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Azoxystrobin - Pesticide Tolerance Petition Filing 3/97

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ENVIRONMENTAL PROTECTION AGENCY
[PF-715; FRL-5589-6]
Zeneca Ag Products; Pesticide Tolerance Petition Filing
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice of filing.
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SUMMARY: This notice announces the initial filing of three pesticide petitions
proposing the establishment of tolerances for residues of azoxystrobin (not
accepted by ANSI) in or on raw agricultural commodities of grape (pesticide
petition (PP) 5F4541), pecan (PP 6F4642), and tomato, peach, banana, peanut,
and wheat (PP 6F4762). This notice includes a summary of the petitions that
was prepared by the petitioner, Zeneca Ag Products.

DATES: Comments, identified by the docket control number [PF-715], must be
received on or before, April 11, 1997.

ADDRESSES: By mail, submit written comments to Public Response and Program
Resources Branch, Field Operations Division (7506C), Office of Pesticide
Programs, Environmental Protection Agency, 401 M St. S.W., Washington, DC
20460. In person, bring comments to Rm. 1132, CM #2, 1921 Jefferson Davis
Highway, Arlington, VA 22202. Comments and data may also be submitted
electronically by sending electronic mail (e- mail) to:
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 in ASCII file format. All comments and data in electronic form must
be identified by docket control number [PF-715]. Electronic comments on this
notice may be filed online at many Federal Depository Libraries. Additional
information on electronic submissions can be found below this document.

Information submitted as comments 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: Cynthia Giles-Parker, Product Manager (22),
Registration Division (7505C), Office of Pesticide Programs, Environmental
Protection Agency, 401 M St., SW., Washington, DC 20460. Office location,
telephone number, and e-mail address: Rm. 229, CM #2, 1921 Jefferson Davis
Highway, Arlington, VA. 22202, 703-305-5540, e- mail: giles-
parker.cynthia@epamail.epa.gov.

SUPPLEMENTARY INFORMATION: EPA has received three pesticide petitions (PP)
5F4541, 6F4642, and 6F4762 from Zeneca Ag Products, 1800 Concord Pike, P.O.
Box 15458, Wilmington, DE 19850-5458, proposing pursuant to section 408(d) of
the Federal Food, Drug and Cosmetic Act, 21 U.S.C. section 346a(d), to amend
40 CFR part 180 by establishing a tolerance for residues of azoxystrobin
(methyl (E)-2-[2-[6-(2- cyanophenoxy)pyrimidin-4-yloxy]phenyl]-3-
methoxyacrylate) and the Z- isomer of azoxystrobin (methyl (Z)-2-[2-[6-(2-
cyanophenoxy)pyrimidin-4- yloxy]phenyl]-3-methoxyacrylate) in or on the
following raw agricultural commodities:

------------------------------------------------------------------------
Commodity                        Part per million (ppm)
------------------------------------------------------------------------
Grapes.................................  1.0   ppm
Pecans.................................  0.01  ppm
Tomato.................................  0.2   ppm
Tomato paste...........................  0.6   ppm
Peanut.................................  0.01  ppm
Peanut oil.............................  0.03  ppm
Peanut hay.............................  1.5   ppm
Peach..................................  0.80  ppm
Banana (whole fruit including peel)....  0.5   ppm
Banana pulp............................  0.05  ppm
Wheat grain............................  0.04  ppm
Wheat bran.............................  0.12  ppm
Wheat hay.............................. 13.0   ppm
Wheat straw............................  4.0   ppm
Cattle, fat............................  0.01  ppm
Cattle, mbyp...........................  0.01  ppm
Cattle, meat...........................  0.01  ppm
Goats, fat.............................  0.01  ppm
Goats, mbyp............................  0.01  ppm
Goats, meat............................  0.01  ppm
Hogs, fat..............................  0.01  ppm
Hogs, mbyp.............................  0.01  ppm
Hogs, meat.............................  0.01  ppm
Horses, fat............................  0.01  ppm
Horses, mbyp...........................  0.01  ppm
Horses, meat...........................  0.01  ppm
Milk...................................  0.006 ppm
Poultry, fat...........................  0.01  ppm
Poultry, liver.........................  0.01  ppm
Poultry, mbyp..........................  0.01  ppm
Poultry, meat..........................  0.01  ppm
Sheep, fat.............................  0.01  ppm
Sheep, mbyp............................  0.01  ppm
Sheep, meat............................  0.01  ppm
------------------------------------------------------------------------

EPA has determined that the 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 petitions.

