[Federal Register Volume 63, Number 238 (Friday, December 11, 1998)]
[Notices]
[Pages 68455-68461]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-32884]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-844; FRL 6043-3]


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-844, must 
be received on or before January 11, 1999.
ADDRESSES: By mail submit written comments to: Public Information and 
Records Integrity Branch, Information Resources and Services Division 
(7502C), Office of Pesticide Programs, Environmental Protection Agency, 
401 M St., SW., Washington, DC 20460. In person bring comments to: Rm. 
119, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
    Comments and data may also be submitted electronically to: opp-
[email protected]. 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. 119 at the address given above, 
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal 
holidays.

FOR FURTHER INFORMATION CONTACT: The product manager listed in the 
table below:

[[Page 68456]]



------------------------------------------------------------------------
                                   Office location/
        Product Manager            telephone number          Address
------------------------------------------------------------------------
Daniel Kenny..................  Rm. 227, CM #2, 703-    1921 Jefferson
                                 305-7546; e-mail:       Davis Hwy.,
                                 kenny.daniel@epamail.   Arlington, VA
                                 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-844 (including comments and data submitted 
electronically as described below). A public version of this record, 
including printed, paper versions of electronic comments, which does 
not include any information claimed as CBI, is available for inspection 
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal 
holidays. The official record is located at the address in 
``ADDRESSES'' at the beginning of this document.
    Electronic comments can be sent directly to EPA at:
    [email protected]


    Electronic comments must be submitted as an ASCII file avoiding the 
use of special characters and any form of encryption. Comments and data 
will also be accepted on disks in Wordperfect 5.1/6.1 or ASCII file 
format. All comments and data in electronic form must be identified by 
the docket number PF-844 and appropriate petition number. Electronic 
comments on notice may be filed online at many Federal Depository 
Libraries.

List of Subjects

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

    Dated: November 25, 1998.

James Jones,
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 with 
minor, non-substantive editorial changes. The petition summary 
announces the availability of a description of the analytical methods 
available to EPA for the detection and measurement of the pesticide 
chemical residues or an explanation of why no such method is needed.

1. Industry Task Force II

 PP 4E3060

     EPA has received a pesticide petition (PP) 4E3060 from Industry 
Task Force II, on 2,4-D Research Data, McKenna & Cuneo, 1900 K St., 
NW., Washington, DC 20006-1108, proposing pursuant to section 408(d) of 
the (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by extending 
for 3 years, until December 31, 2001, the existing time-limited 
tolerance for residues of 2,4-dichlorophenoxyacetic acid (2,4-D) in or 
on the raw agricultural commodity soybeans at 0.02 parts per million 
(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 and animal metabolism. The nature of the residue in plants 
is adequately understood. Acceptable wheat, lemon, and potato 
metabolism studies have been submitted. The nature of the residue in 
animals is adequately understood based upon acceptable ruminant and 
poultry metabolism studies submitted.
    2. Analytical method. The residue field tests on soybeans used as 
gas chromatography (GC) method with electron capture detection (ECD), 
EN-CAS Method ENC-2/93. This GC/ECD method is adequate for determining 
residues in or on soybeans with a limit of quantitation (LOQ) of 0.01 
ppm.
    3. Magnitude of residues. In 27 tests on soybeans conducted in 
Arkansas, Illinois, Louisiana, Missouri, and Tennessee, residues of 
2,4-D were non-detectable (< 0.01 ppm) in/on all samples of forage and 
seeds from soybeans treated with a preplant application of 2,4-D (acid, 
ester, or amine) at 0.5, 1.25, and 2.75 lb active ingredient per acre 
at lx, 2.5x, and 5.5x rates. Residues of 2,4-D were also non-detectable 
(< 0.01 ppm) in/on 21 of 27 hay samples from the same tests. Hay 
samples with detectable residues of 0.01-0.04 ppm only came from 2.5x 
and 5.5x applications of the 2,4-D 2-ethylhexyl ester (2-EHE). Since 
the label restriction against feeding/grazing, soybean forage and hay 
is not proposed for deletion at this time, no tolerances are necessary 
for these feed items. Since data from the 5.5x application demonstrate 
that 2,4-D residues on soybean seeds are non-detectable or (<0.05 ppm), 
a soybean processing study is not required. Based on the residue data 
for seeds from soybeans, a tolerance of 0.02 ppm in or on the raw 
agricultural commodity soybeans is more appropriate than the current 
time-limited tolerance of 0.1 ppm.

