[Federal Register Volume 62, Number 195 (Wednesday, October 8, 1997)]
[Notices]
[Pages 52544-52552]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-26537]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-766; FRL 5746-9]
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-766, must
be received on or before November 7, 1997.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch, Information Resources and Services Division
(7506C), Office of Pesticides Programs, Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments
to: Rm. 1132, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically to: docket@epamail.epa.gov. Follow the instructions under ``SUPPLEMENTARY
INFORMATION'' of this document. No Confidential Business Information
(CBI) 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
CBI. Information so marked will not be disclosed except in accordance
with procedures set forth in 40 CFR part 2. A copy of the comment that
does not contain CBI must be submitted for inclusion in the public
record. Information not marked confidential may be disclosed publicly
by EPA without prior notice. All written comments will be available for
public inspection in Rm. 1132 at the address given above, from 8:30
a.m. to 4 p.m., Monday through Friday, excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: The product manager listed in the
table below:
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Office location/
Product Manager telephone number Address
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Cynthia Giles-Parker, (PM 22). Rm. 247, CM #2, 703- 1921 Jefferson
305-7740; e-mail: Davis Hwy,
giles-parker Arlington, VA
[email protected]
ov.
Joanne Miller (PM 23)......... Rm. 237, CM #2, 703- Do.
305-6224; e-mail:
miller
[email protected]
v.
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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-766] (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. Comment and data
will also be accepted on disks in Wordperfect 5.1 file format or ASCII
file format. All comments and data in electronic form must be
identified by the docket number (PF-766) and appropriate petition
number. Electronic comments on notice may be filed online at many
Federal Depository Libraries.
List of Subjects
Environmental protection, Agricultural commodities, Food additives,
Feed additives, Pesticides and pests, Reporting and recordkeeping
requirements.
Dated: September 29, 1997.
James Jones,
Acting Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
Petitioner summaries of the pesticide petitions are printed below
as required by section 408(d)(3) of the FFDCA. The summaries of the
petitions were prepared by the petitioners and represent the views of
the petitioners. EPA is publishing the petition summaries verbatim
without editing them in any way. The petition summary announces the
availability of a description of the analytical methods available to
EPA for the detection and measurement of the pesticide chemical
residues or an explanation of why no such method is needed.
1. AgrEvo USA Company (AgrEvo)
PP 7F4910 and 7E4911
EPA has received pesticide petitions (PP 7F4910 and 7E4911) from
AgrEvo USA Company (AgrEvo), Wilmington, DE 19808 proposing pursuant to
section 408(d) of the Federal Food, Drug and Cosmetic Act, 21 U.S.C.
346a(d), to amend 40 CFR 180.473(c) and part 186 by establishing
tolerances for residues of glufosinate-ammonium in or on raw
agricultural commodities derived from transgenic sugar beets and canola
that are tolerant to the herbicide, glufosinate-ammonium: sugar beet
roots at 0.7 ppm, sugar beet tops (leaves) at 1.3 ppm, canola seed at
0.4 ppm and the processed feeds: canola meal at 2.0 ppm and sugar beet
molasses at 5.0 ppm. AgrEvo has also proposed to amend 40 CFR
180.473(a)(1) and part 185 by establishing a tolerance for residues of
the herbicide, glufosinate-ammonium: butanoic acid, 2-amino-4-
(hydroxymethylphosphinyl)-, monoammonium salt and its metabolite, 3-
methylphosphinico-propionic acid expressed as glufosinate free acid
[[Page 52545]]
equivalents in or on the following raw agricultural commodity: potatoes
at 0.4 ppm and the processed foods: potato flakes at 1.3 ppm and
processed potatoes (including potato chips) at 1.0 ppm. The proposed
analytical method involves homogenization, filtration, partition and
cleanup with analysis by gas chromatography. 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 glufosinate-ammonium in
plants is adequately understood for the purposes of these tolerances.
The crop residue profile following selective use of glufosinate-
ammonium on transgenic crops is different than that found in
conventional crops. The only crop residue found after non-selective use
is the metabolite, 3-methylphosphinico-propionic acid, which is found
in only trace amounts. The principal residue identified in the
metabolism studies after selective use of glufosinate-ammonium on
transgenic crops is the acetylated derivative of the parent material,
2-acetamido-4-methylphosphinico-butanoic acid, with lesser amounts of
glufosinate and 3-methylphosphinico-propionic acid.
2. Analytical method. There is a practical analytical method
utilizing gas chromatography for detecting and measuring levels of
glufosinate-ammonium and its metabolites in or on food with a general
limit of quantification of 0.05 ppm. This method allows monitoring of
food with residues at or above the levels proposed in these tolerances.
This method has been validated by an independent laboratory and the
petitioner has been advised that the EPA concluded its own successful
method try out.
3. Magnitude of residues. Field residue trials with glufosinate-
ammonium tolerant sugar beets and canola have been conducted in 1995
and 1996 and 1993 and 1994 respectively at several different use rates
and timing intervals to represent the use patterns which would most
likely result in the highest residue. In these trials, the primary
residue in all samples was the combination of glufosinate and 2-
acetamido-4-methylphosphinico-butanoic acid which was typically found
at higher levels than 3-methylphosphinico-propionic acid. In sugar
beets, the mean glufosinate-ammonium derived residues in treated roots
did not exceed 0.70 ppm in trials conducted at 13 different sites
representing the 6 major sugar beet producing regions in the U.S. The
mean glufosinate-ammonium derived residues in treated tops (leaves) in
these trials did not exceed 1.29 ppm when sampled at 60 days or more
after treatment.
In canola, 11 out of 40 samples produced detectable residue levels
above the limit of detection in harvested seed following treatment with
glufosinate-ammonium at 14 trial locations. The highest level of
residue found in these trials was 0.295 ppm and the total mean
glufosinate derived residues in all samples containing detectable
residues was 0.136 ppm.
For both sugar beet and canola, the tolerances levels have been
proposed assuming the following: (1) a seasonal maximum rate of 1.1
pounds of active ingredient per acre for sugar beets and 0.9 pound of
active ingredient per acre for canola and (2) a pre-harvest interval of
60 days for sugar beets and 65 days for canola.
