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Flumioxazin (Valent). February 14, 2001, Petition to Establish Tolerances. Federal Register.
http://www.epa.gov/EPA-PEST/2001/February/Day-14/p3620.htm
[Federal Register: February 14, 2001 (Volume 66, Number 31)]
[Notices]
[Page 10292-10301]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr14fe01-59]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-996; FRL-6765-8]
Notice of Filing a Pesticide Petition to Establish a Tolerance
for a Certain Pesticide Chemical in or on Food
AGENCY: Environmental Protection Agency (EPA).
[[Page 10293]]
ACTION: Notice.
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SUMMARY: This notice announces the initial filing of a pesticide
petition proposing the establishment of regulations for residues of a
certain pesticide chemical in or on various food commodities.
DATES: Comments, identified by docket control number PF-996, must be
received on or before March 16, 2001.
ADDRESSES: Comments may be submitted by mail, electronically, or in
person. Please follow the detailed instructions for each method as
provided in Unit I.C. of the SUPPLEMENTARY INFORMATION. To ensure
proper receipt by EPA, it is imperative that you identify docket
control number PF-996 in the subject line on the first page of your
response.
FOR FURTHER INFORMATION CONTACT: By mail: Joanne Miller, Registration
Division (7505C), Office of Pesticide Programs, Environmental
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460;
telephone number: (703) 305-6224; e-mail address:
miller.joanne@epa.gov.
SUPPLEMENTARY INFORMATION:
I. General Information
A. Does this Action Apply to Me?
You may be affected by this action if you are an agricultural
producer, food manufacturer or pesticide manufacturer. Potentially
affected categories and entities may include, but are not limited to:
------------------------------------------------------------------------
Examples of
Categories NAICS codes potentially
affected entities
------------------------------------------------------------------------
Industry 111 Crop production
112 Animal production
311 Food manufacturing
32532 Pesticide
manufacturing
------------------------------------------------------------------------
This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in the table could also be
affected. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether or not this action might apply to certain entities. If you have
questions regarding the applicability of this action to a particular
entity, consult the person listed under FOR FURTHER INFORMATION
CONTACT.
B. How Can I Get Additional Information, Including Copies of this
Document and Other Related Documents?
1. Electronically. You may obtain electronic copies of this
document, and certain other related documents that might be available
electronically, from the EPA Internet Home Page at http://www.epa.gov/.
To access this document, on the Home Page select ``Laws and
Regulations'' and then look up the entry for this document under the
``Federal Register--Environmental Documents.'' You can also go directly
to the Federal Register listings at http://www.epa.gov/fedrgstr/.
2. In person. The Agency has established an official record for
this action under docket control number PF-996. The official record
consists of the documents specifically referenced in this action, any
public comments received during an applicable comment period, and other
information related to this action, including any information claimed
as confidential business information (CBI). This official record
includes the documents that are physically located in the docket, as
well as the documents that are referenced in those documents. The
public version of the official record does not include any information
claimed as CBI. The public version of the official record, which
includes printed, paper versions of any electronic comments submitted
during an applicable comment period, is available for inspection in the
Public Information and Records Integrity Branch (PIRIB), Rm. 119,
Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA, from 8:30
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The
PIRIB telephone number is (703) 305-5805.
C. How and to Whom Do I Submit Comments?
You may submit comments through the mail, in person, or
electronically. To ensure proper receipt by EPA, it is imperative that
you identify docket control number PF-996 in the subject line on the
first page of your response.
1. By mail. Submit your comments to: Public Information and Records
Integrity Branch (PIRIB), Information Resources and Services Division
(7502C), Office of Pesticide Programs (OPP), Environmental Protection
Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460.
2. In person or by courier. Deliver your comments to: Public
Information and Records Integrity Branch (PIRIB), Information Resources
and Services Division (7502C), Office of Pesticide Programs (OPP),
Environmental Protection Agency, Rm. 119, Crystal Mall #2, 1921
Jefferson Davis Highway, Arlington, VA. The PIRIB is open from 8:30
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The
PIRIB telephone number is (703) 305-5805.
