatoes than the general U.S. 
population and other sub-populations. The chronic DRES found children 
1-6 yrs. utilized 2.63% of the RfD. The general U.S. population 
utilized 1.35% of the RfD and the exposure for infants and children 
ranged from 0.29% of the RfD for nursing infants to 2.63% for children 
1-6 yrs.

F. International Tolerances

    Cymoxanil, a fungicide used to control potato late blight, is 
currently registered for use on potatoes in 35 countries, including the 
major European countries. The following Codex Alimentarius Commission 
(Codex) Maximum Residue Levels (MRL's) for cymoxanil on potatoes have 
been established: Belgium, Germany, Indonesia, Mexico, Netherlands, 
Portugal, Spain, Switzerland - 0.05 ppm, Austria, Brazil, Japan, Italy 
- 0.10 ppm, Hungary - 0.50 ppm, and Luxembourg - 2.0 ppm.
    The U.S. Tolerance for potatoes being proposed is 0.10 ppm which is 
twice the limit of quantitation of 0.05 ppm in the residue enforcement 
method. Tolerances are not required for processed potatoes because no 
residues were detected (detection limit = 0.02 ppm) in the magnitude of 
residue study at highly exaggerated rates.
    MRL's are also established internationally for cymoxanil on grapes, 
tomatoes, hops, tobacco and various other vegetables. MRL's on grapes 
range from 0.05-1.0 ppm and on tomatoes from 0.05-2.0 ppm. MRL's for 
all other crops range from 0.05-2.0 ppm.   (PM 21)

3. Novartis Crop Protection, Inc.

PP 5E4526

    EPA has received a pesticide petition (PP 5E4526) from Novartis 
Crop Protection, Inc. 410 Swing Road, Greensboro, NC 27401, proposing 
to amend 40 CFR Part 180 by establishing a tolerance for residues of 
the fungicide, difenoconazole, in or on the raw agricultural commodity 
bananas at 0.2 ppm.
    Analytical method AG-575B (MRID 42806504) is proposed as the 
regulatory enforcement method. It is a revised version of AG-575A, 
which was used to determine residues of difenoconazole in or on 
bananas. The procedures in AG-575A remain unaltered in the revised 
method, AG-575B, which incorporates specificity data and methodology 
for megabore column gas chromatography. Procedural recoveries on banana 
substrates (peel and pulp), fortified prior to extraction at levels 
ranging from 0.02 ppm to 0.2 ppm, averaged 90.7+12% (n=42). Recoveries 
ranged from 60 to 115%. Storage stability has been demonstrated under 
frozen conditions for periods of up to 364 days.

A. Chemical Uses

    Difenoconazole is the active ingredient in Sico 25EC, Sico 250EC, 
Score 25EC, and Score 250EC, fungicides that offer broad-spectrum 
control of several diseases in bananas and plantains. In the current 
petition, Sico and Score are being developed as foliar treatments for 
bananas. Difenoconazole is highly active at rates of 75 to 100 g a.i./
ha.

B. Difenoconazole Safety

    Novartis has submitted over 20 toxicity studies in support of 
tolerances for difenoconazole. Difenoconazole has a low order of acute 
toxicity, minimal irritation potential, and no sensitization potential. 
There was no evidence of genotoxicity, and it is not fetotoxic, 
embryolethal, or teratogenic. It is not a reproductive toxin. The main 
target organ of toxicity was the liver in the species tested. There was 
an increase in liver tumors only in mice, and only, according to the 
Carcinogenicity Peer Review Committee, at doses considered excessively 
high for carcinogenicity testing. The EPA has concluded that for the 
purpose of risk characterization, the Margin of Exposure (MOE) approach 
(threshold model) should be used for quantification of human risk. 
Margins of exposure are extremely high for the US population and all 
population subgroups for both chronic effects and acute toxicity.
    The following mammalian toxicity studies were conducted and 
submitted in support of tolerances for difenoconazole. No-observable-
effect levels are consistent with those published in the Federal 
Register of August 24, 1994 (FR 59 43491).
    A rat acute oral study with an LD50 of 1,453 mg/kg.
    A rabbit acute dermal study with an LD50 of >2010 mg/kg.
    A rat acute inhalation study with an LC50 of >3.285 mg/
L.
    A primary eye irritation study in the rabbit which showed slight 
irritation.
    A primary dermal irritation study in the rabbit which showed slight 
irritation.
    A dermal sensitization study in the guinea pig which showed no 
irritation.
    A 13-week rat feeding study identified liver as a target organ and 
had a no-observable-effect level (NOEL) of 20 ppm.
    A 13-week mouse feeding study identified liver as a target organ 
and had a NOEL of 20 ppm.
    A 26-week dog feeding study identified liver and eye as target 
organs and had a NOEL of 100 ppm.
    A 21-day dermal study in rabbits had a NOEL of 10 mg/mg/day based 
on decreased body weight gain at 100 and 1,000 mg/kg/day.
    A 24-month feeding study in rats had a NOEL of 20 ppm based on 
liver toxicity at 500 and 2,500 ppm. There