B. Toxicological Profile

    1. Acute toxicity. The oral LD50 of 2,4-D acid is 699 
milligram/kilogram (mg/kg) in the rat. The dermal LD50 in 
the rabbit is > 2,000 mg/kg. The acute inhalation LC50 in 
the rat is > 1.8 mg/liter. A primary eye irritation study in the rabbit 
showed severe irritation. A dermal irritation study in the rabbit 
showed moderate irritation. A dermal sensitization study in the guinea 
pig showed no skin sensitization. An acute neurotoxicity study in the 
rat produced a no observed adverse effect (NOAEL) of 227 mg/kg for 
systemic toxicity and a neurobehavioral NOAEL of 67 mg/kg with a lowest 
observed effect level (LOEL) of 227 mg/kg.
    2. Genotoxicity. Mutagenicity studies including gene mutation, 
chromosomal aberrations, and direct DNA damage tests were negative for 
mutagenic effects.

[[Page 68457]]

    3. Reproductive and developmental toxicity. A 2-generation 
reproduction study was conducted in rats with NOAELs for parental and 
developmental toxicity of 5 mg/kg/day. The LOELs for this study are 
established at 20 mg/kg/day based on reductions in body weight gain in 
F0 and F2b pups, and reduction in pup weight at 
birth and during lactation. A teratology study in rabbits given gavage 
doses at 0, 10, 30, and 90 mg/kg on days 6 through 18 of gestation was 
negative for developmental toxicity at all doses tested. A teratology 
study in rats given gavage doses at 0, 8, 25, and 75 mg/kg on days 6 
through 15 of gestation was negative for developmental toxicity at all 
doses tested. A NOAEL for fetotoxicity was established at 25 mg/kg/day 
based on delayed ossification at the 75 mg/kg dose level. The effects 
on pups occurred in the presence of parental toxicity.
    4. Subchronic toxicity. A subchronic dietary study was conducted 
with mice fed diets containing 0, 1, 15, 100, and 300 mg/kg/day with a 
NOAEL of 15 mg/kg/day. The LOEL was established at 100 mg/kg/day based 
on decreased glucose and thyroxine levels, increases in absolute and 
relative kidney weights, and histopathological lesions in the liver and 
kidneys. A 90-day dietary study in rats fed diets containing 0, 1, 15, 
100, or 300 mg/kg/day resulted in a NOAEL of 15 mg/kg/day and an LOEL 
of 100 mg/kg/day. The LOEL was based on decreases in body weight and 
food consumption, alteration in clinical pathology, changes in organ 
weights, and histopathological lesions in the kidney, liver, and 
adrenal glands of both sexes of rats. A 90-day feeding study was 
conducted in dogs fed diets containing 0, 0.3, 1, 3, and 10 mg/kg/day 
with a NOAEL of 1 mg/kg/day. The LOEL was established at 3 mg/kg/day 
based on histopathological changes in the kidneys of male dogs.
    5.  Chronic toxicity. A 1-year dietary study was conducted in the 
dog using doses of 0, 1, 5, and 7.5 mg/kg/day. The NOAEL was 1 mg/kg/
day and the LOEL was 5 mg/kg/day based on clinical chemistry changes 
and histopathological lesions in the liver and kidney. A 2-year 
feeding/carcinogenicity study was conducted in mice fed diets 
containing 0, 1, 15, and 45 mg/kg/day with a NOAEL of 1 mg/kg/day. The 
systemic LOEL was established at 15 mg/kg/day based on increased kidney 
and adrenal weights and homogeneity of renal tubular epithelium due to 
cytoplasmic vacuoles. No carcinogenic effects were observed under the 
conditions of the study at any dosage level tested. A second 2-year 
oncogenicity study was conducted in mice fed diets containing 0, 5, 
62.5, and 125 mg/kg/day (males) and 0, 5, 150, and 300 mg/kg/day 
(females). No treatment-related oncogenicity was observed. A 2-year 
feeding/carcinogenicity study was conducted in rats fed diets 
containing 0, 1, 15, and 45 mg/kg/day with a NOAEL of 1 mg/ kg/day. 
Although there appeared to be a slight treatment-related incidence of 
benign brain tumors (astrocytomas) in male rats fed diets containing 45 
mg/kg/day, two different statistical evaluations found no strong 
statistical evidence of carcinogenicity in male rats. There were no 
carcinogenic effects observed in female rats. A second 2-year feeding/
carcinogenicity study was conducted in rats fed diets containing 0, 5, 
75, and 150 mg/kg/day. The NOAEL was 5 mg/kg/day and the LOEL was 75 
mg/kg/day based on decreased body weight, body weight gain and food 
consumption; clinical chemistry changes; organ weight changes and 
histopathological lesions. No treatment-related carcinogenic effects or 
increased incidences of astrocytomas were observed.
    6. Animal metabolism. The metabolism of phenyl ring labeled 
14C-2,4-D was studied in the rat following a single 
intravenous or oral dose of approximately 1 mg/kg/day. At 48 hours 
after treatment, recovery of radioactivity in urine was in excess of 
98%. Parent 2,4-D was the major metabolite (72.9% to 90.5%) found in 
the urine.
    7. Metabolite toxicology. Because 2,4-D is rapidly excreted without 
significant metabolism, the toxicology data on the parent compound 
adequately represents metabolite toxicology.
    8. Endocrine disruption. Although tests explicitly designed to 
evaluate the potential endocrine effects of 2,4-D have not been 
conducted, a large and diverse battery of toxicology studies is 
available including acute, subchronic, chronic, reproductive and 
developmental toxicity tests. The results of these studies do not 
provide a pattern of effects suggestive of endocrine modulated 
toxicity.