Total residues of glufosinate-ammonium and its metabolite in
potatoes desiccated with glufosinate-ammonium were determined in more
than 40 trials conducted over approximately 13 locations during the
period from 1987 to 1994. Within the pre-harvest interval of 7 to 56
days, all residue values (with one exception) did not exceed 0.4 ppm. A
pre-harvest interval of 9 days is specified on the product label for
potato desiccation and the seasonal maximum use rate is 0.4 pound of
active ingredient per acre.
4. Residue in processed commodities. Studies have been conducted to
determine the level of glufosinate derived residues found in or on the
processed commodities from glufosinate tolerant sugar beet roots,
canola seed and potatoes. The studies utilized treatments at
significantly exaggerated rates to provide the necessary test
sensitivity. In the sugar beet processing study, a concentration factor
of 6.3x was determined for sugar beet molasses whereas there was no
concentration of residues in either refined sugar or dried pulp.
In the canola processing study, a concentration factor of
approximately 4 times was observed for the meal when the levels of
terminal residues were compared between the seed and the toasted meal.
There was no concentration of residues in the canola oil.
In the potato processing study, glufosinate residues appear to
concentrate 2.3 fold in chips and 3.1 fold in flakes. Glufosinate
residues do not appear to concentrate in the peel.
B. Toxicological Profile
1. Acute toxicity. The acute oral LD50 values for
glufosinate-ammonium technical ranged from 1,510 to 2,000 mg/kg in rats
and from 200 to 464 mg/kg in mice and dogs. The acute dermal
LD50 was 2,000 mg/kg in rabbits and 4,000 mg/kg
in rats. The 4-hour rat inhalation LC50 was 1.26 mg/L in
males and 2.6 mg/L in females. Glufosinate-ammonium was not irritating
to rabbit skin but was slightly irritating to the eyes. Glufosinate-
ammonium did not cause skin sensitization in guinea pigs. Glufosinate-
ammonium should be classified as Tox Category II for oral toxicity, Tox
Category III for inhalation and dermal toxicity and Tox Category IV for
skin irritation and eye irritation.
2. Genotoxicty. No evidence of genotoxicity was noted in an
extensive battery of in vitro and in vivo studies. The petitioner has
been advised by the EPA that negative studies determined acceptable
included Salmonella, E. Coli and mouse lymphoma gene mutation assays, a
mouse micronucleus assay, and an in vitro UDS assay.
3. Reproductive and developmental toxicity. Three developmental
toxicity studies were conducted with rats, at dose levels ranging from
0.5 to 250 mg/kg/day. The No Observed Effect Levels (NOEL's) for
maternal and developmental effects were determined to be 10 mg/kg/day
for maternal toxicity and 50 mg/kg/day for developmental toxicity,
based on the findings of hyperactivity and vaginal bleeding in dams at
50 mg/kg/day and increased incidence of arrested renal and ureter
development in fetuses at 250 mg/kg/day.
A developmental toxicity study was conducted in rabbits at dose
levels of 0, 2, 6.3 and 20 mg/kg/day. The maternal NOEL for this study
was determined to be 6.3 mg/kg/day, based on increases in abortion and
premature delivery, and decreases in food consumption and weight gain
at 20 mg/kg/day. No evidence of developmental toxicity was noted at any
dose level; thus the developmental NOEL was determined to be 20 mg/kg/
day.
A 2-generation rat reproduction study was conducted at dietary
concentrations of 0, 40, 120 and 360 ppm. The parental NOEL was
determined to be 40 ppm (4 mg/kg/day) based on increased kidney weights
at 120 ppm. The NOEL for reproductive effects was determined to be 120
ppm (12 mg/kg/day) based on reduced numbers of pups at 360 ppm.
4. Subchronic toxicity. A 90-day feeding study was conducted in
Fisher
[[Page 52546]]
344 rats at dietary concentrations of 0, 8, 64, 500 and 4,000 ppm.
Although slight evidence of toxicity was observed, there were no
treatment-related histopathological findings at any dose level. The
NOEL for this study was determined to be 8 ppm, based on increased
kidney weights at 64 ppm.
A 90-day feeding study was conducted in NMRI mice at dietary
concentrations of 0, 80, 320 and 1,280 ppm. There were no treatment-
related pathological findings at any dose level but increases in
absolute and relative liver weights, serum AST, and serum potassium
levels were noted at 320 and/or 1,280 ppm. Based on these findings, the
NOEL for this study was determined to be 80 ppm (16.6 mg/kg/day).
A 90-day feeding study was conducted in beagle dogs at dietary
concentrations of 0, 4, 8, 16, 64 and 256 ppm. There were no treatment-
related histopathological findings at any dose level. However, because
of reduced weight gain and decreased thyroid weights at 64 and/or 256
ppm, the NOEL was determined to be 16 ppm (0.53 mg/kg/day).
5. Chronic toxicity. A 12-month feeding study was conducted in
beagle dogs at dose levels of 0, 2, 5 and 8.5 mg/kg/day. The NOEL was 5
mg/kg/day based on clinical signs of toxicity, reduced weight gain and
mortality at 8.5 mg/kg/day.
A 2-year mouse oncogenicity study was conducted in NMRI mice at
dietary concentrations of 0, 20, 80 and 160 (males) or 320 (females)
ppm. The NOEL was determined to be 80 ppm (10.8 and 16.2 mg/kg/day for
males and females, respectively) based on increased blood glucose,
decreased glutathione levels and increased mortality in the high-dose
males and/or females. No evidence of oncogenicity was noted at any dose
level.
A combined chronic toxicity/oncogenicity study was conducted in
Wistar rats for up to 130 weeks at dietary concentrations of 0, 40, 140
and 500 ppm. A dose-related increase in mortality was noted in females
at 140 and 500 ppm, while increased absolute and relative kidney
weights were noted in 140 and 500 ppm males. Thus, the NOEL for this
study was determined to be 40 ppm (2.1 mg/kg/day). No treatment-related
oncogenic response was noted. However, the high-dose level in this
study did not satisfy the EPA criteria for a Maximum Tolerated Dose and
thus a data gap currently exists for a rat carcinogenicity study. All
glufosinate-ammonium tolerances previously established by the EPA are
time-limited because of this gap. A new rat oncogenicity study is
currently being conducted and is due to the EPA by July 1, 1998.