3. Electronically. You may submit your comments electronically by
e-mail to: opp-docket@epa.gov, or you can submit a computer disk as
described above. Do not submit any information electronically that you
consider to be CBI. Avoid the use of special characters and any form of
encryption. Electronic submissions will be accepted in Wordperfect 6.1/
8.0 or ASCII file format. All comments in electronic form must be
identified by docket control number PF-996. Electronic comments may
also be filed online at many Federal Depository Libraries.
D. How Should I Handle CBI That I Want to Submit to the Agency?
Do not submit any information electronically that you consider to
be CBI. You may claim information that you submit to EPA in response to
this document as CBI 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. In addition to one complete
version of the comment that includes any information claimed as CBI, a
copy of the comment that does not contain the information claimed as
CBI must be submitted for inclusion in the public version of the
official record. Information not marked confidential will be included
in the public version of the official record without prior notice. If
you have any questions about CBI or the procedures for claiming CBI,
please consult the person identified under FOR FURTHER INFORMATION
CONTACT.
E. What Should I Consider as I Prepare My Comments for EPA?
You may find the following suggestions helpful for preparing your
comments:
1. Explain your views as clearly as possible.
2. Describe any assumptions that you used.
3. Provide copies of any technical information and/or data you used
that support your views.
4. If you estimate potential burden or costs, explain how you
arrived at the estimate that you provide.
5. Provide specific examples to illustrate your concerns.
[[Page 10294]]
6. Make sure to submit your comments by the deadline in this
notice.
7. To ensure proper receipt by EPA, be sure to identify the docket
control number assigned to this action in the subject line on the first
page of your response. You may also provide the name, date, and Federal
Register citation.
II. What Action is the Agency Taking?
EPA has received a pesticide petition as follows proposing the
establishment and/or amendment of regulations for residues of a certain
pesticide chemical in or on various food commodities under section 408
of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a.
EPA has determined that this petition contains 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 support granting of the petition. Additional data
may be needed before EPA rules on the petition.
List of Subjects
Environmental protection, Agricultural commodities, Feed additives,
Food additives, Pesticides and pests, Reporting and recordkeeping
requirements.
Dated: February 1, 2001.
James Jones,
Director, Registration Division, Office of Pesticide Programs.
Summary of Petition
The petitioner summary of the pesticide petition is printed below
as required by section 408(d)(3) of the FFDCA. The summary of the
petition was prepared by the petitioner and represents the view of the
petitioner. EPA is publishing the petition summary verbatim without
editing them in any way. The petitioner 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.
Valent U.S.A. Corporation
7F4841 and 0F6171
EPA has received pesticide petitions (7F4841 and 0F6171) from
Valent U.S.A. Corporation, 1333 North California Boulevard, Suite 600,
Walnut Creek, CA 94596-8025, proposing, pursuant to section 408(d) of
the FFDCA, 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing
tolerances for residues of flumioxazin, 2-[7-fluoro-3,4-dihydro-3-oxo-
4-(2-propynyl)-2H-1,4-benzoxazin-6-yl]-4,5,6,7-tetrahydro-1H-isoindole-
1,3(2H)-dione, in or on the raw agricultural commodities (RACs) soybean
seed and peanut nutmeat at 0.01 parts per million (ppm), and on sugar
cane at 0.2 ppm. EPA has determined that the petitions 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
petitions. Additional data may be needed before EPA rules on the
petitions.
A. Residue Chemistry
Summary. Radiocarbon plant and animal metabolism studies have
demonstrated that the residue of concern is adequately understood for
the purposes of these tolerances and is best defined as parent,
flumioxazin. Practical, validated residue methodology is available to
analyze all appropriate matrices for flumioxazin residue with a limit
of quantification (LOQ) of 0.01 ppm, adequate to enforce all proposed
tolerances. The potential magnitude of residues of flumioxazin has been
evaluated in peanuts, soybeans, and sugarcane and in appropriate
processed products and animals. These studies are adequate to support
appropriate tolerances and dietary risk analyses.