The proposed analytical methods for non-oily crops are gas chromatography with
nitrogen-phosphorus detection (GC-NPD) or in mobile phase using high
performance liquid chromatography with ultra-violet detection (HPLC-UV).

The proposed analytical method for oily crops is GC-NPD. The proposed
analytical method for animal tissue and eggs is (GC- NPD).

The analytical methods summarized above have not been validated by the Agency.
Public versions of these analytical methods can be obtained from Pesticide
Docket, U.S. Environmental Protection Agency, Office of Pesticide Programs,
401 M St., SW., Washington, DC 20460, (703)305- 5805.

As required by section 408(d) of the FFDCA, as recently amended by the Food
Quality Protection Act, Zeneca Ag Products included in the petition a summary
of the petition and authorization for the summary to be published in the
Federal Register in a notice of receipt of the petition. The summary
represents the views of Zeneca Ag Products; EPA, as mentioned above, is in the
process of evaluating the petition. As required by section 408(d)(3) EPA is
including the summary as a part of this notice of filing. EPA may have made
minor edits to the summary for the purpose of clarity.

Petition Summary:

A. Residue Chemistry

1. Plant metabolism. Plant metabolism has been evaluated in three diverse
crops--grapes, wheat and peanuts--which should serve to define the metabolism
of azoxystrobin in a wide range of crops. Parent azoxystrobin is the major
component found in crops. Azoxystrobin does not accumulate in crop seeds or
fruits, in fact very low residues are found in wheat grain, banana pulp, pecan
nutmeat, and peanut (nuts). Metabolism of azoxystrobin in plants is complex
with more than 15 metabolites identified. These metabolites are present at low
levels, typically much less than 5 percent of the Total Recoverable Residue
(TRR).

Grapes: In grapes parent azoxystrobin was the major component representing
between 34.6 percent and 64.6 percent TRR. The metabolism of azoxystrobin was
complex, involving at least six distinct metabolic pathways, yielding a large
number of minor metabolites. In total 15 metabolites have been identified.
Metabolite Compound 28 (4-hydroxy-6- (2-cyanophenoxy)pyrimidine) was present
at levels of up to 5.2 percent TRR, Compound 13 (2-cyanophenol) was present at
levels of up to 5.7 percent, with no other metabolites present at levels
greater than 4.0 percent TRR.

Wheat: In wheat the total radioactive residues in the grain were very low,
ranging from 0.075 to 0.077 ppm azoxystrobin equivalents. As expected,
residues in forage and straw were higher (1.02 to 2.79 ppm and 3.06 to 9.41
ppm, respectively).

The only significant residue in the grain was parent azoxystrobin (17.1 -22.0
percent TRR, 0.013 - 0.017 ppm). No metabolite was present at > 3.3 percent
TRR.

In wheat straw, the major component of the residue was parent azoxystrobin
(22.1 - 43.3 percent TRR, 0.676 - 4.07 ppm). In total, 14 metabolites were
identified, the most significant of which was Compound 28 (8.2 - 10.4 percent
TRR, 0.319 - 0.731 ppm - sum of free conjugated and bound forms). The Z-isomer
was present at 2.1 - 3.5 percent TRR (0.064 - 0.329 ppm). No other metabolite
was present at > 3.5 percent TRR.

In wheat forage azoxystrobin was the major component of the residue (54.9 -
64.7 percent TRR, 0.56 - 1.81 ppm). The two most significant metabolites were
Compound 28 (3.2 - 3.7 percent TRR, 0.038 - 0.090 ppm - total) and Z-isomer
(1.9 - 2.9 percent TRR, 0.019 - 0.081 ppm). No other metabolite was present at
> 1.1 percent TRR.

Peanuts: In peanuts the total radioactive residues in the nuts and hulls were
low compared to those in the foliage.

