Trifloxystrobin (Novartis). August 17, 1998. Pesticide tolerance petition for CGA-279202 (trifloxystrobin). Federal Register.

FLUORIDE ACTION NETWORK PESTICIDE PROJECT

Trifloxystrobin (Novartis). August 17, 1998. Pesticide Tolerance Petition for CGA-279202. Federal Register.

Note from EC:
CGA-279202 is Trifloxystrobin

http://www.epa.gov/fedrgstr/EPA-PEST/1998/August/Day-17/p22012.htm

[Federal Register: August 17, 1998 (Volume 63, Number 158)]
[Notices]
[Page 43937-43944]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr17au98-61]

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ENVIRONMENTAL PROTECTION AGENCY

[PF-819 FRL-6018-2]

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-819 must be
received on or before September 16, 1998.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch, Information Resources and Services Division
(7502C), 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 to: opp-
docket@epamail.epa.gov. Follow 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:

------------------------------------------------------------------------
Office location/
Product Manager telephone number Address
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Joanne I. Miller.............. Rm. #227, CM #2, 703- 1921 Jefferson
305-6224, e- Davis Hwy,
mail:miller.joanne@ep Arlington, VA
amail.epa.gov.
Cynthia Giles-Parker.......... Rm. #247, CM #2, 703- Do.
305-7740,e-mail:giles-
parker.cynthia@epamai
l.epa.gov.
------------------------------------------------------------------------

SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as
follows proposing the establishment and/or amendment of regulations for
residues of certain pesticide chemicals in or on various food
commodities under section 408 of the Federal Food, Drug, and Comestic
Act (FFDCA), 21 U.S.C. 346a. EPA has determined that these petitions
contain data or information regarding the elements set forth in section
408(d)(2); however, EPA has not fully evaluated the sufficiency of the
submitted data at this time or whether the data supports granting of
the petition. Additional data may be needed before EPA rules on the
petition.
The official record for this notice of filing, as well as the
public version, has been established for this notice of filing under
docket control number [PF-819] (including comments and data submitted
electronically as described below). A public version of this record,
including printed, paper versions of electronic comments, which does
not include any information claimed as CBI, is available for inspection
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal
holidays. The official record is located at the address in
``ADDRESSES'' at the beginning of this document.
Electronic comments can be sent directly to EPA at:
opp-docket@epamail.epa.gov

Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption. Comments and data
will also be accepted on disks in Wordperfect 5.1 file format or ASCII
file format. All comments and data in electronic form must be
identified by the docket number FRL-6018-2 and appropriate petition
number. Electronic comments on notice may be filed online at many
Federal Depository Libraries.

List of Subjects

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

Dated:August 4, 1998.

Arnold E. Layne,

Acting Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

Petitioner summaries of the pesticide petitions are printed below
as required by section 408(d)(3) of the FFDCA. The summaries of the
petitions were prepared by the petitioners and represent the views of
the petitioners. EPA is publishing the petition summaries verbatim
without editing

[[Page 43938]]

them in any way. The petition summary announces the availability of a
description of the analytical methods available to EPA for the
detection and measurement of the pesticide chemical residues or an
explanation of why no such method is needed.

2. Novartis Crop Protection, Inc.

PP 8F4955

EPA has received a pesticide petition (PP 8F4955) from Novartis
Crop Protection, Inc., PO 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 a tolerance
for residues of CGA-279202 in or on the raw agricultural commodity on
pome fruit at 0.4, cucurbit vegetables at 0.25, grapes at 1.5, peanuts
at 0.02, peanut hay at 4.0, apple pomace at 1.5 and imported bananas at
0.1 ppm. EPA has determined that the petition contains data or
information regarding the elements set forth in section 408(d)(2) of
the FFDCA; however, EPA has not fully evaluated the sufficiency of the
submitted data at this time or whether the data supports granting of
the petition. Additional data may be needed before EPA rules on the
petition.

A. Residue Chemistry

1. Plant metabolism. The metabolism of CGA-279202 in plants
(cucumbers,

[[Page 43942]]