C. Aggregate Exposure

    1. Dietary exposure. Residues are below the limit of quantification 
(LOQ = 0.01 ppm) in soybeans. Tolerances have been established (40 CFR 
180.142) for residues of 2,4-D as the acid or various of its salts and 
esters, in or on a variety of raw agricultural commodities. In 
addition, there are also tolerances for 2,4-D for meat, milk, and eggs.
     2.  Drinking water. 2,4-D is soluble in water. The average field 
half-life is 10 days. The chemical is potentially mobile, but rapid 
degradation in soil and removal by plant uptake minimizes leaching. A 
maximum contaminant level (MCL) of 0.07 mg/liter has been established. 
In addition, the following Health Advisories have been established: for 
a 10-kg child, a range of 1 mg/liter from 1-day exposure to 0.1 mg/
liter for longer-term exposure up to 7 years; for a 70 kg adult, a 
range of 0.4 mg/liter for longer-term exposure to 0.07 mg/liter for 
lifetime exposure.
    3.  Non-dietary exposure. 2,4-D is currently registered for use on 
the following residential non-food sites: ornamental turf, lawns, and 
grasses, golf course turf, recreational areas, and several other indoor 
and outdoor uses. 2,4-D is a commonly-used pesticide in non-
agricultural settings. No data exist upon which to base calculation of 
non-dietary exposure of 2,4-D for purposes of inclusion in an aggregate 
risk assessment. However, there are several characteristics of 2,4-D 
which suggest the chemical presents a low risk from non-dietary, non-
occupational exposure, particularly the chemical's high acute toxicity 
NOAEL, the short half life in soil, low dermal penetration, and high 
acute dietary MOE. Further, EPA has concluded that for the purposes of 
short- and intermediate-term risk, the inhalation route was of no 
health concern.

 D. Cumulative Effects

     There are no available data to determine whether 2,4-D has a 
common mechanism of toxicity with other substances or how to include 
this pesticide in a cumulative risk assessment. Unlike other pesticides 
for which EPA has followed a cumulative risk approach based on a common 
mechanism of toxicity, 2,4-D does not appear to produce a toxic 
metabolite produced by other substances.