[[Page 40082]]

was no evidence of an oncogenic response.
    An 18-month mouse feeding study had an overall NOEL of 30 ppm based 
on decreased body weight gain and liver toxicity at 300 ppm. There was 
an increase in liver tumors only at dose levels that exceeded the 
maximum tolerated dose (MTD). The oncogenic NOEL was 300 ppm.
    A 12-month feeding study in dogs had a NOEL of 100 ppm based on 
decreased food consumption and increased alkaline phosphatase levels at 
500 ppm.
    An oral teratology study in rats had a maternal NOEL of 16 mg/kg/
day based on excess salivation and decreased body weight gain and food 
consumption. The developmental NOEL of 85 mg/kg/day was based on 
effects seen secondary to maternal toxicity including slightly reduced 
fetal body weight and minor changes in skeletal ossification.
    An oral teratology study in rabbits had maternal NOEL of 25 mg/kg/
day based on decreased body weight gain, death, and abortion. The 
developmental NOEL of 25 mg/kg/day was based on effects seen secondary 
to maternal toxicity including slight increase in post-implantation 
loss and resorptions, and decreased fetal weight.
    A 2-generation reproduction study in rats had a parental and 
reproductive NOEL of 25 ppm based on significantly reduced female body 
weight gain, and reductions in male pup weights at 21 days.
    There was no evidence of the induction of point mutations in an 
Ames test.
    There was no evidence of mutagenic effects in a mouse lymphoma 
test.
    There was no evidence of mutagenic effects in a nucleus anomaly 
test with Chinese hamsters.
    There was no evidence of induction of DNA damage in a rat 
hepatocyte DNA repair test.
    There was no evidence of induction of DNA damage in a human 
fibroblast DNA repair test.

C. Threshold Effects

    1. Chronic effects. Based on the data from chronic studies in rats, 
mice, and dogs, the Reference Dose (RfD) for difenoconazole is 0.01 mg/
kg/day Federal Register of August 24, 1994 (FR 59 43492). The RfD for 
difenoconazole is based on the chronic study in rats with a threshold 
No-Observable-Effect Level of 1 mg/kg/day and an uncertainty factor of 
100.
    2. Acute toxicity. The EPA has concluded that the dietary acute 
margin of exposure (MOE) for developmental toxicity was 25,000 for high 
exposure in the females 13+ subgroup. The agency is generally not 
concerned unless the MOE is below 100 for substances whose acute NOEL 
is based on animals studies.
    Novartis concurs, and has also considered that since the percentage 
of the RfD utilized in the chronic exposure analysis for all population 
subgroups is less than 10, it is highly unlikely that any acute dietary 
exposure scenario would utilize a significant percentage of the RfD.
    Since margins of exposure of 100 or more are considered 
satisfactory, there is no concern for acute dietary exposure for the US 
population, for various population subgroups, or for either gender.
    3. Non-threshold effects (Carcinogenicity). The Health Effects 
Division Carcinogenicity Peer Review Committee (CPRC) evaluated the 
weight-of-the-evidence on difenoconazole with reference to its 
carcinogenic potential. The CPRC concluded that difenoconazole should 
be classified a Group C carcinogen, and for the purpose of risk 
characterization the Margin of Exposure (MOE) approach should be used 
for quantification of human risk.
    In the 18-month study with CD-1 mice, there was a statistically 
significant increase in hepatocellular adenomas, carcinomas, and 
combined adenomas/carcinomas in both sexes, but only at dose levels 
which were considered excessively high for carcinogenicity testing. 
This is considered very weak evidence of carcinogenic potential. 
Additionally, there was no evidence of carcinogenicity in either sex of 
CD rat after 24 months, and there was no evidence of genotoxicity. 
Therefore, a threshold model should be used for estimating risk. The 
CPRC determined that a NOEL of 4.7 mg/kg/day, based on endpoints 
related to hepatic tumor development, should be used for calculating 
MOE's. The margin of exposure, calculated using worst case assumptions, 
was 9,958 for the US population.