apples, wheat and peanuts) is well understood. Identified metabolic
pathways are substantially similar in plants and animals (goat, rat and
hen). Novartis proposes CGA-279202, per se, as the residue of concern
for tolerance setting purposes.
2. Analytical method. Novartis Crop Protection Inc. has submitted
practical analytical methodology for detecting and measuring levels of
CGA-279202 in or on raw agricultural commodities. The limit of
detection (LOD) for each analyte of this method is 0.08 ng injected,
and the limit of quantitation (LOQ) is 0.02 ppm. The method is based on
crop specific cleanup procedures and determination by gas
chromatography with nitrogen-phosphorus detection.
3 Magnitude of residues--Residue trials. CGA-279202 was applied to
apples in 10 States and to pears in 4 States for a total of 19 field
trials. Twelve field trials were conducted in the following 8
representative peanut-growing States: Alabama, Florida, Georgia, North
Carolina, Oklahoma, South Carolina, Texas, and Virginia. Eighteen
cucurbit field trials in 10 States were successfully harvested,
including 8 cucumber, 5 cantaloupe, and 5 summer squash field trials.
Twelve field trials in 5 States, accounting for 94% of the U.S. grape
production, were conducted to generate residue data on grapes, raisins,
and raw and pasteurized juice. Thirteen banana field trials were
conducted in Costa Rica, Ecuador, Colombia, Guatemala, Mexico,
Honduras, and Puerto Rico.

B. Toxicological Profile

1. Acute toxicity. Studies conducted with the technical material of
CGA-279202 include a rat acute oral toxicity study with a
LD<INF>50</INF> >5,000 mg/kg; a mouse acute oral toxicity study with a
LD<INF>50</INF> >5,000 mg/kg; a rabbit acute dermal toxicity study with
a LD<INF>50</INF> >2,000 mg/kg; a rat acute dermal toxicity study with
a LD<INF>50</INF> >2,000 mg/kg; a rat acute inhalation toxicity study
with a LC<INF>50</INF> >4.65 mg/L; a rabbit eye irritation study
showing slight irritation (Category III); a rabbit dermal irritation
study showing slight irritation (Category IV); a Guinea pig dermal
sensitization study with the Buehler's method showing negative
findings; a Guinea pig dermal sensitization study with the maximization
method showing some positive findings.
2. Genotoxicty. No genotoxic activity is expected of CGA-279202
under in-vivo or physiological conditions. The compound has been tested
for its potential to induce gene mutation and chromosomal changes in 5
different test systems. The only positive finding was seen in the in
vitro test system (Chinese hamster V79 cells) as a slight increase in
mutant frequency at a very narrow range (250 - 278 <greek-m>g/ml) of
cytotoxic and precipitating concentrations (compound solubility in
water was reported to be 0.61 <greek-m>g/ml; precipitate was visually
noted in culture medium at 150 <greek-m>g/ml). The chemical was found
to be non-mutagenic in the in vivo system or all other in vitro
systems. Consequently, the limited gene mutation activity in the V79
cell line is considered a nonspecific effect under non-physiological in
vitro conditions and not indicative of a real mutagenic hazard.
3. Reproductive and developmental toxicity. 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 toxicity and the completeness of the database. Based on the
current toxicological data requirements, the database on CGA-279202
relative to pre- and post-natal effects for children is complete.
In assessing the potential for additional sensitivity of infants
and children to residues of CGA-279202, Novartis considered data from
teratogenicity studies in the rat and the rabbit and a 2-generation
reproduction studies in the rat. The teratogenicity studies are
designed to evaluate adverse effects on the developing embryo as a
result of chemical exposure during the period of organogenesis.
Reproduction studies provide information on effects from chemical
exposure on the reproductive capability of mating animals and systemic
and developmental toxicity from in-utero exposure.
In the rat teratology study, reductions in body weight gain (bwtg)
and food consumption were observed in the dam at 100 mg/kg. No
teratogenic effects or any other effects were seen on pregnancy or
fetal parameters except for the increased incidence of enlarged thymus,
which is a type of variation, at 1,000 mg/kg. The developmental NOEL
was 100 mg/kg.
In the rabbit teratology study, body weight loss and dramatically
reduced food consumption were observed in the dam at <gr-thn-eq>250 mg/
kg. No teratogenic effects or any other effects were seen on pregnancy
or fetal parameters except for the increase in skeletal anomaly of
fused sternebrae-3 and -4 at the top dose level of 500 mg/kg. This
finding is regarded as a marginal effect on skeletal development that
could have resulted from the 40-65% lower food intake during treatment
at this dose level. The developmental NOEL was 250 mg/kg.
In the 2-generation rat reproduction study, bwtg and food
consumption were decreased at <gr-thn-eq>750 ppm, especially in females
during lactation. Consequently, the reduced pup weight gain during
lactation (<gr-thn-eq>750 ppm) and the slight delay in eye opening
(1,500 ppm) are judged to be a secondary effect of maternal toxicity.
No other fetal effects or any reproductive changes were noted. The low
developmental NOEL, 50 ppm (5 mg/kg), seen in this study was probably
due to the lack of intermediate dose levels between 50 and 750 ppm.
Based on an evaluation of the dose-response relationship for pup weight
at 750 ppm and 1,500 ppm, the NOEL should have been nearly ten-fold
higher if such a dose was available.
Based on all these teratology and reproduction studies, the lowest
NOEL for developmental toxicity is 5 mg/kg while the lowest NOEL in the
subchronic and chronic studies is 2.5 mg/kg/day (from the rat chronic
study). Therefore, no additional sensitivity for infants and children
to CGA-279202 is suggested by the data base.
4. Subchronic toxicity. In subchronic studies, several mortality
related changes were reported for the top dose in dogs (500 mg/kg) and
rats (800 mg/kg). At these dose levels, excessive toxicity has resulted
in body weight loss and mortality with the associated and nonspecific
changes in several organs (such as atrophy in the thymus, pancreas,
bone marrow, lymph node, and spleen) which are not considered specific
target organs for the test compound. In the dog, specific effects were
limited to hepatocellular hypertrophy at <gr-thn-eq>150 mg/kg and
hyperplasia of the epithelium of the gall bladder at 500 mg/kg. Target
organ effects in the rat were noted as hepatocellular hypertrophy
(<gr-thn-eq>200 mg/kg) and the related liver weight increase
(<gr-thn-eq>50 mg/kg). In the mouse, target organ effects included
single cell necrosis (<gr-thn-eq>300 mg/kg) and hypertrophy (1,050 mg/
kg) in the liver and extramedullary hematopoiesis (<gr-thn-eq>300 mg/
kg) and hemosiderosis in the spleen (1,050 mg/kg).
In general, definitive target organ toxicity, mostly in the liver,
was seen at high feeding levels of over 100 mg/kg for an extended
treatment period. At LOEL, no serious toxicity was observed other than
mostly non-specific effects including a reduction in body weight and
food consumption or liver hypertrophy.
5. Chronic toxicity. The liver appears to be the major primary
target organ based on the chronic studies conducted in mice, rats, and
dogs. It was identified as a target organ in both the mouse and