The majority of the residue in the nuts was identified as radiolabeled natural
products, resulting from the mineralization of azoxystrobin in soil and
subsequent incorporation of the evolved 14CO2 via photosynthesis. The major
radiolabeled natural products identified were fatty acids and these accounted
for 42.1 - 49.1 percent TRR (0.101 - 0.319 ppm). Incorporation of
radioactivity into simple sugars was also confirmed, accounting for 5.8 - 8.5
percent TRR (0.014 - 0.042 ppm). The presence of radiolabeled glutamic acid,
an amino acid, was also confirmed. Azoxystrobin was not detected in the nut
(0.001 ppm) and no individual metabolite was present at a level greater than
0.002 ppm.

In the hay the major component of the residue was parent azoxystrobin (33.0 -
43.8 percent TRR, 13.3 - 20.4 ppm). In total 10 metabolites were identified,
the most significant of which was Compound 28, in both the free and conjugated
forms (7.0 - 9.0 percent TRR, 2.74 - 3.62 ppm). The next most significant
metabolites were Compound 13 in both the free and conjugated forms (6.3
percent TRR, 2.53 ppm) and Z- isomer (2.4 - 2.8 percent TRR, 0.965 - 1.30
ppm).

2. Analytical Method. Non-oily Crops: Azoxystrobin and Z-isomer residues in
grape and grain samples are extracted in 90:10/ acetonitrile:water. An aliquot
of the extract is cleaned up by adsorption chromatography on a silica sorbent.
The eluate is evaporated to dryness and taken up in a known volume of acetone
for analysis by GC-NPD or in mobile phase for analysis by high performance
liquid chromatography with ultraviolet detection (HPLC-UV). The limit of
quantitation of the method is typically 0.02 to 0.05 ppm.

Oily Crops: Azoxystrobin and Z-isomer residues in oily crop samples are
extracted in 90:10/ acetonitrile:water. An aliquot of the extract is cleaned
up by passing through a C18 sep-pak. All extracts were cleaned up by gel
permeation chromatography eluting through alumina and Florisil solid phase
extraction cartridges. The eluate was evaporated to dryness and redissolved in
a known volume of acetone for analysis by GC-NPD. The limit of quantitation of
the method is typically 0.01 ppm.

Animal Tissues (Liver), Milk and Eggs: Residues of azoxystrobin in tissue and
egg samples are extracted in acetonitrile . An aliquot of the extract is
cleaned up by gel permeation chromatography (GPC) eluting through alumina-n
and Florisil solid phase extraction cartridges. The eluate is evaporated to
dryness and taken up in a known volume of acetone for analysis by GC-NPD. The
limit of quantitation is typically 0.01 ppm.

Residues of azoxystrobin in milk samples are extracted in acetonitrile and
partitioned in dichloromethane. The extract is again cleaned up by GPC eluting
through alumina-n and Florisil solid phase cartridges. The eluate is
evaporated to dryness and taken up in a known volume of acetone for analysis
by GC-NPD. The limit of quantitation is typically 0.006 ppm.

3. Magnitude of residues. Grapes: Trials were carried out in 1994 in 5
different states: California, New York, Arkansas, Michigan, and Washington. An
additional 9 trials were conducted in 1995 in New York, California (6) and
Oregon and Washington.

Azoxystrobin 80WG was applied at a rate of 0.25 lb ai/A. A total of 6
applications was made. The first application was at 1 to 5 inch shoot growth,
the second at 8 to 12 inch shoot growth. The third application was at bloom
plus or minus 2 days. The last three applications were made at 46 (+/- 3), 35
(+/- 3), and 12-14 days prior to normal harvest.

Residues in grapes ranged between 0.20 and 0.84 ppm, supporting the proposed
tolerance of 1 ppm. No concentration of residues was seen in grape juice or
raisins.

Pecans: Trials were carried out between June and November 1994 in 4 different
states: Alabama, Georgia, Mississippi and Texas.

Azoxystrobin 80WG was applied at a rate of 0.2 lb ai/A. A total of 6
applications was made. Applications were made from bud break up to 42 days
preharvest on a three week application schedule.

Azoxystrobin and Z-isomer residues on pecans after the final spray were < 0.01
ppm, supporting the proposed tolerance of 0.01 ppm.

Banana: A total of 6 residue trials was conducted in Hawaii, Florida, and
Puerto Rico during 1995-1996. Azoxystrobin was applied eight times at a rate
of 0.135 lb ai/A. Applications were made every 12-14 days with the last
application just prior to harvest. Immediately following the second
application, bags were placed over several bunches of bananas in both the
treated and untreated plots. The bags were left in place until harvest.
Samples of bagged and unbagged bananas were collected immediately after the
last application, after the spray deposit had dried. Samples of whole bananas
and banana pulp were analyzed for residues of azoxystrobin and the Z-isomer.