D. Aggregate Exposure

    When the potential dietary exposure to difenoconazole is 
calculated, the theoretical maximum residue concentration (TMRC) of 
0.00041 mg/kg/day utilizes 4% of the RfD for the overall US population. 
For the most exposed population subgroups, children and non-nursing 
infants, the TMRC is 0.000946 mg/kg/day, utilizing 9% of the RfD 
(Federal Register, August 24, 1994 FR 59 43492).
    Novartis has conducted another exposure analysis using additional 
crops and similar conservative assumptions. In this analysis, oats, 
barley, and bananas (pending import tolerance) were included in 
addition to wheat. Tolerances or proposed tolerances were 0.1 ppm each 
for wheat, oats, and barley, and 0.2 ppm for bananas. Tolerances were 
0.01 ppm for milk and 0.05 ppm for all other commodities: beef, goat, 
horse, rabbit, sheep, pork, turkey, eggs, chicken, and other poultry. 
Very conservative assumptions were used to estimate residues (i.e. 100% 
of all wheat, oats, barley and imported bananas used for human 
consumption or forage was treated and all RACs contained tolerance 
level residues). These estimates result in a extreme overestimate of 
human dietary exposure. Calculated TMRC values from these assumptions 
utilize 4.7% of the RfD for the US population and 12.51% of the RfD for 
non-nursing infants.
    Although the import tolerance for bananas would not lead to the 
exposure of the general population to residues of pesticides in 
drinking water, this source of exposure was considered in the risk 
assessment. Difenoconazole is currently used in the U.S. as a seed 
treatment and residues are, therefore, incorporated into the soil at 
very low rates (0.0125 to 0.025 lb a.i./100 lb of seed). The likelihood 
of contamination of surface water from run-off is essentially 
negligible. In addition, parent and aged leaching, soil adsorption/ 
desorption, and radiolabeled pipe studies indicated that difenoconazole 
has a low potential to leach in the soil and would not be expected to 
reach aquatic environments. For these reasons and because of the low 
use rate, exposures to residues in ground water are not anticipated.
    Non-occupational exposure for difenoconazole has not been estimated 
since the current registration in the U.S. is limited to seed 
treatment. Therefore, the potential for non-occupational exposure to 
the general population is insignificant.
    Novartis has considered the potential for cumulative effects of 
difenoconazole and other substances of common mechanism of toxicity. 
Novartis has concluded that consideration of a common mechanism of 
toxicity in aggregate exposure assessment is not appropriate at this 
time. Novartis has no information to indicate that the toxic effects 
(generalized liver toxicity) seen at high doses of difenoconazole would 
be cumulative with those of any other compound. Thus, Novartis is 
considering only the potential risk of difenoconazole from dietary 
exposure in its aggregate and cumulative exposure assessment.

[[Page 40083]]

E. Safety Determination

    1.U.S. population. Reference Dose (RfD); using the very 
conservative exposure assumptions described above, and based on the 
completeness of the toxicity data base for difenoconazole, Novartis 
calculates that aggregate exposure to difenoconazole utilizes <5% of 
the RfD for the US population based on chronic toxicity endpoints (NOEL 
= 1 mg/kg/day). When using the carcinogenic NOEL of 4.7 mg/kg/day and 
the margin of exposure approach recommended by the CPRC, approximately 
1% of the RfD is utilized.
    If more realistic assumptions were used to estimate anticipated 
residues and appropriate market share, this percentage would be 
considerably lower, and would be significantly lower than 100%, even 
for the highest exposed population subgroup. EPA generally has no 
concern for exposures below 100% of the RfD. Therefore, Novartis 
concludes that there is reasonable certainty that no harm will result 
from daily aggregate exposure to residues of difenoconazole over a 
lifetime.
    2. Infants and children. Developmental toxicity and 2-generation 
toxicity studies were evaluated to determine if there is a special 
concern for the safety of infants and children from exposure to 
residues of difenoconazole. There was no evidence of embryotoxicity or 
teratogenicity, and no effects on reproductive parameters, including 
number of live births, birth weights, and post-natal development, at 
dose levels which did not cause significant maternal toxicity. In 
addition, there were no effects in young post-weaning animals that were 
not seen in adult animals in the 2-generation reproduction study. 
Therefore, Novartis concludes that it is inappropriate to assume that 
infants and children are more sensitive than the general population to 
effects from exposure to residues of difenoconazole.