6. Animal metabolism. Numerous studies have been conducted to
evaluate the absorption, distribution, metabolism and/or excretion of
glufosinate-ammonium in rats. These studies indicate that glufosinate-
ammonium is poorly absorbed (5-10%) after oral administration and is
rapidly eliminated, primarily as parent compound. Small amounts of the
metabolites 3-methylphosphinico-propionic acid and 2-acetamido-4-
methylphosphinico-butanoic acid were found in the excreta, although the
latter is believed to be a result of a revisable acetylation and
decetylation process by intestinal bacteria.
7. Metabolite toxicology . The primary residue resulting from the
use of glufosinate-ammonium in genetically transformed sugar beets and
canola that are tolerant to the herbicide, glufosinate-ammonium,
consists of the metabolites, 2-acetamido-4-methylphosphinico-butanoic
acid and 3-methylphosphinico-propionic acid. Only the latter metabolite
is formed in conventional crops. A considerable number of toxicity
studies have been conducted with these metabolites, including
developmental toxicity studies in rats and rabbits with both
metabolites and a 2-generation rat reproduction study with 2-acetamido-
4-methylphosphinico-butanoic acid. Neither metabolite presents an acute
toxicity hazard and both were determined to be non-genotoxic in an
extensive battery of in vitro and in vivo genotoxicity studies. Neither
metabolite demonstrated significant developmental toxicity to either
rats or rabbits. Subchronic studies in rats, mice and dogs were
conducted with both metabolites with no clear evidence for any specific
target organ toxicity and with NOEL's or No Observed Adverse Effects
Levels (NOAEL's) substantially higher than those seen with glufosinate-
ammonium. Thus, these studies indicate that both metabolites are less
toxic than the parent compound and do not pose any reproductive or
developmental concerns.
C. Endocrine Effects
No special studies investigating potential estrogenic or endocrine
effects of glufosinate-ammonium have been conducted. However, the
standard battery of required studies has been completed. These studies
include an evaluation of the potential effects on reproduction and
development, and an evaluation of the pathology of the endocrine organs
following repeated or long-term exposure. These studies are generally
considered to be sufficient to detect any endocrine effects but no such
effects were noted in any of the studies with either glufosinate-
ammonium or its metabolites.
D. Aggregate Exposure
Glufosinate-ammonium is a non-selective, post-emergent herbicide
with both food and non-food uses. As such, aggregate non-occupational
exposure would include exposures resulting from consumption of
potential residues in food and water, as well as from residue exposure
resulting from non-crop use around trees, shrubs, lawns, walks,
driveways, etc. Thus, the possible human exposure from food, drinking
water and residential uses has been assessed below.
1. Food. For purposes of assessing the potential dietary exposure
from food under the proposed tolerances, the petitioner has been
advised that the EPA has estimated exposure based on the Theoretical
Maximum Residue Contribution (TMRC) derived from the initially
established tolerances for glufosinate-ammonium on apples, grapes, tree
nuts, bananas, milk and the fat, meat and meat-by-products of cattle,
goats, hogs, horses and sheep as well as the subsequently established
tolerances for glufosinate-ammonium on field corn, soybeans, aspirated
grain fractions, and the eggs, fat, meat and meat-by-products of
poultry. The TMRC is obtained by using a model which multiplies the
tolerance level residue for each commodity by consumption data which
estimate the amount of each commodity and products derived from the
commodity that are eaten by the U.S. population and various population
subgroups. In conducting this exposure assessment, the EPA has made
very conservative assumptions--100% of all commodities will contain
glufosinate-ammonium residues and those residues would be at the level
of the tolerance--which result in a large overestimate of human
exposure. Thus, in making a safety determination for these tolerances,
the Agency took into account this very conservative exposure
assessment. In 62 FR 5333 (February 5, 1997), the Agency concluded that
the original tolerances for apples, nuts, grapes and the secondary
tolerances in animal commodities utilize 2.07% of the Reference Dose
(RfD) and that the subsequent tolerances for the corn and soybean
commodities will utilize 3.7% of the RfD.
2. Drinking water. There is presently no EPA Lifetime Health
Advisory level or Maximum Contaminant Level established for residues of
glufosinate-ammonium in water. The petitioner has
[[Page 52547]]
been advised by the EPA that all environmental fate data requirements
for glufosinate-ammonium have been satisfied. The potential for
glufosinate-ammonium to leach into groundwater has been assessed in a
total of nine terrestrial field dissipation studies conducted in
several states and in varying soil types. The degradation of
glufosinate-ammonium in these studies was rapid, with half-lives
ranging from a low of 6 to a high of 23 days. Despite the relatively
high water solubility of glufosinate-ammonium, this compound did not
appear to leach under typical test conditions. This is a result of the
combination of its rapid degradation and its tendency to bind to
certain soil elements such as clay or organic matter. Based on these
studies and the expected conditions of use, the potential for finding
significant glufosinate-ammonium residues in water is minimal and the
contribution of any such residues to the total dietary intake of
glufosinate-ammonium will be negligible.
3. Non-dietary exposure. As a non-selective, post-emergent
herbicide, homeowner use of glufosinate-ammonium will consist primarily
of spot spraying of weeds around trees, shrubs, walks, driveways,
flower beds, etc. There will be minimal opportunity for post-
application exposure since contact with the treated weeds will rarely
occur. Thus, any exposures to glufosinate-ammonium resulting from
homeowner use will result from dermal exposure during the application
and will be limited to adults, not to infants or children. These
exposures are not expected to pose any acute toxicity concerns.
Furthermore, based on the US EPA National Home and Garden Pesticide Use
Survey (RTI/5100/17-01F, March 1992), the average homeowner is expected
to use non-selective herbicides only about 4 times a year. Thus, these
exposures would not normally be factored into a chronic exposure
assessment.