 E. Safety Determination

     1.  U.S. population. For chronic dietary exposure, EPA has 
established the RfD for 2,4-D at 0.01 mg/kg/day. This RfD is based on a 
1-year oral toxicity study in dogs with a NOAEL of 1 mg/kg/day and an 
uncertainty factor of 100. In the most recent final rule establishing 
tolerances for 2,4-D (time-limited tolerance in wild rice associated 
with EPA's granting of an emergency exemption under section 18 of the 
FIFRA (62 FR 46900; September 5, 1997), EPA calculated aggregate risks 
for the existing uses of 2,4-D at that time (including soybeans and all 
other existing uses). Since those uses have not changed in the interim, 
it is appropriate to utilize the same calculations to

[[Page 68458]]

support removal of the expiration date for tolerances in or on 
soybeans. Using anticipated residue contributions for existing uses and 
the high-end residue value of 57.1 mg/liter in drinking water, the 
aggregate exposure to 2,4-D from food and water utilizes 47% of the RfD 
for the U.S. population. 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.
     For acute dietary exposure, the NOAEL of 67 mg/kg/day from the rat 
acute neurotoxicity study should be used for risk assessment. As 
neurotoxicity is the effect of concern, the acute dietary risk 
assessment should evaluate acute dietary risk to all population 
subgroups. Again, relying upon the EPA calculations underlying the most 
recent final rule establishing tolerances for 2,4-D cited above, which 
included soybeans and all other existing uses, EPA calculated acute 
aggregate risk taking into account MOEs from food and MOEs from water. 
For the U.S. population, the MOE for food is 223, the MOE for water is 
42,000, and together the aggregate MOE is 222. This figure does not 
exceed EPA's level of concern for acute dietary exposure.
     Regarding dietary cancer risk assessment, EPA's Cancer Peer Review 
Committee has classified 2,4-D as a Group D chemical ``not classifiable 
as to human carcinogenicity'' on the basis that, ``the evidence is 
inadequate and cannot be interpreted as showing either the presence or 
absence of a carcinogenic effect.''
    2. Infants and children. The database on 2,4-D relative to pre-and 
post-natal toxicity is complete with respect to current data 
requirements. Since the developmental NOAELs for rats and rabbits are 
25-fold greater and 90-fold greater, respectively, than the RfD NOAEL 
of 1 mg/kg/day in the 1-year oral toxicity study in dogs, an additional 
uncertainty factor to protect infants and children is not warranted.
     Using conservative EPA calculations underlying the most recent 
final rule establishing tolerances for 2,4-D cited above, which 
included soybeans and all other existing uses, aggregate acute MOEs for 
exposure to 2,4-D from food and water are 111 for infants less than 1 
year old, 147 for children 1-6 years old, and 556 for females 13 and 
older.
     Also using these same conservative assumptions to estimate chronic 
risk to aggregate chronic exposure to 2,4-D from food and water, 87% of 
the RfD is utilized for nursing infants, 115% for non-nursing infants, 
114% for children 1-6 years old, and 100% for children 7-12 years old.
    Further refinement using additional anticipated residue values in 
crops and percent crop-treated information, and well water monitoring 
data would result in lower chronic dietary (food) and chronic dietary 
(water) exposure estimates, thus reducing the aggregate risk estimate.

F. International Tolerances

     There are no Codex, Canadian, or Mexican maximum residue limits 
(MRLs) for use of 2,4-D on soybeans. FAO review in September 1998 has 
preliminarily proposed an MRL of 0.01 mg/kg for soybeans. (Dan Kenny)

2. Zeneca Ag Products

PP 8F4995

    EPA has received a pesticide petition (PP 8F4995) 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. 346a(d), to amend 40 CFR part 180 by 
establishing permanent tolerances 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 raw agricultural commodities bananas at 2.0 parts per million 
(ppm), canola at 1.0 ppm, potatoes at 0.03 ppm, stone fruit at 1.5 ppm, 
and wheat aspirated grain fractions at 15.0 ppm. EPA has determined 
that the petition contains data or information regarding the elements 
set forth in section 408(d)(2) of the FFDCA; however, EPA has not fully 
evaluated the sufficiency of the submitted data at this time or whether 
the data support granting of the petition. Additional data may be 
needed before EPA rules on the petition.