1. Plant metabolism. Metabolism of 14C-flumioxazin
labelled in the phenyl- or tetrahydrophthalimido-rings has been studied
in soybeans and peanuts. Flumioxazin was rapidly and extensively
metabolized to many metabolites in both plants. Even with exaggerated
treatment, individual metabolites and parent were only found at very
low concentrations. Comparisons of metabolites detected and quantified
from plants and animals show that there are no significant aglycones in
plants which are not also present in the excreta or tissues of animals.
The residue of concern is best defined as the parent.
2. Analytical method. Practical analytical methods for detecting
and measuring levels of flumioxazin have been developed and validated
in/on all appropriate agricultural commodities and respective
processing fractions. The extraction methodology has been validated
using aged radiochemical residue samples from 14C-metabolism
studies. The enforcement method has been validated in soybean at an
independent laboratory and by EPA. The LOQ of flumioxazin in the
methods is 0.01 ppm which will allow monitoring of food with residues
at the levels proposed for the tolerances.
3. Magnitude of residues--i. Soybean. Forty-two (42) field trials
in soybeans were conducted in 1989 through 1993 in EPA regions II (2
trials), IV (9 trials, and V (31 trials), representing approximately
99% of the U.S. soybean growing region. Treatments ranged from 0.09 to
0.47 pounds active per acre, 1-to 5-times the proposed application
rate. No residues of flumioxazin were detected in soybean seed from any
of the trials, even when application rates were 5 times the proposed
label rate. Analysis for the major plant metabolite, 1-OH-HPA, was
conducted on seed samples from 13 residue trials. In all cases no
residues of the degradate were found, including 2 trials which at a 5X
treatment rate.
No residues of flumioxazin were found in any of the processed
commodities in 2 processing studies of soybeans treated at 5 times the
proposed label rate. In 1 of the processing studies, no residue of 1-
OH-HPA was found in any processed fraction. All the data support a
proposed tolerance for flumioxazin in/on soybean seed at 0.01 ppm, the
LOQ of the enforcement method. No separate tolerances are needed for
soybean processed commodities.
ii. Peanut. Sixteen (16) field trials in peanuts were conducted in
1992, 1993, and 1996 in EPA regions II (8 trials), III (3 trials), IV
(3 trials), and VIII (2 trials), representing virtually all of the U.S.
peanut growing regions. Treatments ranged from 0.09 to 0.47 pounds
active per acre, 1-to 5-times the proposed application rate. No
residues of flumioxazin were detected in any peanut seed sample from
any of the trials, even when application rates were 5 times the
proposed label rate. Analysis for the major plant metabolite, 1-OH-HPA,
was conducted on seed samples from 1 5X processing trial. No residues
of the degradate were found.
No residues of flumioxazin were found in any of the processed
commodities in 2 processing studies of peanuts treated at 5 times the
proposed label rate. One of the processing studies was analyzed for
degradate, no residue of 1-OH-HPA was found in any processed fraction.
All the data support a proposed tolerance for flumioxazin in/on
peanut seed at 0.01 ppm, the LOQ of the enforcement method. No separate
tolerances are needed for peanut processed commodities.
iii. Sugarcane. Nine (9) field trials in sugarcane were conducted
in 1998 in EPA regions III (4 trials), IV (3 trials), VI (1 trial), and
XIII (1 trial), representative of all of the U.S. sugarcane growing
[[Page 10295]]
regions. Treatments ranged from 0.37 to 1.12 pounds active per acre, 1-
to 3-times the proposed application rate for high organic soils. Finite
residues of flumioxazin were detected in fourteen (14) of eighteen (18)
duplicate samples. Residues of flumioxazin averaged 0.039 ppm (standard
deviation = 0.033 ppm) from the trials conducted at the proposed
maximum application rate. Analysis for the major plant metabolite, 1-
OH-HPA, was conducted on all cane samples including those from the 2 3X
processing trials. No residues of the degradate were found in any cane
sample.