Azoxystrobin residues on bagged whole bananas sampled immediately after the
last application ranged from < 0.01 to 0.15 ppm. Azoxystrobin residues on
unbagged whole bananas sampled immediately after the last application ranged
from 0.08 to 0.26 ppm. Residues of azoxystrobin in banana pulp were low in
both bagged and unbagged bananas ranging from < 0.01 to 0.03 ppm. Residues of
Z-isomer were < 0.01 ppm in all samples of whole bananas and banana pulp, both
bagged and unbagged. These data support the proposed tolerances of 0.5 ppm in
whole bananas and 0.05 ppm in banana pulp.

Peaches: Fourteen trials were carried out in North Carolina (2), California
(4), Michigan (2), Texas, Arkansas, Pennsylvania (2), Georgia, and South
Carolina on peaches during 1995. Azoxystrobin was applied at 0.15 lb ai/A
starting at pink bud to 5 percent blossom and repeating at 5-10 day intervals.
All the samples were analyzed for azoxystrobin and the Z-isomer.

Azoxystrobin residues on peaches, sampled 11-14 days after the final spray,
ranged from 0.07 - 0.70 ppm. Residues of the Z-isomer were low and ranged from
< 0.01 - 0.05 ppm. These data support the proposed tolerance of 0.8 ppm.

Peanuts: Twelve residue trials were carried out in Georgia (2), North Carolina
(3), Oklahoma, Texas (2), Florida, and Alabama on peanuts during 1994 and in
1995. Azoxystrobin was applied as a foliar broadcast spray at 0.4 lb ai/A at
two spray intervals: 8 to 9 weeks after planting and 12 to 13 weeks after
planting.

Azoxystrobin residues on peanut hay, sampled about 50 days after the final
spray, ranged from 0.25-0.91 ppm. Residues of the Z-isomer were low and ranged
from < 0.02 - 0.38 ppm. A trace residue of azoxystrobin (0.01 ppm), was found
in one nutmeat sample only, all the remainder were < 0.01 ppm. These data
support the proposed tolerances of 0.01 ppm in the peanut and 1.5 ppm in
peanut hay. Processing data indicate a possible 3 x concentration in peanut
oil supporting a proposed tolerance of 0.03 ppm.

Tomato: Sixteen residue trials were carried out in California (10), Florida
(2), New Jersey, North Carolina, and Indiana on tomatoes during 1994 and 1995.
Azoxystrobin was applied at 0.1 lb ai/A starting at early fruiting and
repeating on a 6-8 day interval until eight applications had been made.
Samples of mature fruits were taken 1 day after the final spray and analyzed
for azoxystrobin and the Z-isomer.

Azoxystrobin residues, one day after the final spray, ranged from 0.01 - 0.16
ppm. Only traces of the Z-isomer ranging from < 0.01 - 0.02 ppm were found.
These data support the proposed tolerances of 0.2 ppm in tomato; processing
data showing a possible 3 x concentration in tomato paste support a proposed
tolerance of 0.6 ppm.

Wheat: Six magnitude of the residue trials were carried out on wheat in
Georgia, Tennessee, Montana, Nebraska, Virginia, and Oregon during 1994.
Azoxystrobin was applied twice at growth stages Zadoks 43- 45 and 55-59 at 0.2
lb ai/A Samples of hay, straw and grain were analyzed for azoxystrobin and the
Z-isomer.

Azoxystrobin residues on hay, sampled two weeks after the final spray, were
0.19 to 6.5 ppm. At harvest, 33-74 days after treatment, residues in wheat
grain were low and ranged from < 0.01 - 0.03 ppm. Residues on straw ranged
from 0.03 - 3.4 ppm.

A total of 16 residue trials were conducted in Mississippi, Illinois, Ohio,
Wisconsin, Texas (2), Nebraska, Montana (2), North Dakota, Colorado, Kansas
(2), Oklahoma, New Mexico, and California during 1995. Azoxystrobin was
applied 2 times at a rate of 0.2 lb ai/A. Application timings were at Zadoks
43-45 (boot) and 30-45 days prior to grain harvest (no later than Zadoks 58,
head emergence).