A. Residue Chemistry

    1. Plant metabolism. The metabolism of azoxystrobin as well as the 
nature of the residues is adequately understood for purposes of the 
tolerances. Plant metabolism has been evaluated in three diverse crops, 
grapes, wheat and peanuts, which should serve to define the similar 
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. 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% of 
the total recoverable residue (TRR).
    2. Analytical method. An adequate analytical method, gas 
chromatography with nitrogen-phosphorus detection (GC-NPD) or in mobile 
phase by high performance liquid chromatography with ultra-violet 
detection (HPLC-UV), is available for enforcement purposes with a limit 
of detection that allows monitoring of food with residues at or above 
the levels set in these tolerances. The Analytical Chemistry Section of 
the EPA concluded that the method(s) are adequate for enforcement. 
Analytical methods are also available for analyzing meat, milk, poultry 
and eggs which also underwent successful independent laboratory 
validations.
    3. Magnitude of residues. Six banana trials were carried out in 
Central America (Mexico - 2, Guatemala - 2, and Costa Rica - 2) during 
1998 in typical commercial banana growing areas in each designated 
country. Maximum residues of 1.15 ppm in whole bananas resulted from 
post-harvest treatments. Residue trials on canola were conducted in 
Canada and the United States in 1996 and 1997 in 12 locations. Maximum 
residues of 0.8 ppm in canola resulted from multiple foliar 
applications. No concentration of residues was observed in processing 
the canola to oil. Sixteen potato trials were carried out in the United 
States in 1997. Maximum resides of 0.03 ppm in potatoes resulted from 
multiple foliar applications. No concentration of residues was observed 
on processing of the potatoes. Over 27 trials were carried out on stone 
fruits (cherries, peaches and plums) in 1997. Maximum residues of 1.5 
ppm on peaches resulted from multiple foliar applications. No 
concentration of residues were observed in processing of plums to 
prunes.

B. Toxicological Profile

    1. Acute toxicity. The acute oral toxicity study in rats of 
technical azoxystrobin resulted in an LD50 of >5,000 
milligrams/kilogram (mg/kg) (limit test) for both males and females. 
The acute dermal toxicity study in rats of technical azoxystrobin 
resulted in an LD50 of >2,000 mg/kg (limit dose). The acute 
inhalation study of technical azoxystrobin in rats resulted in an 
LC50 of 0.962 milligrams/liter in males and 0.698 
milligrams/liter in females. In an acute oral neurotoxicity study in 
rats dosed once by gavage with 0, 200, 600, or 2,000 mg/kg 
azoxystrobin, the systemic toxicity no observed adverse effect level 
(NOAEL) was <200 mg/kg and the systemic toxicity NOAEL was 200 mg/kg, 
based on the occurrence of transient diarrhea in both sexes. There

[[Page 68459]]