E. Cumulative Effects
The potential for cumulative effects of glufosinate-ammonium and
other substances that have a common mechanism of toxicity must also be
considered. The precise mechanism of action for the toxic effects of
glufosinate-ammonium in animals is not known but is believed to result,
at least in part, from interference with the neurotransmitter function
of glutamate, to which it is a close structural analog. No other
registered active ingredients are known to have a similar mechanism of
action. Thus, no cumulative effects with other substances are
anticipated. Furthermore, the residues in or on transgenic crops will
consist primarily of the metabolites of glufosinate-ammonium, not
glufosinate-ammonium itself. These metabolites are less toxic than
glufosinate-ammonium and, because they are not structural analogs of
glutamate, they should not cause the same effects. Thus, consideration
of a common mechanism of toxicity is not appropriate at this time and
only the potential risks of glufosinate-ammonium need to be considered
in its aggregate exposure assessment.
F. Safety Determinations
1. U.S. population. Based on a complete and reliable toxicity
database, the EPA has adopted an RfD value of 0.02 mg/kg/day using the
NOEL of 2.1 mg/kg/day from the chronic rat toxicity study and a 100-
fold safety factor. Using the Dietary Risk Evaluation System (DRES)
with raw agricultural commodity residue values set at the established
and proposed tolerance levels and with reasonable maximum market share
estimates applied (``realistic'' case assessment), AgrEvo has
calculated that aggregate dietary exposure to glufosinate-ammonium from
the previously established tolerances and the proposed tolerances on
sugar beets, canola and potatoes will utilize 2.1% of the RfD for the
U.S. population (48 states). There is generally 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. Therefore, there is a
reasonable certainty that no harm will result from aggregate exposure
to glufosinate-ammonium residues to the U.S. population in general.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of glufosinate-
ammonium, one should consider data from developmental toxicity studies
in the rat and rabbit and a 2-generation reproduction study in the rat.
The developmental toxicity studies are designed to evaluate adverse
effects on the developing organism resulting from pesticide exposure
during pre-natal development. Reproduction studies provide information
relating to reproductive and other effects on adults and offspring from
pre-natal and post-natal exposure to the pesticide.
Three developmental toxicity studies in rats (including pre- and
post-natal phases), a developmental toxicity study in rabbits, and a 2-
generation rat reproduction study have been conducted with glufosinate-
ammonium. No evidence of developmental toxicity was noted in rabbits,
even at the maternally toxic dose level of 20 mg/kg/day. No
developmental or reproductive effects were noted in rats except at
parentally toxic dose levels. The NOEL's for maternal and developmental
toxicity in the rat developmental toxicity studies were determined to
be 10 mg/kg/day and 50 mg/kg/day, respectively, based on findings of
hyperactivity and vaginal bleeding in dams at 50 mg/kg/day and
increased incidence of arrested renal and ureter development in fetuses
at 250 mg/kg/day. The parental and reproductive NOEL's in the 2-
generation rat reproduction study were determined to be 40 ppm (4 mg/
kg/day) and 120 ppm (12 mg/kg/day), respectively, based on increased
parental kidney weights at 120 ppm and decreased numbers of pups at 360
ppm. In all cases, the reproductive and developmental NOEL's were
greater than or equal to the parental NOEL's, thus indicating that
glufosinate-ammonium does not pose any increased risk to infants or
children.
FFDCA section 408 provides that EPA may apply an additional safety
factor for infants and children in the case of threshold effects to
account for pre- and post-natal toxicity and the completeness of the
database. Based on the current toxicological data requirements, the
database relative to pre- and post-natal effects for children is
complete. Further, the NOEL at 2.1 mg/kg/day from the chronic rat study
with glufosinate-ammonium, which was used to calculate the RfD
(discussed above), is already lower than the NOEL's from the
reproductive and developmental studies with glufosinate-ammonium by a
factor of at least 6-fold. Therefore, an additional safety factor is
not warranted and an RfD of 0.02 mg/kg/day is appropriate for assessing
aggregate risk to infants and children.
Using the DRES analysis with raw agricultural commodity residue
values set at the established and proposed tolerance levels and with
reasonable maximum market share estimates applied (``realistic'' case
assessment), AgrEvo has calculated that aggregate dietary exposure to
glufosinate-ammonium from the previously established tolerances and the
proposed tolerances on sugar beets, canola and potatoes will utilize
5.5% of the RfD for non-nursing infants (1- year old), the most
sensitive population sub-group and 5.3% of the RfD for children (1-6
year old), the second most sensitive population sub-group. Therefore,
based on the completeness and reliability of the toxicity data and a
comprehensive exposure assessment, it may be concluded that there is a
reasonable certainty that no harm will result to
[[Page 52548]]
infants and children from aggregate exposure to glufosinate-ammonium
residues.
G. International Tolerances
An analysis of the Codex Alimentarius Commission (Codex) tolerances
has been conducted. While no international Codex tolerances for
selective uses of tolerances for glufosinate-ammonium in the
desiccation use pattern have been established for conventional canola
(rapeseed) at 5 ppm, crude rapeseed oil at 0.05 ppm and potatoes at 0.5
ppm. These tolerances are established for the sum of glufosinate-
ammonium and 3-methylphosphinico-propionic acid, calculated as
glufosinate (free acid). The U.S. proposal for a 0.4 ppm tolerance for
residues of glufosinate-ammonium in potatoes will be harmonized with
the Canadian tolerance which has already been established at this
level.
The Codex tolerances for glufosinate-ammonium in or on sugar beets
have been established at 0.05 ppm in the beet and 0.1 ppm in the tops
(leaves). AgrEvo intends to propose higher tolerances to the Codex
commission for glufosinate-ammonium use on transgenic sugar beets in
order to harmonize these tolerances with those proposed in the U.S. and
elsewhere. (Joanne Miller)
2. K-I Chemical U.S.A., Inc.
PP 7F4821
EPA has received an amendment to pesticide petition (PP 7F4821)
from K-I Chemical U.S.A., Inc. , White Plains, New York 10606,
proposing pursuant to section 408(d) of the Federal Food, Drug and
Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR part 180 by
establishing a tolerance for residues of herbicide, fluthiacet-methyl
in or on the raw agricultural commodity popcorn grain at 0.02 ppm.