F. Estrogenic Effects

    Developmental toxicity studies in rats and rabbits and a 2-
generation reproduction study in rats gave no specific indication that 
difenoconazole may have effects on the endocrine system with regard to 
development or reproduction. Furthermore, histologic investigations 
were conducted on endocrine organs (thyroid, adrenal, and pituitary, as 
well as endocrine sex organs) from long-term studies in dogs, rats and 
mice. There was no indication that the endocrine system was targeted by 
difenoconazole, even when animals were treated with maximally tolerated 
doses over the majority of their lifetime.
    Difenoconazole has not been found in raw agricultural commodities 
at the limit of quantification. Based on the available toxicity 
information and the lack of detected residues, it is concluded that 
difenoconazole has no potential to interfere with the endocrine system, 
and there is no risk of endocrine disruption in humans.

G. Chemical Residues

    The nature of the residue is adequately understood in plants and 
animals. The metabolism of difenoconazole has been studied in wheat, 
tomatoes, potatoes, and grapes. The metabolic pathway was the same in 
these 4 separate and distinct crops. There are no Codex maximum residue 
levels established for residues of difenoconazole in bananas. Novartis 
has submitted a practical analytical method for detecting and measuring 
levels of difenoconazole in or on food with the limit of quantitation 
that allows monitoring of food with residues at or above the levels set 
in the proposed tolerances. EPA will provide information on this method 
to FDA. The method is available to anyone who is interested in 
pesticide residue enforcement from the Field Operations Division, 
Office of Pesticide Programs. Confirmatory methods have also been 
supplied.
    Eleven field residue studies were conducted in the major banana-
producing regions of Central America (Belize, Costa Rica, Guatemala), 
South America (Ecuador), and Mexico. Up to 8 applications were made at 
the label maximum of 100 g a.i./ha. Some applications were made at a 
200 g a.i./ha (2 x ) rate for comparison purposes. Samples of bagged 
(standard commercial practice in many countries) and unbagged bananas 
were obtained 0, 1, and 2 days after the last application. Ten studies 
were conducted using ground equipment and one study was applied by air. 
Six replicate bunches were collected in several studies to determine 
sample variation. Selected samples were split; one-half was frozen 
immediately and the other half was stored under refrigerated or room 
temperature conditions to mimic typical transport to market. Samples 
were separated into peel and pulp for analysis using analytical method 
AG-575A.
    Difenoconazole was found in only 4 of 76 pulp samples at the 1 x  
rate and 5 of 36 samples at the exaggerated (2 x ) rate. The maximum 
residues found in pulp were 0.03 ppm and 0.05 ppm for the 1 x  and 2 x  
treatments, respectively. On a whole fruit basis, the maximum residues 
found for the 1 x  and 2 x  treatments were 0.16 ppm and 0.24 ppm, 
respectively. Residues in bagged fruit were generally lower than 
unbagged fruit. Residues were independent of the preharvest intervals 
(PHIs) used in these studies. The data support a 0.2 ppm tolerance in 
bananas with no PHI.
    There were no differences in residues between samples of green 
fruit frozen immediately and fruit allowed to ripen at temperatures 
normally encountered in transit to the US, indicating some residue 
stability even at temperatures above freezing.
    Freezer storage stability has also been demonstrated. Banana whole 
fruit samples were macerated, fortified at 0.2 ppm with difenoconazole, 
and stored for one year in the freezer. Samples analyzed at 0-, 28-, 
84-, 168-, and 364-day intervals exhibited no degradation of the 
difenoconazole, demonstrating stability under these storage conditions.
    Information on the transfer of residues to animals is not required 
or relevant to this petition. Since there are no animal feedstuffs 
produced from this use on bananas, transfer of residues to livestock 
will not occur.
    There are no Codex tolerances established for difenoconazole in 
bananas.