[[Page 43943]]

the dog studies with CGA-279202. However, no liver effect was seen in
the chronic rat study which produced the lowest NOEL of 2.5 mg/kg based
on reduced bwtg and food consumption seen at higher dose levels (HDL).
The compound did not cause any treatment-related increase in general
tumor incidence, any elevated incidence of rare tumors, or shortened
time to the development of palpable or rapidly lethal tumors in the 18-
month mouse and the 24-month rat studies. Dosages in both studies were
sufficient for identifying a cancer risk. In the absence of
carcinogenicity, Novartis believes that a Reference Dose (RfD)
rapproach is appropriate for quantitation of human risks.
6. Animal metabolism. CGA-279202 is moderately absorbed from the
gastrointestinal tract of rats and is rapidly distributed. Subsequent
to a single oral dose, the half life of elimination is about 2-days and
excretion is primarily via bile. CGA-279202 is extensively metabolized
by the rat into about 35 metabolites, but the primary actions are on
the methyl ester (hydrolysis into an acid), the methoxyimino group (O-
demethylation), and the methyl side chain (oxidation to a primary
alcohol). Metabolism is dose dependent as it was almost complete at low
doses but only about 60% complete at high doses.
In the goat, elimination of orally administered CGA-279202 is
primarily via the feces. The major residues were the parent compound
and the acid metabolite (CGA-321113) plus its conjugates. In the hen,
CGA-279202 is found as the major compound in tissues and in the
excreta, but hydroxylation of the trifluormethyl-phenyl moiety and
other transformations, including methyl ester hydrolysis and
demethylation of the methoxyimino group, are also seen. In conclusion,
the major pathways of metabolism in the rat, goat, and hen are the
same.
7. Metabolite toxicology. Metabolism of CGA-279202 has been well
characterized in plants, soil, and animals. In plants and soil,
photolytically induced isomerization results in a few minor metabolites
not seen in the rat; however, most of the applied materials remained as
parent compound as shown in the apple and cucumber studies. All
quantitatively major plant and/or soil metabolites were also seen in
the rat. The toxicity of the major acid metabolite, CGA-321113 (formed
by hydrolysis of the methyl ester), has been evaluated in cultured rat
hepatocytes and found to be 20-times less cytotoxic than the parent
compound. Additional toxicity studies were conducted for several minor
metabolites seen uniquely in plants and/or soil. The studies indicate
that these metabolites, including CGA-357261, CGA-373466, and NOA-
414412, are not mutagenic to bacteria and are of low acute toxicity
(LD<INF>50</INF> >2,000 mg/kg). In conclusion, the metabolism and
toxicity profiles support the use of an analytical enforcement method
that accounts for parent CGA-279202.
8. Endocrine disruption. CGA-279202 does not belong to a class of
chemicals known for having adverse effects on the endocrine system.
Developmental toxicity studies in rats and rabbits and reproduction
study in rats gave no indication that CGA-279202 might have any effects
on endocrine function related to development and reproduction. The
subchronic and chronic studies also showed no evidence of a long-term
effect related to the endocrine system.