On April 14, l997, EPA announces receipt of a pesticide petition
(PP 7F4821) from K-I Chemical U.S.A., Inc., 11 Martine Avenue, 9th
Floor, White Plains, NY 10606, proposing pursuant to section 408(d) of
the Federal Food, Drug and Cosmetic Act, 21 U.S.C. 346a(d), to amend 40
CFR part 180 by establishing a tolerance for residues of the herbicide
fluthiacet-methyl: Acetic acid, [[2-chloro-4-fluoro-5-[(tetrahydro-3-
oxo-1H,3H-[1,3,4]thiadiazolo[3,4-a] pyridazin-1-
ylidene)amino]phenyl]thio]-methylester in or on the raw agricultural
commodities field corn grain and sweet corn grain (K + CWHR) at 0.02
ppm and corn forage and fodder at 0.05 ppm.
On September 4, 1997 K-I Chemical, U.S.A., Inc., amended PP 7F4821
to include a proposed tolerance for popcorn grain at 0.02 ppm. EPA has
determined that the amended petition contains data or information
regarding the elements set forth in section 408(d)(2) of the FFDCA;
however, EPA has not fully evaluated the sufficiency of the submitted
data at this time or whether the data supports granting of the
petition. Additional data may be needed before EPA rules on the
petition.
A. Residue Chemistry
1. Plant metabolism. The nature of the residues in corn is
adequately understood following application of fluthiacet-methyl.
Residue levels and the metabolic pathway are consistent with those in
soybeans. Parent fluthiacet-methyl was the primary component of the
residue seen in corn grain, forage, fodder and silage. Results of these
studies have been submitted to the EPA.
2. Analytical method. K-I Chemical has submitted practical
analytical methods (AG-603B and AG-624) for detecting and measuring the
level of fluthiacet-methyl in or on corn and corn commodities and in
animal tissues with a limit of detection that allows monitoring
residues at or above the levels set for the proposed tolerance. The
limit of quantitation of the crop method is 0.01 ppm in corn and corn
commodities, 0.05 ppm in animal tissues and 0.01 ppm in milk. The crop
method involves extraction, filtration, and solid phase clean up.
Residue levels of fluthiacet-methyl are determined by gas
chromatographic analysis utilizing a nitrogen phosphorus detector and a
fused-silica column. The animal tissue method involves extraction,
filtration, and partition. Determination of residue levels in animal
tissues is by HPLC with UV detection via column switching using C1 and
C18 columns. The analyte of interest in animal tissues and milk is the
major animal metabolite CGA-300403. Residues of fluthiacet-methyl in
corn are determined by gas chromatography.
3. Magnitude of residues. The residue of concern in corn is
fluthiacet-methyl per se. Twenty-one field residue studies were
conducted with corn grown in nineteen states. Fifteen of the studies
were on field corn and six on sweet corn. No studies were conducted
with popcorn, however K-I believes that the data on field and sweet
corn support a tolerance in popcorn as well. Because the proposed use
rate and pattern is the same for popcorn, it is reasonable to conclude
that residues in popcorn grain will not exceed the proposed tolerance
of 0.02 ppm. Residues in field and sweet corn forage after the day of
application were less than the proposed tolerance of 0.05 ppm. Popcorn
forage is not a fed commodity. Nonetheless, residues in popcorn forage
or fodder are not expected to exceed the proposed tolerance of 0.05
ppm. The proposed tolerances of 0.02 ppm in field corn, sweet corn, and
popcorn grain and 0.05 ppm in field corn and sweet corn forage and
fodder are adequate to cover residues likely to occur when Action
herbicide is applied to corn as directed.
This position is based on section 180.34(d) of the CFR which states
that ``If the pesticide chemical is not absorbed into the living plant
or animal when applied (is not systemic), it may be possible to make a
reliable estimate of the residues to be expected on each commodity in a
group of related commodities on the basis of less data than would be
required for each commodity in the group, considered separately.'' And,
section 180.34(e) states that ``Each of the following groups of crops
lists raw agricultural commodities that are considered to be related
for the purpose of paragraph (d) of this section; field corn, popcorn,
sweet corn (each in grain form).''
Residues of fluthiacet-methyl in treated field and sweet corn grain
and sweet corn ears were less than the method LOQ (<0.01 ppm).="" because="" the="" proposed="" use="" rate="" and="" pattern="" is="" the="" same="" for="" popcorn,="" it="" is="" reasonable="" to="" conclude="" that="" residues="" in="" popcorn="" grain="" will="" not="" exceed="" the="" proposed="" tolerance="" of="" 0.02="" ppm.="" residues="" in="" field="" and="" sweet="" corn="" forage="" after="" the="" day="" of="" application="" were="" less="" than="" the="" proposed="" tolerance="" of="" 0.05="" ppm.="" popcorn="" forage="" is="" not="" a="" feed="" commodity.="" nonetheless,="" residues="" in="" popcorn="" forage="" or="" fodder="" are="" not="" expected="" to="" exceed="" the="" proposed="" tolerance="" of="" 0.05="" ppm.="" the="" proposed="" tolerances="" of="" 0.02="" ppm="" in="" field="" corn,="" sweet="" corn,="" and="" popcorn="" grain="" and="" 0.05="" ppm="" in="" field="" corn="" and="" sweet="" corn="" forage="" and="" fodder="" are="" adequate="" to="" cover="" residues="" likely="" to="" occur="" when="" action="" herbicide="" is="" applied="" to="" corn="" as="" directed.="" b.="" toxicological="" profile="" 1.="" acute="" toxicity.="" \a="" rat="" acute="" oral="" study="" with="" an="">50 > 5,000 mg/kg.
\A rabbit acute dermal study with an LD50 > 2,000 mg/kg.
\A rat inhalation study with an LC50 > 5.05 mg/liter.
\A primary eye irritation study in the rabbit showing moderate eye
irritation.
\A primary dermal irritation study in the rabbit showing no skin
irritation.
\A primary dermal sensitization study in the Guinea pig showing no
sensitization.
[[Page 52549]]
\Acute neurotoxicity study in rats. Neurotoxic effects were not
observed. The NOEL was 2,000 mg/kg.