was no indication of neurotoxicity at the doses tested.
    2. Genotoxicity. Azoxystrobin was negative for mutagenicity in the 
salmonella/mammalian activation gene mutation assay, the mouse 
micronucleus test, and the unscheduled DNA synthesis in rat 
hepatocytes/mammalian cells (in vivo/in vitro procedure) study. In the 
forward mutation study using L5178 mouse lymphoma cells in culture, 
azoxystrobin tested positive for forward gene mutation at the TK locus. 
In the in vitro human lymphocytes cytogenetics assay of azoxystrobin, 
there was evidence of a concentration related induction of chromosomal 
aberrations over background in the presence of moderate to severe 
cytotoxicity.
    3. Reproductive and developmental toxicity. In a prenatal 
development study in rats gavaged with azoxystrobin at dose levels of 
0, 25, 100, or 300 mg/kg/day during days 7-16 of gestation, lethality 
at the highest dose caused the discontinuation of dosing at that level. 
The developmental NOAEL was greater than or equal to 100 mg/kg/day and 
the developmental lowest observed adverse effect level (LOAEL) was >100 
mg/kg/day because no significant adverse developmental effects were 
observed. In this same study, the maternal NOAEL was not established; 
the maternal LOAEL was 25 mg/kg/day, based on increased salivation.
    In a prenatal developmental study in rabbits gavaged with 0, 50, 
150, or 500 mg/kg/day during days 8-20 of gestation, the developmental 
NOAEL was 500 mg/kg/day and the developmental LOAEL was >500 mg/kg/day 
because no treatment-related adverse effects on development were seen. 
The maternal NOAEL was 150 mg/kg/day and the maternal LOAEL was 500 mg/
kg/day, based on decreased body weight gain.
    In a 2-generation reproduction study, rats were fed 0, 60, 300, or 
1,500 ppm of azoxystrobin. The reproductive NOAEL was 32.2 mg/kg/day. 
The reproductive LOAEL was 165.4 mg/kg/day; reproductive toxicity was 
demonstrated as treatment-related reductions in adjusted pup body 
weights as observed in the F1a and F2 pups dosed 
at 1,500 ppm (165.4 mg/kg/day).
    4. Subchronic toxicity. In a 90-day rat feeding study the NOAEL was 
20.4 mg/kg/day for males and females. The LOAEL was 211.0 mg/kg/day 
based on decreased weight gain in both sexes, clinical observations of 
distended abdomens and reduced body size, and clinical pathology 
findings attributable to reduced nutritional status.
    In a subchronic toxicity study in which azoxystrobin was 
administered to dogs by capsule for 92 or 93 days, the NOAEL for both 
males and females was 50 mg/kg/day. The LOAEL was 250 mg/kg/day, based 
on treatment-related clinical observations and clinical chemistry 
alterations at this dose.
    In a 21-day repeated-dose dermal rat study using azoxystrobin, the 
NOAEL for both males and females was greater than or equal to 1,000 mg/
kg/day (the highest dosing regimen); a LOAEL was therefore not 
determined.
    5. Chronic toxicity. In a 2-year feeding study in rats fed diets 
containing 0, 60, 300, and 750/1,500 ppm (males/females), the systemic 
toxicity NOAEL was 18.2 mg/kg/day for males and 22.3 mg/kg/day for 
females. The systemic toxicity LOAEL for males was 34 mg/kg/day, based 
on reduced body weights, food consumption, and food efficiency; and 
bile duct lesions. The systemic toxicity LOAEL for females was 117.1 
mg/kg/day, based on reduced body weights. There was no evidence of 
carcinogenic activity in this study.
    In a 1-year feeding study in dogs to which azoxystrobin was fed by 
capsule at doses of 0, 3, 25, or 200 mg/kg/day, the NOAEL for both 
males and females was 25 mg/kg/day and the LOAEL was 200 mg/kg/day for 
both sexes, based on clinical observations, clinical chemistry changes, 
and liver weight increases that were observed in both sexes.
    In a 2-year carcinogenicity feeding study in mice using dosing 
concentrations of 0, 50, 300, or 2,000 ppm, the systemic toxicity NOAEL 
was 37.5 mg/kg/day for both males and females. The systemic toxicity 
LOAEL was 272.4 mg/kg/day for both sexes, based on reduced body weights 
in both at this dose. There was no evidence of carcinogenicity at the 
dose levels tested.
    According to the new proposed guidelines for Carcinogen Risk 
Assessment (April, 1996), the appropriate descriptor for human 
carcinogenic potential of azoxystrobin is therefore ``Not Likely.'' The 
appropriate subdescriptor is ``has been evaluated in at least two well 
conducted studies in two appropriate species without demonstrating 
carcinogenic effects.''
    6. Animal metabolism. In this study, azoxystrobin, unlabeled or 
with a pyrimidinyl, phenylacrylate, or cyanophenyl label, was 
administered to rats by gavage as a single or 14-day repeated doses. 
Less than 0.5% of the administered dose was detected in the tissues and 
carcass up to 7-days post-dosing and most of it was in excretion-
related organs. There was no evidence of potential for bioaccumulation. 
The primary route of excretion was via the feces, though 9 to 18% was 
detected in the urine of the various dose groups. Absorbed azoxystrobin 
appeared to be extensively metabolized. A metabolic pathway was 
proposed showing hydrolysis and subsequent glucuronide conjugation as 
the major biotransformation process.
    7. Endocrine disruption. EPA is required to develop a screening 
program to determine whether certain substances (including all 
pesticides and inerts) ``may have an effect in humans that is similar 
to an effect produced by a naturally occurring estrogen, or such other 
endocrine effect.'' The Agency is currently working with interested 
stakeholders, including other government agencies, public interest 
groups, industry, and research scientists, to develop a screening and 
testing program and a priority setting scheme to implement this 
program. Congress has allowed 3-years from the passage of the Food 
Quality Protection Act (FQPA) (until August 3, 1999) to implement this 
program. When this program is implemented, EPA may require further 
testing of azoxystrobin and end-use product formulations for endocrine 
disrupter effects. There are currently no data or information 
suggesting azoxystrobin has any endocrine effects.