H. Environmental Fate

    Although the import tolerance for bananas would not lead to the 
exposure of the general population to residues of pesticides in the 
environment, these sources of exposure were considered in the risk 
assessment. Difenoconazole is hydrolytically stable in solution at 25 
degrees Celcius at pH 5, 7, and 9. The aerobic soil metabolism half-
life ranges from 75 to over 1,000 days in various soils and 
environmental conditions. Difenoconazole is considered to be immobile 
in soil.   (PM 22)

4. Novartis Crop Protection Inc.

PP 6F4723

    EPA has received a pesticide petition (PP) 6F4723 from Novartis 
Crop Protection, Inc. (Novartis), P.O. Box 18300, Greensboro, NC 27419 
proposing, pursuant to section 408(d) of the Federal Food, Drug and 
Cosmetic Act (FFDCA), 21 U.S.C. Section 346a, to amend 40 CFR 180.474 
by establishing revised tolerances for residues of the fungicide 
CGA329351 ([(R)-2-[(2,6-dimethylphenyl)-methoxyacetylamino]-propionic 
acid methyl ester). CGA329351 is the more active enantiomer contained 
in the racemic fungicide metalaxyl. Novartis believes

[[Page 40084]]

that because of its systemic and intrinsic activity, effective disease 
control can be obtained with mefenoxam at one-half the rate required 
for metalaxyl. This petition reflects the reduced dietary exposure 
associated with using CGA329351.

A. Residue Chemistry

    1. CGA329351 uses. CGA329351 is highly efficacious against Pythium 
spp., Phytophthora spp., and fungi which cause downy mildews of turf, 
ornamental, and agricultural crops. Application methods include seed 
treatment, in-furrow, soil drenches, and/or foliar.
    2. Metabolism. Novartis believes the studies supporting this 
CGA329351 petition well characterize metabolism in plants and animals. 
The metabolism profile supports the use of an analytical enforcement 
method that accounts for combined residues of CGA329351 and its 
metabolites which contain the 2,6-dimethylaniline (DMA) moiety.
    3. Analytical methodology. Novartis has submitted a practical 
analytical method involving extraction, filtration, acid reflux, steam 
distillation, and solid phase cleanup with analysis by confirmatory gas 
chromatography using Nitrogen/Phosphorous (N/P) detection. A total 
residue method is used for determination of the combined residues of 
CGA329351 and its metabolites which contain the 2,6-dimethylaniline 
(DMA) moiety. The limit of quantitation (LOQ) for the method is 0.05 
ppm.
    4. Magnitude of residue. This petition is supported by field 
residue trials conducted at various rates, timing intervals, and 
applications methods to represent the use patterns which would most 
likely result in the highest residues. In comparative side-by-side 
residue tests where CGA329351 was applied at one-half the labeled use 
rate of metalaxyl, resultant CGA329351 residues averaged one-half of 
those produced from the use of metalaxyl. For all samples, the total 
residue method was used for determination of the combined residues of 
parent and its metabolites which contain the DMA moiety.