Azoxystrobin residues on hay sampled 13 to 33 days after the last application
ranged from 0.09 to 11.1 ppm. Residues of azoxystrobin on straw sampled 36 to
52 days after the last application ranged from 0.03 to 1.31 ppm. Residues of
azoxystrobin on grain sampled 36 to 52 days after the last application were
low, ranging from < 0.01 to 0.06 ppm.

Residues of Z-isomer on hay ranged from < 0.01 to 0.8 ppm. Residues of Z-
isomer on straw were low, ranging from < 0.01 to 0.13 ppm. Residues of the Z-
isomer on grain were < 0.01 ppm on all samples. These data support proposed
tolerances of 0.04 ppm on grain, 4.0 ppm on straw and 13 ppm on hay.
Processing data indicate a possible 3 x concentration in wheat bran,
supporting a proposed tolerance of 0.12 ppm.

B. Toxicological Profile (Azoxystrobin Technical)

1. Acute toxicity.

------------------------------------------------------------------------
Study Type                Study Results                   Tox. Category
------------------------------------------------------------------------
Acute Oral Rat            LD50 > 5,000 mg/kg..                 IV
Acute Dermal Rat          LD50 > 2,000 mg/kg..                 III
Acute Inhalation Rat      LC50 = 698 mg/l for females.
                          LC50 = 962 mg/l for males.           III
Eye Irritation Rabbit     Slight irritant, no                  III
                            corneal effects.
Skin Irritation Rabbit    Slight irritant                      IV
Skin Sensitization
  Guinea Pig              Not a skin sensitizer.
------------------------------------------------------------------------

2. Genotoxicity. Azoxystrobin gave a weak clastogenic response in mammalian
cells in vitro at cytotoxic doses. In the whole animal azoxystrobin was
negative in established assays for chromosomal damage (clastogenicity) and
general DNA damage, at high dose levels (greater than or equal to 2,000
mg/kg). The weak clastogenic effects seen in vitro are not expressed in the
whole animal and azoxystrobin is considered to have no genotoxicity in vivo.

------------------------------------------------------------------------
Assay                        Type                 Results
------------------------------------------------------------------------
In vitro.................... Ames................ negative
............................ L5178Y.............. weakly positive
............................ IVC................. weakly positive
In vivo..................... Micronucleus........ negative
............................ UDS................. negative
------------------------------------------------------------------------

3. Reproductive and developmental toxicity. Reproductive toxicity.
Azoxystrobin showed no evidence of reproductive toxicity.

The No Observed Effect Level (NOEL) for toxicity was judged to be 300 ppm
azoxystrobin, which for the premating period, translates into a daily dose of
32 mg azoxystrobin/kg body weight/day based on body weight reductions relative
to control and liver toxicity in adult males.

The liver toxicity observed in the reproductive toxicity study was manifest as
gross distension of the common bile duct accompanied by histological change.
The histological changes in the intraduodenal bile duct were characterized by
an increase (a hyperplasia) in the number of lining (epithelial) cells and
bile duct inflammation (cholangitis). In the liver, there was an increased
severity of hepatic proliferative cholangitis. The increased severity of the
microscopic liver effects were confined to those animals showing gross bile
duct changes, suggesting that these effects were secondary to biliary
toxicity.

These observations were confined to male F0 and F1 adult rats and were not
detected in female animals or in pups.

------------------------------------------------------------------------
Azoxystrobin in Diet (ppm)                   Dose (mg/kg/day)
------------------------------------------------------------------------
60................................................   6.5
300...............................................  32
1,500............................................. 162
------------------------------------------------------------------------

Developmental Toxicity. There were no adverse effects in the rat or rabbit on
the number, survival and growth of the fetuses in utero. Azoxystrobin caused
no developmental toxicity in the rat or in the rabbit up to and including dose
levels shown to be maternally toxic.

-----------------------------------------------------------------------------
Study Type: Developmental        NOEL/LEL
        Toxicity                 (mg/kg/day)         Effect Description
-----------------------------------------------------------------------------
Rabbit (by gavage)            No developmental       No developmental
                              effects. NOEL for      effects. NOAEL for
                              developmental          maternal toxicity
                              toxicity >500 mg/      = 50 mg/kg/day.
                              kg/day. NOAEL for      LEL for maternal
                              maternal toxicity      toxicity = 150 mg/
                              = 50 mg/kg/day.        kg/day; effects
                                                     were reduced body
                                                     weight, clinical
                                                     effects.