C. Aggregate Exposure

    1. Food. Permanent tolerances have been established (40 CFR 
180.507(a)) for the combined residues of azoxystrobin and its Z isomer, 
in or on a variety of raw agricultural commodities at levels ranging 
from 0.01 ppm on pecans to 1.0 ppm on grapes. In addition, time-limited 
tolerances have been established (40 CFR 180.507(b)) at levels ranging 
from 0.006 ppm in milk to 20 ppm in rice hulls. The following risk 
assessments have been conducted to assess dietary exposure and risks 
from azoxystrobin as follows:
    i. Acute exposure and risk. The Agency has concluded that there is 
no toxicological end-point of concern from the review of available data 
for this scenario. Therefore an acute dietary risk assessment is not 
necessary.
    ii. Chronic exposure and risk. In conducting this chronic dietary 
risk assessment Zeneca has made the a conservative assumption that 100% 
of all commodities having azoxystrobin tolerances or proposed 
tolerances will contain azoxystrobin residues at the level of the 
tolerance. This assumption is termed the Theoretical Maximum Residue 
Concentration (TMRC). Zeneca's chronic dietary exposure analysis was 
performed (for combined

[[Page 68460]]

years 1989 - 1992 of the U. S. Department of Agriculture's Nationwide 
Food Consumption Survey) using the Novigen DEEM89N Software.

 
----------------------------------------------------------------------------------------------------------------
          Population Sub-Group                     TMRC (mg/kg/day)                          % RfD
----------------------------------------------------------------------------------------------------------------
U.S. population (48 States).............                              0.0027                                 1.8
All infants (<1 year)...................                              0.0087                                 5.8
Nursing infants (<1 year old)...........                              0.0025                                 1.7
Non-nursing infants (<1 year old).......                              0.0113                                 7.6
Children (1-6 years old)................                              0.0065                                 4.3
Children (7-12 years old)...............                              0.0036                                 2.4
Hispanics...............................                              0.0036                                 2.4
Non-Hispanics Others....................                              0.0047                                 3.1
U.S. Population (summer season).........                              0.0032                                 2.1
Northeast region........................                              0.0031                                 2.0
Western.................................                              0.0030                                 2.0
Pacific.................................                              0.0033                                 2.2
Females (13-19, non-pregnant or nursing)                              0.0020                                 1.3
Females (13+/nursing)...................                              0.0031                                 2.0
----------------------------------------------------------------------------------------------------------------

    The subgroups listed above are those for infants and children, 
females 13-19 not pregnant or nursing and other subgroups for which the 
percentage of the Reference Dose (RfD) occupied is greater than that 
occupied by the U.S. population (48 States).
    2. Drinking water. There is no established Maximum Concentration 
Level for residues of azoxystrobin in drinking water. No health 
advisory levels for azoxystrobin in drinking water have been 
established.
    i. Acute exposure and risk. An assessment is not appropriate since 
no toxicological end-point of concern was identified by the Agency for 
this scenario during review of the available data.
    ii. Chronic exposure and risk. Based on the chronic dietary (food) 
exposure estimated, chronic drinking water levels of concern (DWLOC) 
for azoxystrobin were calculated and summarized in the following table. 
EPA has estimated that the highest estimated environmental 
concentration (EEC) of azoxystrobin in surface water is from the 
application of azoxystrobin on grapes (39g/L) and is 
substantially lower than the DWLOC's calculated.