No residues of flumioxazin or its degradate were found in the
processed commodity refined sugar. In molasses, produced from cane
treated at 3 times the proposed label rate, flumioxazin was detected
(0.055 ppm) at approximately half of the concentration in the starting
sugarcane. The degradate, 1-OH-HPA, was also detected in molasses
(0.036 ppm). Because these detections were in a processed sample from
cane treated at 3X, and are still less than the proposed RAC tolerance,
no separate processed product tolerances are necessary.
All the data support a proposed tolerance for flumioxazin in/on
sugarcane at 0.2 ppm. No separate tolerances for parent or degradate
are needed for processed commodities.
iv. Secondary residues. Using proposed tolerances to calculate the
maximum feed exposure to fed animals, and using the very low potential
for residue transfer demonstrated in the goat and hen metabolism
studies, detectable secondary residues in animal tissues, milk, and
eggs are not expected. Therefore, no cow or hen residue feeding studies
were performed,and tolerances are not proposed for these commodities.
v. Rotational crops. The results of a confined rotational crop
accumulation study indicate that no rotational crop planting
restrictions or rotational crop tolerances are required.
B. Toxicological Profile
Summary. A full battery of toxicology testing has been performed
on flumioxazin including acute, chronic, oncogenicity, developmental,
mutagenicity, and reproductive effects. Flumioxazin has low toxicity
via oral and dermal routes and is not carcinogenic. Overall, it does
not present a genetic hazard. Although developmental and reproductive
effects were observed in rats, acute and chronic dietary assessments
and worker exposure assessments demonstrate large margins of safety
when worst case exposures are compared to the proposed toxic endpoints,
along with appropriate uncertainty factors (UF). Valent proposes a
chronic population adjusted dose (c-PAD) of 0.018 milligram/kilogram
(mg/kg)/day for adults and 0.0018 mg/kg/day for women of child bearing
age and infants and children based on the no observed adverse effect
level (NOAEL) of 1.8 mg/kg/day for males in the rat 2 year chronic
toxicity oncogenicity study. Valent also proposes 3.0 mg/kg/day as the
acute oral endpoint based on the developmental toxicity NOAEL from the
rat oral developmental toxicity study.
1. Acute toxicity. The acute toxicity of technical grade
flumioxazin is low by all routes. The battery of acute toxicity studies
place flumioxazin in toxicity category III.
i. No abnormal clinical signs, body weight (bwt) changes, or gross
pathological findings were observed and no rats died following
administration of an oral dose of 5 gram/kilogram (g/kg) of flumioxazin
technical. The LD50 was greater than 5 g/kg.
ii. No deaths, abnormal clinical signs, bwt changes, or gross
pathological findings were observed in rats exposed to a 2.0 g/kg
dermal dose of flumioxazin technical. The LD50 was greater
than 2.0 g/kg.
iii. Rats were exposed to a dust aerosol of flumioxazin technical
for 4 hours at measured concentrations of 1.55 or 3.93 milligrams/Liter
(mg/L), the maximum attainable concentration. Irregular respiration,
bradypnea and a decrease in spontaneous activity were observed in many
of the rats, but these effects disappeared within 2 hours after
termination of the exposure. No deaths, bwt changes, gross pathological
findings or histopathological changes in the respiratory organs were
observed. The LC50 for flumioxazin technical was determined
to be greater than 3.93 mg/L.
iv. Flumioxazin technical produced minimal eye irritation in
rabbits which cleared within 48 hours.
v. Flumioxazin technical did not produce any signs of skin
irritation in abraded or intact skin of rabbits.
vi. Flumioxazin technical was not a skin sensitizer when tested in
guinea pigs using the Magnussen and Kligman maximization test
methodology.