Rat (by gavage)               No developmental       LEL for
                              effects, NOEL = 25     fetotoxicity is
                              mg/kg/day for          100 mg/kg/day;
                              maternal and           effect was
                              fetotoxicity.          "delayed
                                                     ossification".
                                                     LEL for maternal
                                                     toxicity 100 mg/kg/
                                                     day; effect was
                                                     reduced body
                                                     weight.
------------------------------------------------------------------------

4. Subchronic Toxicity. Azoxystrobin is of low subchronic toxicity in 21-day
dermal testing.

5. Chronic Toxicity. Oncogenicity - Rat: Azoxystrobin is non- oncogenic in the

rat.
------------------------------------------------------------------------
Azoxystrobin in Diet (ppm)    Male rat          Female rat
                             (mg/kg/day)        (mg/kg/day)
------------------------------------------------------------------------
60..............................  3.6...............  4.5
300............................. 18.2..............  22.3
1500/750........................ 82.4.............. 117.6
------------------------------------------------------------------------

The NOEL/NOAEL for azoxystrobin in the rat is 18 mg/kg bwt/day.

Zeneca suggests that this chronic rat study has the lowest No Observed Adverse
Effect Level (NOAEL) of the chronic studies conducted with azoxystrobin. The
Reference Dose (RfD) for azoxystrobin should be based upon the NOAEL of 18
mg/kg bwt/day with an uncertainty factor of 100, RfD = 0.18 mg/kg bwt/day.

A dietary inclusion level of 1,500 ppm was established as a Maximum Tolerated
Dose (MTD) in female rats, where decrements in body weight gain relative to
control of approx. 19 percent at week 53 and 11 percent at week 105 were
observed. The maximum reduction relative to control was seen at week 73
(approx. 20 percent). In male rats this dose level was in excess of an MTD
(biliary toxicity), resulting in a reduction in the top dose level from 1500
ppm to 750 ppm for the second year of the study. Reductions in male body
weight gain relative to control animals were seen throughout the duration of
the study with a maximum reduction of approx. 11 percent in the first year (at
week 45), continuing into the second year (maximum reduction of approx. 13
percent at week 99).

In the rat, there was no statistical increase in the number of tumor-bearing
animals, animals with malignant tumors, benign tumors, multiple tumors, single
tumors or metastic tumors in animals treated with azoxystrobin at dose levels
of up to 1,500 ppm (up to 117.1 mg azoxystrobin/kg bwt/day) for 2 years.

Oncogenicity - Mouse.
Azoxystrobin is non-oncogenic in the mouse.

------------------------------------------------------------------------
Azoxystrobin in Diet (ppm)    Male mouse       Female mouse
                             (mg/kg/day)        (mg/kg/day)
------------------------------------------------------------------------
50............................   6.2..............   8.5
300...........................  37.5..............  51.3
2000.......................... 272.4.............. 363.3
------------------------------------------------------------------------

There was no increased tumor incidence or early onset of tumors in mice
receiving up to 2,000 ppm azoxystrobin for up to 2 years. Dietary
administration of 2,000 ppm Azoxystrobin was associated with reduced growth
and food utilization.

An MTD was established in the mouse oncogenicity study based on body weight
gain depression and decreased food utilization seen at the highest dose test
of 2000 ppm. At this dose level body weight gain was depressed 20 percent at

week 13 and 28 percent at week 53 in males, and 11 percent at week 13 and 19
percent at week 53 in females.

There was no statistically significant change or alteration in tumor incidence
in the mouse attributable to treatment with azoxystrobin at dose levels of up
to 2,000 ppm (up to 363.3 mg azoxystrobin/kg bwt/day) for 2 years.

One-year Feeding Study - Dog. Azoxystrobin was administered to groups of 4
beagle dogs at dose levels of 0, 3, 25 and 200 mg/kg bwt/ day, as a daily oral
dose.

