[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: docket@epamail.epa.gov. Follow the instructions under ``SUPPLEMENTARY
INFORMATION.'' No confidential business information should be submitted
through e-mail.
Information submitted as a comment concerning this document may be
claimed confidential by marking any part or all of that information as
Confidential Business Information (CBI). CBI should not be submitted
through e-mail. Information marked as CBI will not be disclosed except
in accordance with procedures set forth in 40 CFR part 2. A copy of the
comment that does not contain CBI must be submitted for inclusion in
the public record. Information not marked confidential may be disclosed
publicly by EPA without prior notice. All written comments will be
available for public inspection in Rm. 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]]
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Office location/
Product Manager telephone number Address
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Daniel Kenny.................. Rm. 227, CM #2, 703- 1921 Jefferson
305-7546; e-mail: Davis Hwy.,
[email protected] Arlington, VA
epa.gov.
Cynthia Giles-Parker.......... Rm. 247, CM #2, 703- Do.
305-7740; e-mail:
parker.cynthia@epamai.
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SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as
follows proposing the establishment and/or amendment of regulations for
residues of certain pesticide chemicals in or on various 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:
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 5.1/6.1 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="">50 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.
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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="">g/L) and is
substantially lower than the DWLOC's calculated.
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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="">