2. Genotoxicity. Flumioxazin does not present a genetic hazard.
Flumioxazin was evaluated in the following tests for mutagenicity:
i. A reverse gene mutation assay in Salmonella typhimurium and
Escherichia coli was negative with or without metabolic activation.
ii. An in vitro chromosome aberration assay using chinese hamster
ovary (CHO) cells was negative in the absence of metabolic activation.
However, an increase in cells with aberrations was observed at doses of
1X10-4 M and higher in the presence of S9.
iii. An in vivo chromosomal aberration study in the rat was
negative. No significant increase in the incidence of chromosomal
aberrations in bone marrow cells was observed following treatments as
high as 5,000 mg/kg.
iv. An in vitro unscheduled DNA synthesis (UDS) assay with rat
hepatocytes was negative.
v. A mouse micronucleus assay was negative following
intraperitoneal injection of 5,000 mg/kg.
3. Reproductive and developmental toxicity. Flumioxazin shows
developmental toxicity in the absence of maternal toxicity in rats.
Mechanistic studies demonstrate that the effect is specifically related
to the inhibition of heme synthesis, that the effect shows considerable
species specificity, and that the rat is a conservative surrogate
species for the potential for developmental toxicity in man. No
developmental toxicity was observed in rabbits. Developmental toxicity
to the pups was seen in the rat reproduction study at doses that were
not toxic to the parental animals.
i. Rat--Developmental toxicity. A pilot dose range-finding study
was conducted to determine appropriate doses for the definitive oral
developmental toxicity study. Flumioxazin technical was administered by
oral gavage at dosages of 0, 30, 100, 200, and 500 mg/kg/day to
pregnant rats on days 6 through 15 of gestation. No animals died during
the course of this study and maternal toxicity was limited to decreased
weight gain associated with high embryolethality observed in all dose
groups. Fetuses obtained from the 30 mg/kg/day dams had significantly
reduced bwts and were found to have both skeletal and visceral
abnormalities primarily wavy ribs and ventricular septal defects (VSD).
Because of the high degree of embryolethality at doses of 100 mg/kg/day
and greater, the highest dose selected for the definitive study was 30
mg/kg/day.
In the definitive study, pregnant rats were administered oral doses
of 0, 1, 3, 10, or 30 mg/kg/day of flumioxazin technical on days 6
through 15 of gestation. No maternal deaths were observed at any dosage
and no treatment-related effects on clinical signs or food consumption
were noted. A decrease in maternal bwt gain was found at 30 mg/kg/day.
The number of live fetuses and fetal bwts were decreased in the 30 mg/
kg/day group
[[Page 10296]]
and the incidence of embryo mortality tended to be higher but was not
statistically significant. No effects on the number of implantations,
sex ratios, or external abnormalities were found. The incidence of
fetuses with cardiovascular abnormalities, primarily VSD, was increased
in the 30 mg/kg/day group. Other developmental effects observed at 30
mg/kg/day included an increase in the incidence of wavy ribs and
curvature of the scapula, and a decrease in the number of ossified
sacrococcygeal vertebral bodies. Based on these findings, a maternal
NOAEL of 30 mg/kg/day and a developmental NOAEL of 3 mg/kg/day are
proposed.
In a range-finding dermal developmental toxicity study flumioxazin
technical was administered dermally at levels of 100, 200, 400, and 800
mg/kg/day in corn oil. No adverse effects on the dams were observed at
doses up to 800 mg/kg/day. Because of the high degree of
embryolethality at doses of 400 mg/kg/day and greater, the highest dose
selected for the definitive study was 300 mg/kg/day.