B. Toxicological Profile of CGA329351

    Rat acute oral study with a LD50 value of 490 mg/kg.
    Rat acute dermal study with a LD50 > 2000 mg/kg.
    Rat inhalation study with a LC50 > 2.29 mg/liter air.
    Primary eye irritation study in rabbit showing CGA329351 as 
severely irritating.
    Primary dermal irritation study in rabbit showing CGA329351 as 
slightly irritating.
    Skin sensitization studies in guinea pigs (Maximization and Buehler 
Test) showing CGA329351 is not a sensitizer.
    A 28-days cumulative toxicity study in rats with a No Observed 
Effect Level (NOEL) of 50 mg/kg based on liver changes.
    A 90-day subchronic dietary toxicity study in rats with a NOEL of 
250 ppm based on liver changes.
    A 90-day subchronic dietary toxicity study in dogs with a NOEL of 
250 ppm basedon changes in blood biochemistry and hematology indicative 
of functional liver changes.
    A 21-day dermal toxicity study in rats with a NOEL equal to or 
higher than the limit dose of 1,000 mg/kg. No local or systemic signs 
of toxicity were found.
    A 6-month dietary toxicity study in dogs with a NOEL of 250 ppm 
based on changes in blood biochemistry indicative of hepatocellular 
damage.
    A 24-month combined chronic toxicity / carcinogenicity study 
conducted in rats with a NOEL of 250 ppm based on liver changes. No 
evidence of oncogenicity was seen.
    A 24-month oncogenicity study conducted in mice with a NOEL of 250 
ppm based on liver changes. No evidence of oncogenicity was seen.
    Teratology study in rats with a maternal NOEL of 10 mg/kg based on 
reduced body weight gain. The fetuses remained entirely unaffected at 
the highest dose tested, 250 mg/kg.
    Teratology study in rabbits with a maternal NOEL of 150 mg/kg based 
on body weight loss. The developmental NOEL was greater than or equal 
to the highest dose tested, 300 mg/kg.
    3-generation reproduction study in rats with a NOEL of 1,250 ppm, 
which was the highest dose tested. The treatment had no effect on 
reproduction or fertility.
    In vitro gene mutation test: Ames test - negative.
    In vitro chromosomal aberration test: Chinese hamster ovary (CHO)- 
negative.
    In vitro gene mutation tests: Ames tests (3 independent studies) - 
negative; gene mutation in mouse lymphoma cells - negative; reverse 
mutation in Saccharomyces cerevisiae - negative.
    In vitro chromosomal aberration tests: Chinese hamster bone marrow 
cytogenetic test - negative.
    DNA repair study in rat hepatoctes - negative.
    Dominant lethal study in mouse - negative.

C. Threshold Effects

    1. Chronic effects. Based upon chronic toxicity data, Novartis 
believes the Reference Dose (RfD) for CGA329351 is 0.08 mg/kg/day. This 
RfD is based on a 6-months feeding study conducted in dogs using an 
uncertainty factor of 100. The No-Observed Effect Level was 8 mg/kg/
day.
    2. Acute toxicity. The risk from acute dietary exposure to 
CGA329351 is considered to be very low. The NOEL in a 28-day study was 
50 mg/kg, which is 6-fold higher than the chronic NOEL. Since chronic 
exposure assessment did not result in any unacceptable exposure for 
even the most impacted population subgroup, it is anticipated that also 
the acute exposure will be in an acceptable range.
    3. Non-threshold effects. From toxicity studies supporting the 
registration of CGA329351, the active ingredient is classified as a 
Group ``E'' compound (evidence of noncarcinogenicty for humans). There 
was no evidence of carcinogenicity in a 24-month feeding trial in mice 
nor in a 24-month feeding study in rats at the dosage levels tested. 
The doses tested were adequate for identifying a cancer risk.

D. Aggregate Exposure

    1. Dietary Exposure. For the purposes of assessing the potential 
dietary exposure under the proposed tolerances, 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 percent of all crops for which tolerances 
are established are treated. Residue studies indicate a significant 
reduction in plant residue levels for CGA329351 relative to those for 
metalaxyl. With use rates that are one-half that of metalaxyl, 
CGA329351 plant residue levels are also 50% lower. Novartis has 
requested the following tolerances for CGA329351:


                                                                        
------------------------------------------------------------------------
                 commodity                     parts per million (ppm)  
------------------------------------------------------------------------
Alfalfa, forage...........................  3.0 ppm                     
Alfalfa, hay..............................  10.0 ppm                    
Almonds...................................  0.3 ppm                     
Almond, hulls.............................  5.0 ppm                     
Apples....................................  0.1 ppm                     
Asparagus.................................  3.5 ppm                     
Berries Group 1.0 ppm.....................                              
Brassica (Cole) Leafy Vegetable Crop        0.05 ppm                    
 Grouping (Except Broccoli, Cabbage,                                    
 Cauliflower, Brussels Sprouts, Mustard                                 
 Greens).                                                               
Broccoli..................................  1.0 ppm                     
Brussels Sprouts..........................  1.0 ppm                     

[[Page 40085]]