2. Genotoxicity. In vitro gene mutation tests: Ames test -
negative; Chinese hamster V79 test - negative; rat hepatocyte DNA
repair test - negative; E. Coli letal DNA damage test - negative. In
vitro chromosomal aberration tests: Chinese hamster ovary - positive at
cytotoxic doses; Chinese hamster lung - positive at cytotoxic doses;
human lymphocyes - positive at cytotoxic doses. In vivo chromosome
aberration tests: Micronucleus assays in rat liver - negative; mouse
bone marrow test - negative.
3. Reproductive and developmental toxicity. Reproductive and
developmental toxicity. Teratology study in rats with a maternal and
developmental NOEL equal to or greater than 1,000 mg/kg/day.
Teratology study in rabbits with a maternal NOEL greater than or
equal to 1,000 mg/kg/day and a fetal NOEL of 300 mg/kg based on a
slight delay in fetal maturation. 2-generation reproduction study in
rats with a NOEL of 36 mg/kg/day, based on liver lesions in parental
animals and slightly reduced body weight development in parental
animals and pups. [The treatment had no effect on reproduction or
fertility.]
4. Subchronic toxicity. 90-day subchronic neurotoxicity study in
rats. The NOEL was 0.5 mg/kg/day based on reduced body weight gain. No
clinical or morphological signs of neurotoxicity were detected at any
dose level. 28-day dermal toxicity study in rats with a NOEL equal to
or higher than the limit dose of 1,000 mg/kg.
6-week dietary toxicity study in dogs with a NOEL of 162 mg/kg/day
in males and 50 mg/kg/day in females based on decreased body weight
gain and modest hematological changes.
90-day subchronic dietary toxicity study in rats with a NOEL of 6.2
mg/kg/day based on liver changes and hematological effects.
5. Chronic toxicity. 24-month combined chronic toxicity/
carcinogenicity study in rats with a NOEL of 2.1 mg/kg/day. Based on
reduced body weight development and changes in bone marrow, liver,
pancreas and uterus the MTD was exceeded at 130 mg/kg/day. A positive
trend of adenomas of the pancreas in male rats treated at 130 mg/kg/day
and above may be attributable to the increased survival of the rats
treated at high doses. 18-month oncogenicity study in mice with a NOEL
of 0.14 mg/kg/day. Based on liver changes, the MTD was reached at 1.2
mg/kg/day. The incidence of hepatocellular tumors was increased in
males treated at 12 and 37 mg/kg/day.
C. Endocrine effects
Based on the results of short-term, chronic, and reproductive
toxicity studies there is no indication that fluthiacet-methyl might
interfere with the endocrine system. Considering further the low
environmental concentrations and the lack of bioaccumulation, there is
no risk of endocrine disruption in humans or wildlife.
Animal metabolism. The results from hen and goat metabolism
studies, wherein fluthiacet-methyl was fed at exaggerated rates, showed
that the transfer of fluthiacet-methyl residues from feed to tissues,
milk and eggs is extremely low. No detectable residues of fluthiacet-
methyl (or metabolite CGA-300403) would be expected in meat, milk,
poultry, or eggs after feeding the maximum allowable amount of treated
corn and soybeans. This conclusion is based on residue data from the
corn and soybean metabolism and field residue chemistry studies coupled
with the residue transfer from feed to tissues, milk and eggs obtained
in the goat and hen metabolism studies.
D. Aggregate Exposure
Aggregate exposure includes exposure from dietary exposure from
food and drinking water; and non-dietary exposure from non-dietary uses
of pesticides products containing the active ingredient, fluthiacet-
methyl.
1. Dietary exposure. Dietary exposure consists of exposures from
food and drinking water.
2. Food. In this assessment, K-I Chemical has conservatively
assumed that 100% of all soybeans and corn used for human consumption
would contain residues of fluthiacet-methyl and all residues would be
at the level of the proposed tolerances. The potential dietary exposure
to fluthiacet-methyl was calculated on the basis of the proposed
tolerance which is based on an LOQ of 0.01 ppm in soybeans and 0.02 ppm
in corn (2 x LOQ). The anticipated residues in milk, meat and eggs
resulting from feeding the maximum allowable amount of soybean and corn
commodities to cattle and poultry were calculated, and the resulting
quantities were well below the analytical method LOQ. Therefore,
tolerances for milk, meat and eggs are not required. Assuming 100% crop
treated values, the chronic dietary exposure of the general U.S.
population to fluthiacet-methyl would correspond to 2.3% of the RfD.
3. Drinking water. Although fluthiacet-methyl has a slight to
medium leaching potential; the risk of the parent compound to leach to
deeper soil layers is negligible under practical conditions in view of
the fast degradation of the product. For example, the soil metabolism
half-life was extremely short, ranging from 1.1 days under aerobic
conditions to 1.6 days under an aerobic conditions. Even in the event
of very heavy rainfalls immediately after application, which could lead
to a certain downward movement of the parent compound, parent
fluthiacet-methyl continues to be degraded during the transport into
deeper soil zones. Considering the low application rate of fluthiacet-
methyl, the strong soil binding characteristics of fluthiacet-methyl
and its degradates, and the rapid degradation of fluthiacet-methyl in
the soil, there is no risk of ground water contamination with
fluthiacet-methyl or its metabolites. Thus, aggregate risk of exposure
to fluthiacet-methyl does not include drinking water
4. Non-dietary exposure. Fluthiacet-methyl is not registered for
any other use and is only proposed for use on agricultural crops. Thus,
there is no potential for non-occupational exposure other than
consumption of treated commodities containing fluthiacet-methyl
residue.
E. Cumulative Effects
A cumulative exposure assessment is not appropriate at this time
because there is no information available to indicate that effects of
fluthiacet-methyl in mammals would be cumulative with those of another
chemical compound.