C. Aggregate Exposure

1. Dietary exposure. For the purposes of assessing the potential
dietary exposure under the proposed tolerances for the residue of CGA-
279202 and its metabolites, Novartis has estimated aggregate exposure
based upon the Theoretical Maximum Residue Concentration (TMRC). The
values range from 0.0031 ppm in milk to 1.5 ppm in grapes and include
tolerances for various crops; pome fruit - 0.4 ppm for the raw
agricultural commodities (RAC); cucurbits - 0.25 ppm for the RAC;
grapes - 1.5 ppm for the RAC; peanuts - 0.02 ppm for the RAC; banana -
0.1 ppm for the RAC. 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.
2. Food--i. Chronic. The RfD of 0.025 mg/ kg/day is derived from
the 24-month rat NOEL of 2.5 mg/kg/day. Even under worst-case
assumptions, dietary exposure analysis for CGA-279202 in the most
exposed population (non-nursing infants <1-year old) shows the percent
RfD utilization to be only 18.9%. Although tolerances in meat and milk
are not required for these uses, anticipated residues in meat and milk
were also included in this exposure analysis. For average U.S.
populations (48 States), dietary exposure for CGA-279202 shows a
minimal utilization of 3.4% of the RfD.
ii. Acute. For CGA-279202, the appropriate NOEL for acute exposure
is 2,000 mg/kg/day from the acute oral neurotoxicity study in rats.
Acute dietary exposure analysis predicted the general population will
be exposed to less than 0.0045 mg/kg/day of CGA-279202, which
corresponds to a MOE of 44,237 at the 99.9 percentile. Children 1-6
years constitute the sub-population with the highest predicted
exposure. Predicted acute exposure for this subgroup is less than 0.026
mg/kg/day, corresponding to a MOE of at least 7,797 for 99.9% of the
individuals.
3. Drinking water. The potential for exposure to CGA-279202 through
drinking water (surface or ground water) is low; this is due to the
strong binding affinity of CGA-279202 to soil and to its low use rates
(0.04-0.125 lb ai/acre/application). The highest average (56-days)
surface water concentration due to runoff predicted by the GENEEC model
is 0.06 ppb, resulting from application on turf. Assuming a daily water
consumption rate of 2 L/day for an adult (70 kg), this would lead to an
adult intake of 0.0000017 mg/kgrm: /diskb/cgi-bin-tmp/TMPBaaaambqa: No such file or directory
/day which is only 0.007% of the chronic
reference dose of 0.025 mg/kg/day. Assuming a three-fold increase in
water consumption per unit body weight for children, the potential
exposure increases only to 0.02% of RfD for this population subgroup.
Estimated concentrations for treating other crops or for ground water
are even lower and do not indicate any cause for concern.
4. Non-dietary exposure. Non-dietary exposure to CGA-279202 is
considered negligible as the chemical is intended primarily for
commercial and agricultural use. Exposure due to professional use on
turf is considered negligible. For workers handling this chemical,
acceptable margins of exposure (in the range of thousands) have been
obtained for both acute and chronic scenarios.

D. Cumulative Effects

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 CGA-279202 would be cumulative with those of any
other types of chemicals. Furthermore, the oximinoacetate is a new type
of fungicide and no compound in this general chemical class currently
has a significant market share. Consequently, Novartis is considering
only the potential exposure to CGA-279202 in its aggregate risk
assessment.

E. Safety Determination

1. U.S. population. Using the conservative exposure assumptions
described above and based on the completeness and reliability of the
toxicity data base for CGA-279202,

[[Page 43944]]

Novartis has calculated aggregate exposure levels for this chemical.
The calculation shows that only 3.4% 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 CGA-279202 residue.
2. Infants and children. Developmental toxicity, manifested as
reduced weaning pup weight, enlarged thymus, or fused sternabrae, was
observed in the teratology study and 2-generation rat reproduction
studies at maternally toxic doses. All of these findings are judged to
be non-specific, secondary effects of maternal toxicity. The lowest
NOEL for developmental toxicity was established in the rat reproduction
study at 5 mg/kg, a level that is likely to be an overly low estimate
(as a result of dose gap) but is still higher than the chronic NOEL of
2.5 mg/kg on which the RfD is based. 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 CGA-279202 is
only 19% for non-nursing infants less than 1-year old (the most
impacted sub-population). 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 CGA-279202 residues.

F. International Tolerances

No Codex MRLs have been established for residues of CGA-279202.
(Janet Whitehurst).
[FR Doc. 98-22012 Filed 8-14-98; 8:45 am]
BILLING CODE 6560-50-F