On days 6-15 of gestation, pregnant rats were exposed dermally to
dose levels of 30, 100, or 300 mg/kg/day of flumioxazin technical in
corn oil. No adverse effects were observed in the dams throughout the
study. Increased fetal mortality was accompanied by decreases in the
number of live fetuses and fetal bwts at doses of 300 mg/kg/day. No
external abnormalities were observed at any dose level. An increase in
cardiovascular abnormalities, primarily VSD, an increase in wavy ribs
and a decrease in the number of ossified sacrococcygeal vertebral
bodies was observed at 300 mg/kg/day. Based on these results, a
maternal NOAEL of 300 mg/kg/day and a developmental NOAEL of 30 mg/kg/
day are proposed.
To measure the dermal penetration of flumioxazin under the
conditions of the dermal teratology study, 13-day pregnant rats were
dermally exposed to (phenyl-14C) flumioxazin. The systemic
absorption ranged from 3.8% at 2 hours to 6.9% of the recovered
14C at 48 hours.
ii. Mechanistic studies. A series of scientific studies were
conducted to examine the mechanism and species differences in the
production of developmental toxicity by flumioxazin. This research
demonstrates clear species differences between rats, rabbits, mice, and
(in vitro) humans and indicates a high degree of correlation between
the interruption of heme synthesis and the production of developmental
toxicity in rats. The data support that the rat is a conservative model
for use in the risk assessment for humans. Specifically the studies
demonstrate that:
Flumioxazin interferes with normal heme biosynthesis
resulting in sidroblastic anemia and porphyria in adult rats.
14C-Flumioxazin administered to pregnant rats
on day 12 of gestation crosses the placenta and reaches the rat fetus
at maximum levels of radiocarbon (and flumioxazin), 4 hours later.
No clear pattern of adsorption, distribution, metabolism,
or excretion was evident which could account for the species-specific
development toxicity in rats.
The critical period of sensitivity to the developmental
effects of flumioxazin in rats is day 12 of gestation. This correlates
with the peak period of protoporphyrin IX (PPIX) accumulation in
maternal rat liver and the rat fetus.
A histological examination of rat fetus indicated signs of
fetal anemia within 6 hours after dosing, but no histological changes
in the fetal rat heart were observed until 36 or 48 hour after
treatment. No effects were observed in rabbit fetus treated in the same
manner as the rats.
Other observations in the pathogenesis of the
developmental effects of flumioxazin in rat fetuses included; enlarged
heart, edema, anemia, (decreased red blood cell count, and hemoglobin),
delayed closure of the interventricular foramen, reduced serum protein,
and incomplete/delayed ossification of the ribs.
The observation of enlarged heart, edema, and anemia
preceding the occurrence of fetal mortality suggest these effects may
be instrumental in the cause of fetal deaths.
The occurrence of an enlarged heart preceding the failure
of interventricular foramen closure could be related to the
pathogenesis rather than a direct toxic effect of flumioxazin on
cardiac tissue.
A strong correlation exists between PPIX accumulation, an
indicator of disrupted heme synthesis, and developmental toxicity.
Evidence of this correlation exists on the basis of species differences
between rats and rabbits; the critical period of sensitivity in the
rat; and compound-specific differences with two chemicals structurally
related to flumioxazin, one which produces developmental effects in
rats and one which does not.
iii. Rabbits. In a pilot dose range-finding study in rabbits,
flumioxazin technical was administered to rabbits on days 7 through 19
of gestation via oral intubation at dosages of 0, 300, 500, 1,000, and
1,500 mg/kg/day. Clinical observations were recorded and on day 29 of
gestation, all does were sacrificed, caesarean sectioned, and examined
for gross lesions, number of corpora lutea, and number and placement of
implantation sites, early and late resorptions and live and dead
fetuses. No deaths, abortions, or premature deliveries occurred during
this study. Dosages of flumioxazin technical as high as 1,500 mg/kg/day
did not result in significant clinical or necropsy observations nor
affect maternal bwt gains or feed consumption values. Similarly, there
were no adverse effects of dosages of flumioxazin technical up to 1,500
mg/kg/day on embryo-fetal viability, sex ratios, body weights or
external morphology.