Adaptive liver responses were observed at 25 and 200 mg/kg bwt/day which were
not considered to be toxicologically significant. The adaptive liver responses
were increased liver weights and increased serum liver enzyme activities in
the absence of any liver histopathology. Liver weights were increased in both
sexes at 200 mg/kg bwt/day, and in females at 25 mg/kg bwt/day. Plasma
alkaline phosphatase, cholesterol and triglyceride levels were elevated at the
top dose in both sexes, with plasma albumin elevated at 200 mg/kg/day in males
only. Plasma triglycerides were also elevated at 25 mg/kg bwt/ day in males
only. No such effects were observed at 3 mg/kg bwt/day.

These changes were not accompanied by any histopathological change in the
liver. Such changes in the absence of signs of a toxic lesion are generally
considered to reflect the liver compensating for the increased work it must
perform in metabolizing the test compound. While they can be considered to be
effects of azoxystrobin treatment, these changes are of no toxicological
significance.

The NOEL in this study was 200 mg/kg bwt/day. 6. Animal metabolism.
Azoxystrobin is well absorbed and completely metabolized in the rat. Excretion
is rapid and there is no accumulation of azoxystrobin or metabolites. There
are no significant plant metabolites that are not animal metabolites.

7. Metabolite toxicology. Toxicity testing results on the azoxystrobin parent
compound are indicative of the toxicity of all significant metabolites seen in
either plants or mammals.

C. Aggregate Exposure

1. Dietary exposure. a. Food. For the purpose of assessing the potential
dietary exposure from these proposed tolerances, EPA generally estimates
aggregate exposure based on the Theoretical Maximum Residue Contribution
(TMRC) from the tolerances proposed for azoxystrobin as listed above. The TMRC
is obtained by multiplying the tolerance level residue for each food by the
consumption data which estimate the amount of food and food products eaten by
the U.S. population and various population subgroups. Animal feeds (such as
wheat forage) are fed to animals; thus, exposure of humans to residue in the
animal feeds might result if such residues are transferred to meat, milk or
poultry. Animal metabolism and feeding studies indicate that low residues may
occur in meat and milk when azoxystrobin is used as proposed. The TMRC for
each animal product is obtained by multiplying the tolerance (worst-case)
level of residues possible in meat and milk by the food consumption data which
estimate the amount of food and food products eaten by various population
subgroups. These are very conservative assumptions--100 percent of foods, meat
and milk products will contain azoxystrobin residues and those residues would
be at the level of the tolerance--that produce a very conservative
overestimate of human dietary exposure. Zeneca performed chronic dietary
exposure analyses using the food consumption data in the U.S. Department of
Agriculture's (USDA) Nationwide Food Consumption Survey for 1989 through 1992
combined and Technical Assessment System Inc.'s "EXPOSURE 1" analysis
software. The potential exposure for the U.S. population is 0.0009 mg/kg
bwt/day. Potential exposure for children's population subgroups ranged from
0.0013 mg/kg bwt/day for children 7-12 Years Old to 0.0029 mg/kg bwt/day for
children 1-6 Years Old.

b. Drinking water. Azoxystrobin does not leach. It is unlikely that
azoxystrobin could be present in drinking water or groundwater. Therefore it
is not appropriate to assess aggregate exposure from drinking water.

Azoxystrobin is an analogue of naturally occurring strobilurins which are
sensitive to sunlight (photolysis). Azoxystrobin, although more stable than
the strobilurins, has a favorable environmental profile. Azoxystrobin is
degraded rapidly under agricultural field conditions with a soil half-life of
less than 2 weeks. The compound is non-volatile and does not leach, but it is
very susceptible to photolysis. Photolysis accounts for the majority of the
initial loss of the compound, the remainder being degraded microbially.

Based on laboratory data the predicted mobility of azoxystrobin in soil is
relatively low. The soil adsorption coefficient corrected for soil organic
matter (Koc) ranges from 300 to 1690. Consequently, the potential mobility is
low to medium. As a measure of possible mobility the standard GUS index value
is 1.0; which equates to a non- leacher.

Results from field trials support these laboratory data. After using 14C-
labeled azoxystrobin as a "worst case" field application - bare surface,
irrigated and poorly retentive soil (light texture and low organic matter
content), the compound was retained in the upper 2 inches or so of the soil
throughout its lifetime.

As azoxystrobin does not leach it is very unlikely to enter into water bodies
except by accidental, direct over-spray. However, the compound in laboratory
tests degrades with a half-life of approximately 7 weeks in flooded anaerobic
soils. There is also potential for photolytic degradation in natural aqueous
environments; the aqueous photolysis half-life is 11-17 days.