 
----------------------------------------------------------------------------------------------------------------
                                                                                        Max Water       DWLOC
                         Sub-group                           RfD (mg/kg/  TMRC (Food)    Exposure   (g/
                                                                 day)     (mg/kg/day)  (mg/kg/day)       L)
----------------------------------------------------------------------------------------------------------------
U.S. Population............................................         0.18       0.0027        0.177          6195
Females (13+ not pregnant or nursing)......................         0.18       0.0020        0.178          5300
Non-nursing infants (<1 year old)..........................         0.18       0.0113        0.169          1690
----------------------------------------------------------------------------------------------------------------

    iii. Non-dietary exposure. The Agency evaluated the existing 
toxicological database for azoxystrobin and assessed appropriate 
toxicological end-points and dose levels of concern that should be 
assessed for risk assessment purposes. Dermal absorption data indicate 
that absorption is less than or equal to 4%. No appropriate end-points 
were identified for acute dietary or short term, intermediate term, and 
chronic term (noncancer) dermal and inhalation occupational exposure. 
Therefore, risk assessments are not required for these exposure 
scenarios. Azoxystrobin is currently registered for use on residential 
non-food sites, only on turf.

D. Cumulative Effects

    Azoxystrobin is related to the naturally occurring strobilurins. 
One other strobilurin-type pesticide has recently been registered with 
the EPA. Zeneca has concluded that further consideration of a common 
mechanism of toxicity is not appropriate at this time since there are 
no data to establish whether a common mechanism exists with any other 
substance.

E. Safety Determination

    1. Acute risk. This safety determination is not applicable since no 
toxicological end-point of concern was identified for this scenario 
during Agency review of the available data.
    2. Chronic risk. The RfD for azoxystrobin is 0.18 mg/kg/day, based 
on the NOAEL of 18.2 mg/kg/day from the rat chronic toxicity/
carcinogenicity feeding study in which decreased body weight and bile 
duct lesions were observed in male rats at the LOAEL of 34 mg/kg/day. 
This NOAEL was divided by an uncertainty factor of 100, to allow for 
interspecies sensitivity and intraspecies variability.
    The chronic dietary exposure analysis showed that exposure from the 
proposed new tolerances in or on bananas, canola, potatoes, stone 
fruit, and wheat aspirated grain fractions for non-nursing infants (the 
subgroup with the highest exposure) would be 7.6% of the RfD. The 
exposure for the general U.S. population would be 1.8% of the RfD.
    3. Short- and intermediate-term risk. This risk assessment has not 
previously been performed since no dermal or systemic effects were seen 
in the repeated dose dermal study at the limit dose. Also, the only 
indoor or outdoor residential exposure use currently registered for 
azoxystrobin is residential turf.

F. Additional Safety Factor for Infants and Children

    Federal Food, Drug, and Cosmetic Act (FFDCA) section 408 provides 
that EPA shall apply an additional tenfold margin of safety for infants 
and children in the case of threshold effects to account for pre- and 
post-natal toxicity and the

[[Page 68461]]

completeness of the database unless EPA determines that a different 
margin of safety will be safe for infants and children. Margins of 
safety are incorporated into EPA risk assessments either directly 
through use of a margin of exposure (MOE) analysis or through using 
uncertainty (safety) factors in calculating a dose level that poses no 
appreciable risk to humans. In either case, EPA generally defines the 
level of appreciable risk as exposure that is greater than 1/100 of the 
NOAEL in the animal study appropriate to the particular risk 
assessment. This hundredfold uncertainty (safety) factor/MOE is 
designed to account for combined inter- and intra-species variability. 
EPA believes that reliable data support using the standard hundredfold 
margin/factor but not the additional tenfold margin/factor when EPA has 
a complete data base under existing guidelines and when the severity of 
the effect in infants or children or the potency or unusual toxic 
properties of a compound do not raise concerns regarding the adequacy 
of the standard margin/factor.
    The Agency ad hoc FQPA Safety Factor Committee removed the 
additional 10x safety factor to account for sensitivity of infants and 
children.
    Zeneca has considered the potential aggregate exposure from food, 
water and non-occupational exposure routes and concludes that aggregate 
exposure is not expected to exceed 100% of the RfD and that there is a 
reasonable certainty that no harm will result to infants and children 
from the aggregate exposure to azoxystrobin residues.

G. International Tolerances

    There are no Codex Maximum Residue Levels established for 
azoxystrobin. (Cynthia Giles-Parker)

[FR Doc. 98-32884 Filed 12-11-98; 8:45 am]
BILLING CODE 6560-50-F