                                                                        
Cabbage...................................  0.5 ppm                     
Cattle (fat, liver, and kidney)...........  0.2 ppm                     
Cattle, meat and meat by products (except   0.05 ppm                    
 kidney and liver).                                                     
Cauliflower...............................  0.5 ppm                     
Cereal Grains (Except Barley, Oats, and     0.05 ppm                    
 Wheat).                                                                
Citrus Fruits Group.......................  0.5 ppm                     
Clover, forage............................  0.5 ppm                     
Clover, hay...............................  1.3 ppm                     
Cottonseed, undelinted seed...............  0.05 ppm                    
Cranberries...............................  2.0 ppm                     
Cucurbit Vegetables Group.................  0.5 ppm                     
Eggs......................................  0.05 ppm                    
Fruiting Vegetables.......................  0.5 ppm                     
Ginseng...................................  1.5 ppm                     
Goats (fat, liver, and kidney)............  0.2 ppm                     
Goat, meat and meat by products (except     0.05 ppm                    
 kidney and liver).                                                     
Grapes....................................  1.0 ppm                     
Grass, Forage.............................  5.0 ppm                     
Grass, Hay................................  12.5 ppm                    
Hogs (fat, liver, and kidney).............  0.2 ppm                     
Hogs, meat and meat by products (except     0.05 ppm                    
 kidney and liver).                                                     
Hops cones, dried.........................  10.0 ppm                    
Horses (fat, liver, and kidney)...........  0.2 ppm                     
Horses, meat and meat by products (except   0.05 ppm                    
 kidney and liver).                                                     
Leafy Vegetables Group (Except Brassica,    2.5 ppm                     
 Except Spinach).                                                       
Leaves of Root and Tuber Vegetables (human  7.5 ppm                     
 food or animal feed) Group.                                            
Legume Vegetable Group, Foliage of........  4.0 ppm                     
Legume Vegetables (succulent or dried)      0.1 ppm                     
 Group, except Soybeans.                                                
Milk......................................  0.01 ppm                    
Mustard Greens............................  2.5 ppm                     
Bulb Vegetables Group.....................  5.0 ppm                     
Peanut, hay...............................  10.0 ppm                    
Peanut, nutmeat...........................  0.1 ppm                     
Pineapples................................  0.05 ppm                    
Poultry (fat, liver, and kidney)..........  0.2 ppm                     
Poultry, meat and meat by products (except  0.05 ppm                    
 kidney and liver).                                                     
Root and Tuber Vegetables, Except Ginseng.  0.3 ppm                     
Sheep (fat, liver, and kidney)............  0.2 ppm                     
Sheep, meat and meat by products (except    0.05 ppm                    
 kidney and liver).                                                     
Soybeans..................................  0.5 ppm                     
Spinach...................................  5.0 ppm                     
Stone Fruit Group.........................  0.5 ppm                     
Strawberries..............................  5.0 ppm                     
Sunflower, seed...........................  0.05 ppm                    
Walnuts...................................  0.3 ppm                     
Papaya (Regional tolerance for Hawaii)....  0.05 ppm                    
Citrus Oil................................  3.5 ppm                     
Potatoes, granules / flakes...............  1.0 ppm                     
Potatoes, chips...........................  1.0 ppm                     
Prunes....................................  2.0 ppm                     
Raisins...................................  3.0 ppm                     
Tomatoes, puree...........................  1.5 ppm                     
Apples, pomace............................  0.2 ppm                     
Citrus, dried pulp........................  3.5 ppm                     
Peanut, meal..............................  0.5 ppm                     
Pineapple, process residue................  0.3 ppm                     
Potato, waste from processing.............  5.0 ppm                     
Soybeans, hulls...........................  1.0 ppm                     
Soybeans, meal............................  1.0 ppm                     
Sugar beets, molasses.....................  2.5 ppm                     
Sunflower seeds, meal.....................  0.1 ppm                     
Wheat, milling byproducts.................  1.0 ppm                     
------------------------------------------------------------------------


    The following indirect or inadvertent tolerances also have been 
requested:

                                                                        
------------------------------------------------------------------------
                 commodity                     parts per million (ppm)  
------------------------------------------------------------------------
Barley, forage............................  2.0 ppm                     
Barley, grain.............................  0.2 ppm                     
Barley, hay...............................  6.0 ppm                     
Barley, straw.............................  2.0 ppm                     
Forage, Fodder, and Straw of Cereal Grains  1.0 ppm                     
 Group (except wheat, barley, and oats)                                 
 Fodder, Forage and Straw.                                              
Forage, Fodder, and Straw of Cereal Grains  3.0 ppm                     
 Group (except wheat, barley, and oats)                                 
 Fodder, Forage and Hay.                                                
Oat, forage...............................  2.0 ppm                     
Oat, hay..................................  6.0 ppm                     
Oat, grain................................  0.2 ppm                     
Oat, straw................................  2.0 ppm                     
Wheat, forage.............................  2.0 ppm                     
Wheat, hay................................  6.0 ppm                     
Wheat, grain..............................  0.2 ppm                     
Wheat, straw..............................  2.0 ppm                     
Barley, milling fractions.................  1.0 ppm                     
Oat, milling fractions....................  1.0 ppm                     
Wheat, milling fractions..................  1.0 ppm                     
------------------------------------------------------------------------


