[Federal Register Volume 62, Number 48 (Wednesday, March 12, 1997)]
[Notices]
[Pages 11441-11447]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-5683]
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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: [email protected]. Electronic comments must be
submitted as an ASCII file avoiding the use of special characters and
any form of encryption.
[[Page 11442]]
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: [email protected].
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
[[Page 11443]]
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
[[Page 11444]]
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 III
males.
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
( 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
[[Page 11445]]
........................... 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 (mg/kg/
Toxicity 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.
------------------------------------------------------------------------
Male rat (mg/kg/ Female rat (mg/kg/
Azoxystrobin in Diet (ppm) day) 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.
[[Page 11446]]
------------------------------------------------------------------------
Male mouse (mg/kg/ Female mouse (mg/kg/
Azoxystrobin in Diet (ppm) day) 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.
[[Page 11447]]
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:
[email protected]
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]
BILLING CODE 6560-50-F