F. Safety Determination
1. U.S. population. Using the very conservative exposure
assumptions described above coupled with toxicity data for fluthiacet-
methyl, K-I Chemical calculated that aggregate, chronic exposure to
fluthiacet-methyl will utilize no more than 2.3% of the RfD for the
U.S. population. Because the actual anticipated residues are well below
tolerance levels and the percent crop treated with fluthiacet-methyl is
expected to be less than 25% of planted corn or soybeans, a more
realistic estimate is that dietary exposure will likely be at least 20
times less than the conservative estimate previously noted (the margins
of exposure will be accordingly higher). Exposures below 100% of the
RfD are generally not of concern 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.
[[Page 52550]]
Also the acute dietary risk to consumers will be far below any
significant level; the lowest NOEL from a short term exposure scenario
comes from the teratology study in rabbits with a NOEL of 300 mg/kg.
This NOEL is 2,000-fold higher than the chronic NOEL which provides the
basis for the RfD (see above). Acute dietary exposure estimates which
are based on a combined food survey from 1989 to 1992 predict margins
of exposure of at least one million for 99.9% of the general population
and for women of child bearing age. Margins of exposure of 100 or more
are generally considered satisfactory. Therefore, K-I Chemical
concludes that there is a reasonable certainty that no harm will result
from aggregate exposure to fluthiacet-methyl residues.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of fluthiacet-methyl,
K-I Chemical considered data from developmental toxicity studies in the
rat and rabbit and a 2-generation reproduction study in the rat. A
slight delay in fetal maturation was observed in a teratology study in
rabbits at a daily dose of 1,000 mg/kg. In a 2-generation reproduction
study fluthiacet-methyl did not affect the reproductive performance of
the parental animals or the physiological development of the pups. The
NOEL was 500 ppm for maternal animals and their offspring, which is
50,000 fold higher than the RfD.
3. Reference dose. Using the same conservative exposure assumptions
as was used for the general population, the percent of the RfD that
will be utilized by aggregate exposure to residues of fluthiacet-methyl
is as follows: 1.5% for nursing infants less than 1 year old, 5.9% for
non-nursing infants, and 5.2% for children 1-6 years old. K-I Chemical
concludes that there is a reasonable certainty that no harm will result
to infants and children from aggregate exposure to residues of
fluthiacet-methyl.
G. International Tolerances
No international tolerances have been established under CODEX for
fluthiacet-methyl. (Joanne Miller)
3. Zeneca Ag Products
PP 7F4864
EPA has received a pesticide petition (PP 7F4864) 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 180.507 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 raw
agricultural commodities almond hulls at 4.0 ppm, cucurbits (chayotes,
Chinese waxgourds, citron melons, cucumbers, gherkins, edible gourds,
Mordica spp., cantaloupes, casabas, crenshaw melons, golden pershaw
melons, honeydew melons, honey balls, mango melons, Persian melons,
summer squashes, winter squashes, and watermelons) at 0.3 ppm, peanut
hay at 1.5 ppm, pistachios at 0.01 ppm, rice grain at 4.0 ppm, rice
hulls at 20 ppm, rice straw at 11 ppm, tree nuts (almonds, beech nuts,
Brazil nuts, butternuts, cashews, chestnuts, chinquapins, filberts,
hickory nuts, macadamia nuts, pecans, and walnuts) at 0.01 ppm, wheat
bran at 0.12 ppm, wheat grain at 0.04 ppm, wheat hay at 13.0 ppm, and
wheat straw at 4.0 ppm. It is also proposed that 40 CFR 180.507 be
amended by establishment of a tolerance for the residues of
azoxystrobin (methyl (E)-2-[2-[6-(2-cyanophenoxy)pyrimidin-4-
yloxy]phenyl]-3-methoxyacrylate) in or on the following animal
products: eggs at 0.4 ppm, cattle kidney at 0.06 ppm, liver of cattle,
goat, horse, and sheep at 0.3 ppm, hog liver at 0.2 ppm, poultry liver
at 0.4 ppm, meat and fat of cattle, goat, horse, sheep, poultry and
swine at 0.01 ppm, and milk at 0.006 ppm. The proposed analytical
methods use gas chromatography with nitrogen-phosphorous detection (GC-
NPD) or, in mobile phase, high performance liquid chromatography with
ultraviolet detection (HPLC-UV). EPA has determined that the petition
contains data or information regarding the elements set forth in
section 408(d)(2) of the FFDCA; however, EPA has not fully evaluated
the sufficiency of the submitted data at this time or whether the data
supports granting of the petition. Additional data may be needed before
EPA rules on the petition.
A. Residue Chemistry
1. Plant metabolism. The metabolism of 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 TRR.
2. Analytical method. An adequate analytical method, gas
chromatography with nitrogen-phosphorous detection (GC-NDP) or, in
mobile phase, by high performance liquid chromatography with
ultraviolet 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 and also underwent successful independent
laboratory validations.
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 (limit test) for both males and females. The acute
dermal toxicity study in rats of technical azoxystrobin resulted in an
LD50 of >2,000 milligrams/kilogram (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 milligrams/
kilogram azoxystrobin, the systemic toxicity no observed effect level
(NOEL) was 200 milligrams/kilogram and the systemic toxicity lowest
observed effect level (LOEL) was 200 milligrams/kilogram, based on the
occurrence of transient diarrhea in both sexes. There was no indication
of neurotoxicity at the doses tested. This acute neurotoxicity study is
considered supplementary (upgradable) but the data required are
considered only to be confirmatory. Zeneca has submitted the required
confirmatory data; these data have been scheduled for review by the
Agency.
2. Genotoxicty (mutagenicity). 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
[[Page 52551]]
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 through 16 of gestation,
lethality at the highest dose caused the discontinuation of dosing at
that level. The developmental NOEL was greater than or equal to 100 mg/
kg/day and the developmental lowest observed effect level (LOEL) was
>100 mg/kg/day because no significant adverse developmental effects
were observed. In this same study, the maternal NOEL was not
established; the maternal LOEL 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 through 20 of gestation, the
developmental NOEL was 500 mg/kg/day and the developmental LOEL was
>500 mg/kg/day because no treatment-related adverse effects on
development were seen. The maternal NOEL was 150 mg/kg/day and the
maternal LOEL was 500 mg/kg/day, based on decreased body weight gain.