Based on these results, pregnant rabbits were administered 0, 300,
1,000, or 3,000 mg/kg/day of flumioxazin technical on days 7-19 of
gestation by oral gavage. The highest dose was well in excess of the
1,000 mg/kg/day limit dose for developmental toxicity studies. The
3,000 mg/kg/day dosage tended to reduce maternal bwt gains and relative
and absolute feed consumption values. No gross lesions were produced at
any dose level. The 3,000 mg/kg/day dosage group litters tended to have
reduced fetal bwts but these differences were not statistically
different. No fetal external, soft tissue, or skeletal malformations or
variants were attributable to the test substance. Based on the data,
the maternal NOAEL was 1,000 mg/kg/day and the developmental NOAEL was
3,000 mg/kg/day.
iv. Reproduction. Two pilot range-finding rat reproduction studies
were conducted with flumioxazin technical at dosages from 100 to 5,000
ppm in the diet. In the definitive 2-generation reproduction study in
the rat dietary levels of 0, 50, 100, 200, and 300 ppm established a
systemic NOAEL of 200 ppm based on increased clinical signs (both sexes
and generations); mortality, gross, and histopathology findings in the
liver (F1 females); decreased body weight/weight w/w gain
(F0 and F1 females during gestation,
F1 males during premating) and decreased food consumption
(F0 and F1 females during lactation). The
reproductive NOAEL of 100 ppm was mainly based on developmental
toxicity at 200 ppm. Observed at 200 ppm were a decreased number of
liveborn pups and reduced pup bwts. At 300 ppm the following effects
were observed: decreased pup bwt (both generations); decreased number
of live pups/litter and viability index (both generations); increased
incidence of abnormalities of the reproductive organs (predominately
atrophied or hypoplastic testes and/or epididymides in F1
males); decreased gestation index (F0 females); decreased
[[Page 10297]]
mating and fertility indices (F1 males) and increased
clinical signs (F1 pups).
4. Subchronic toxicity. Subchronic toxicity studies conducted with
flumioxazin technical in the rat (oral and dermal), mouse and dog
indicate a low level of toxicity. Effects observed at high dose levels
consisted primarily of anemia and histological changes in the spleen,
liver and bone marrow related to the anemia.
i. Rats. A 90-day subchronic toxicity study was conducted in rats,
with dietary intake levels of 0, 30, 300, 1,000 and 3,000 ppm
flumioxazin technical (98.4% purity). The NOAEL of 300 ppm was based on
decreased bwts; anemia; increases in absolute and/or relative liver,
kidney, brain, heart, and thyroid weights, and histological changes in
the spleen, liver, and bone marrow related to the anemia.
A second 90-day subchronic toxicity study was conducted with a
sample of flumioxazin technical of typical purity (94.8%) at dietary
concentrations of 0, 30, 300, 1,000, and 3,000 ppm. The NOAEL was 30
ppm based on anemia and related hematological changes; increases in
liver, heart, kidney, and thyroid weights; and histological changes in
the spleen, liver, and bone marrow related to the anemia.
ii. Mice. Dose levels for the mouse oncogenicity study were
selected on the basis of results from a 4-week study of flumioxazin in
the diets of mice at levels of 0, 1,000, 3,000, and 10,000 ppm. In this
range-finding study, increases in absolute and/or relative liver
weights were noted for males at 10,000 ppm, and at 3,000, and 10,000
ppm for females.
iii. Dogs. A 90-day study was conducted in dogs given gelatin
capsules containing 0, 10, 100, or 1,000 mg/kg/day. The NOAEL of 10 mg/
kg/day for this study was based on a slight prolongation of activated
partial thromboplastin time; increased total cholesterol and
phospholipid and elevated alkaline phosphatase activity; increased
absolute and relative liver weights; and histological changes in the
liver.
iv. A 21-day dermal toxicity study was conducted in rats at dose
levels of 0, 100, 200, or 1,000 mg/kg/day. The NOAEL was determined to
be 300 mg/kg/day based on significantly decreased hemoglobin and
hematocrit values for females.