    In conducting this exposure assessment, Novartis has made very 
conservative assumptions -- 100% of all requested commodities will 
contain CGA329351 at tolerance levels which result in an overestimate 
of human exposure.
    2. Drinking water exposure. Novartis anticipates the potential 
exposure from residues of CGA329351 in drinking water to be relatively 
low. Although the potential for groundwater contamination cannot be 
completely excluded where soils are highly permeable and the water 
table is shallow, the reduced use rate associated with CGA329351 
reduces potential groundwater contamination relative to that for 
metalaxyl. Based on historical groundwater monitoring data for 
metalaxyl from 5 states, levels typically do not exceed 3 ppb. This 
contamination level would lead to a potential uptake of 0.09 x 10-3 mg/
kg/day CGA329351 (for an adult person consuming 2 liters of water per 
day), which is equivalent to 0.1% of the RfD. On the basis of this 
worst case estimate for CGA329351, Novartis concludes that the 
contribution of any potential groundwater contamination will be 
negligible.
    3. Non-dietary exposure. In addition to uses on agricultural crops, 
CGA329351 is registered for use against soil-borne disease in turf and 
ornamentals. The product, however, is not used residentially by 
homeowners and potential exposure to the general public is extremely 
low. Novartis believes the non-occupational exposure to the general 
public from turf andornamentals uses of CGA329351 to be negligible.
    Novartis believes that consideration of a common mechanism of 
toxicity is not appropriate at this time since there is no information 
to indicate that toxic effects produced by CGA329351 would be 
cumulative with those of any other chemicals. Consequently, Novartis is 
considering only the potential exposure to CGA329351 in its aggregate 
risk assessment.

E. Safety Determination

    1. U.S. population. Under the conservative exposure assumptions of 
100 percent of all crops for which tolerances are established are 
treated, and CGA329351 residue levels are at tolerance level (i.e., 
TMRC), less than 9% of the RfD will be utilized by the U.S. general 
population. EPA generally has no concern for exposures below 100 
percent of the RfD. Therefore, based on the completeness and 
reliability of the toxicity data supporting this petition, Novartis 
believes that there is a reasonable certainty that no harm will result 
from aggregate exposure to residues of CGA329351, including anticipated 
dietary exposure and all other types of non-occupational exposures.
    2. Infants and children. There is no indication that CGA329351 
interferes with the pre-or neonatal development, even when experimental 
animals were exposed to very high doses leading to maternal toxicity. 
Infants and children are not expected to show any particular 
sensitivity to CGA329351. Calculated on the basis of the TMRC, 
utilization of RfD from dietary exposure of children is estimated as: 
6% for nursing infants less than 1 year old, 16% for non-nursing 
infants less than 1 year old, 18% for 1 to 6 year old and 13% for 
children 7-12 years old.
    Novartis believes that under the worst case assumptions which 
overestimate exposure to infants and children, there is a reasonable 
certainty that no harm

[[Page 40086]]

will result to infants and children form aggregate exposure to 
CGA329351.

F. Estrogenic Effects

    CGA329351 does not belong to a class of chemicals known or 
suspected of having adverse effects on the endocrine system. 
Furthermore, supporting developmental toxicity studies in rats and 
rabbits and a reproduction study in rats gave no indication of any 
effects on endocrine function related to development and reproduction. 
Subchronic and chronic treatment did not induce any morphological 
changes in endocrine organs and tissues.

G. International Tolerances

    There are no Codex Alimentarius Commission (CODEX) maximum residue 
levels (MRL's) established for residues of CGA329351 in or on raw 
agricultural commodities.   (PM 21)

[FR Doc. 97-19669 Filed 7-24-97; 8:45 am]
BILLING CODE 6560-50-F