In a 2-generation study, rats were fed 0, 60, 300, or 1,500 ppm of
azoxystrobin. The reproductive NOEL was 32.2 mg/kg/day. The
reproductive LOEL was 165.4 mg/kg/day. Reproductive toxicity was
demonstrated as treatment-related reductions in adjusted pup body
weights as observed in the F18 and F2. pups dosed at 1500 ppm (165.4
mg/kg/day).
4. Subchronic toxicity. In a 90-day rat feeding study the NOEL was
20.4 mg/kg/day for males and females. The LOEL 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 NOEL for both
males and females was 50 mg/kg/day. The LOEL 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
NOEL for both males and females was greater than or equal to 1,000 mg/
kg/day (the highest dosing regimen); a LOEL was therefore not
determined.
5. Chronic toxicity and carcinogenicity. In a 2-year feeding study
in rats fed diets containing 0, 60, 300, and 750/1,500 ppm (males/
females), the systemic toxicity NOEL was 18.2 mg/kg/day for males and
22.3 mg/kg/day for females. The systemic toxicity LOEL for males was 34
mg/kg/day, based on reduced body weights, food consumption, and food
efficiency; and bile duct lesions. The systemic toxicity LOEL 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 NOEL for both males
and females was 25 mg/kg/day and the LOEL 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 NOEL
was 37.5 mg/kg/day for both males and females. The systemic toxicity
LOEL 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 ``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 the study of metabolism in the rat,
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. This study was classified as supplementary but upgradable; the
company has submitted data intended to upgrade the study and these data
have been reviewed.
C. Dietary Exposure
1. Food. The primary route of human exposure to azoxystrobin is
expected to be dietary ingestion of both raw and processed agricultural
commodities from bananas, grapes, peaches, peanuts, tomatoes, tree
nuts, pistachios, rice, cucurbits, and wheat. A chronic dietary
exposure analysis (combined years 1989 - 1992 U.S. Department of
Agriculture's Nationwide Food Consumption Survey using the Technical
Assessment Systems, Inc. ``EXPOSURE 1'' software) was conducted using
tolerance level residues and 100% crop treated information to estimate
the TMRC for the general population and 22 subgroups.
2. Drinking water. There is no established Maximum Concentration
Level for residues of azoxystrobin in drinking water. The potential
exposures associated with azoxystrobin in water, even at the higher
levels the Agency is considering as a conservative upper bound, would
not prevent the Agency from determining that there is a reasonable
certainty of no harm if the proposed uses were granted.
3. Non-dietary exposure. The Agency evaluated the existing
toxicological database for azoxystrobin and assessed appropriate
toxicological endpoints 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 endpoints
were identified for acute dietary or short term, intermediate term, and
chronic term (noncancer) dermal and inhalation occupational or
residential exposure. Therefore, risk assessments are not required for
these exposure scenarios and there are no residential risk assessments
to aggregate with the chronic dietary risk assessment.
D. Cumulative Effects
Section 408(b)(2)(D)(v) requires that, when considering whether to
establish, modify, or revoke a tolerance, the Agency consider
``available information'' concerning the cumulative effects of a
particular pesticide's residues and ``other substances that have a
common mechanism of toxicity.'' EPA does not have, at this time,
available data to determine whether azoxystrobin 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, azoxystrobin does not appear to be structurally similar to
any other pesticide chemical at this time. No metabolites of
azoxystrobin that are of toxicological concern are known to the Agency.
Azoxystrobin appears to the only pesticide member of its class of
[[Page 52552]]
chemistry and there are no reliable data to indicate that this chemical
is structurally or toxicologically similar to existing chemical
substances at this time. Therefore, it appears unlikely that
azoxystrobin bears a common mechanism of activity with other
substances. For the purposes of this tolerance action, it is not
appropriate to assume that azoxystrobin has a common mechanism of
toxicity with other substances.
E. Safety Determination
The chronic toxicity Reference Dose (RfD) for azoxystrobin is 0.18
mg/kg/day, based on the NOEL 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 LOEL of 34 mg/
kg/day. This NOEL was divided by an Uncertainty Factor of 100, to allow
for interspecies sensitivity and intraspecies variability.
1.As part of the hazard assessment process, the available
toxicological database was reviewed to determine if there are
toxicological endpoints of concern. For azoxystrobin, the Agency does
not have a concern for acute dietary exposure since the available data
do not indicate any evidence of significant toxicity from a 1-day or
single event exposure by the oral route. Therefore, an acute dietary
risk assessment is not required for azoxystrobin at this time.
2. U.S. population. The chronic dietary exposure analysis showed
that exposure from the proposed new tolerances in or on tree nuts,
pistachios, cucurbits, rice, and wheat for the general U.S. population
would be 1.1% of the RfD. This analysis used a value of 0.05 ppm for
banana pulp rather than the value of 0.5 that has been established for
banana (whole fruit including peel) because adequate data were
submitted to support use of the lower value in the dietary risk
analyses.
3. Infants and children. The chronic dietary exposure analysis,
using the same tolerances and commodities that were used for the same
analysis for the general U.S. population showed that the exposure of
Non-nursing Infants (the subgroup with the highest exposure) would be
4.1% of the RfD.
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
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 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 1/100th of
the no observed effect level in the animal study appropriate to the
particular risk assessment. This hundredfold uncertainty (safety)
factor/margin of exposure (safety) is designed to account for combined
inter- and intraspecies variability. EPA believes that reliable data
support using the standard hundredfold margin/factor not the additional
tenfold margin/factor when EPA has a complete database 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
database for azoxystrobin is complete except that the acute and
subchronic neurotoxicity studies require upgrading. The upgrade data
are confirmatory only, have been submitted by the company, and await
review by the Agency.
There was no evidence of increased susceptibility of infants or
children to azoxystrobin. Therefore, no additional uncertainty factors
are considered necessary at this time.
F. Endocrine Effects
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 shareholders, 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 three
(3) years from the passage pf FQPA (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 that azoxystrobin has any endocrine effects.
G. International Tolerances
There are no Codex Maximum Residue Levels established for
azoxystrobin. (Cynthia Giles-Parker)
[FR Doc. 97-26537 Filed 10-8-97; 8:45 am]
BILLING CODE 6560-50-F