2. Non-dietary exposure. Other potential sources of exposure of the general
population to residues of pesticides is non-occupation exposure. Since the
proposed registrations for azoxystrobin are limited to commercial crop
production, turf farms and golf courses, the potential for non-occupational
exposure to the general population is not expected to be significant.

D. Cumulative Effects

Azoxystrobin is a new class of chemistry for pesticides, a beta-
methoxyacrylate fungicide. Azoxystrobin has the same biochemical mode of
action as the naturally occurring strobilurins, inhibition of electron
transport. Since there are no other registered pesticides in this chemical
class or with this mode of action or mechanism of action, cumulative exposure
assessment is not appropriate at this time.

No evidence or information exists to suggest that toxic effects produced by
azoxystrobin would be cumulative with those of any other chemical compounds.

E. Safety Determination

1. U.S. population in general. Using the conservative assumptions described
above, based on the completeness and reliability of the toxicity data, Zeneca
estimates that the aggregate exposure to azoxystrobin will utilize 0.5 percent
of the RfD for the U.S. population. This chronic dietary exposure analysis is
based on food consumption for the combined years 1989-1992 in the USDA's
Nationwide Food Consumption Survey and analysis using Technical Assessment
Systems, Inc.'s "EXPOSURE 1" analysis software. Generally there are no
concerns for exposures below 100 percent of the RfD. The EPA defines the RfD
to represent the level at or below which daily aggregate dietary exposure over
a lifetime will not pose appreciable risk to human health.

2. Infants and children. In assessing the potential for additional sensitivity
of infants and children to residues of azoxystrobin Zeneca has considered the
2-generation reproduction study in the rat and the developmental toxicity
studies in the rat and rabbit. Azoxystrobin showed no evidence of reproductive
toxicity. Azoxystrobin caused no developmental toxicity in the rat or rabbit
up to and including dose levels shown to be maternally toxic. There were no
adverse effects, in the rat or rabbit, on the number, survival and growth of
the fetuses in utero.

Based on the current toxicological data requirements, the database relative to
pre- and post- natal effects for children is complete. Further, azoxystrobin
shows no evidence of reproductive or developmental toxicity, therefore we
suggest that use of an additional uncertainty factor is not warranted and that
the RfD of 0.18 mg/kg/day is appropriate for assessing aggregate risk to
infants and children.

Using the conservative exposure assumption described above, Zeneca concludes
that the percent of the RfD that will be utilized by aggregate exposure to
residues of azoxystrobin ranges from 0.8 percent for the population subgroups
Nursing infants and children 7-12 years old up to 1.6 percent for the
population subgroup Children 1-6 years old. Zeneca concludes that there is
reasonable certainty that no harm will result to infants and children from
aggregate exposure to azoxystrobin residues.

F. International Tolerances

There are no Codex Maximum Residue Levels established for azoxystrobin.

II. Public Record

Interested persons are invited to submit comments on this notice of filing.
Comments must bear a notation indicating the docket control number, [PF-715].
All written comments filed in response to this petition will be available in
the Public Response and Program Resources Branch, at the address given above
from 8:30 a.m. to 4 p.m., Monday through Friday, except legal holidays.

A record has been established for this notice under docket control number [PF-
715] (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 public record is located in Rm. 1132 of the
Public Response and Program Resources Branch, Field Operations Division
(7506C), Office of Pesticide Programs, Environmental Protection Agency,
Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA.

Electronic comments can be sent directly to EPA at: opp-docket@epamail.epa.gov

Electronic comments must be submitted as ASCII files avoiding the use of
special characters and any form of encryption.

The official record for this notice, as well as the public version, as
described above will be kept in paper form. Accordingly, EPA will transfer all
comments received electronically into printed, paper form as they are received
and will place the paper copies in the official record which will also include
all comments submitted directly in writing. The official record is the paper
record maintained at the address in "ADDRESSES" at the beginning of this
document.

Authority: 21 U.S.C. 346a.

List of Subjects

Environmental protection, Administrative practice and procedure, Agricultural
commodities, Pesticides and pests, Reporting and recordkeeping requirements.

Dated: February 24, 1997.

Peter Caulkins,
Acting Director, Registration Division, Office of Pesticide Programs.

[FR Doc. 97-5683 Filed 3-11-97; 8:45 am]