5. Chronic toxicity. Flumioxazin technical has been tested in
chronic studies with dogs, rats and mice. Valent proposes a chronic
oral endpoint of 1.8 mg/kg bw/day, based on the NOAEL for male rats in
the 2-year chronic toxicity oncogenicity feeding study.
i. Rats. In a 2-year study in rats, flumioxazin technical
administered in the diet at levels of 0, 50, 500, and 1,000 ppm
produced anemia and chronic nephropathy in rats of the 500 and 1,000
ppm groups. The anemia lasted throughout the treatment period, however,
it was not progressive nor aplastic in nature. No evidence of an
oncogenic effect was observed in rats and the NOAEL for this study was
50 ppm (1.8 mg/kg/day for males and 2.2 mg/kg/day for females).
ii. Mice. Flumioxazin technical was administered to mice at doses
of 0, 300, 3,000, and 7,000 ppm in diet for 78 weeks. An increased
incidence of hypertrophy of centrilobular hepatocytes was observed in
males of the 3,000 and 7,000 ppm groups. Increases in the incidence of
diffuse hypertrophy and single cell necrosis of hepatocytes were
observed in females of the 3,000 and 7,000 ppm groups. There was no
evidence of any treatment-related effect on the incidence of tumors.
Flumioxazin technical was not carcinogenic to mice, and the NOAEL for
this study was 300 ppm (31.1 mg/kg/day for males and 36.6 mg/kg/day for
females).
iii. Dogs. Flumioxazin technical was administered to dogs in
capsules at daily doses of 0, 10, 100, and 1,000 mg/kg bwt/day for one
year. Treatment-related changes in blood biochemistry included
increased total cholesterol and phospholipid values, elevated alpha-2-
globulin ratio at 1,000 mg/kg/day and increased alkaline phosphatase
activity in the 100 and 1,000 mg/kg/day groups. The absolute and/or
relative liver weights were elevated in one animal in the 100 mg/kg/day
group and four animals of the 1,000 mg/kg/day group. Minimal treatment-
related histological changes were noted in the livers of animals at the
1,000 mg/kg/day group. Based on these data the NOAEL was determined to
be 10 mg/kg/day.
iv. Carcinogenicity. Flumioxazin is not a carcinogen. Adequately
designed studies with both rats and mice have shown that repeated high
dose exposures produced anemia, liver effects, and nephropathy, but did
not produce cancer in test animals. No oncogenic response was observed
in a rat 2-year chronic feeding/oncogenicity study or in a 78 week
study on mice. Valent anticipates that the oncogenicity classification
of flumioxazin will be ``E'' (no evidence of carcinogenicity for
humans).
6. Animal metabolism. The absorption, tissue distribution,
metabolism and excretion of phenyl-14C-labeled flumioxazin
were studied in rats after single oral doses of 1 or 100 mg/kg, and
after a single oral dose of 1 mg/kg following 14 daily oral doses at 1
mg/kg of unlabelled material. For all dose groups, most (97.9-102.3%)
of the administered radiolabel was excreted in the urine and feces
within seven days after radiolabeled test material dosing. Radiocarbon
tissue residue levels were generally low on the seventh day post-
dosing. Radiocarbon residues were higher in blood cells than tissues.
Tissue 14C-residue levels, including those for fat, were
lower than blood levels which suggests little potential for
bioaccumulation. Urinary radiocarbon excretion was greater in females
than males in all dose groups.
Flumioxazin was extensively metabolized by rats and 35 metabolites
were detected and quantitated. The main metabolic reactions in rats
were:
Hydroxylation of the tetrahydrophthalimide moiety.
Incorporation of the sulfonic acid group into the
tetrahydrophthalimide moiety.
Cleavage of the imide linkage.
Cleavage of the benzoxazinoneamide.
Acetylation of the aniline nitrogen group.
7. Metabolite toxicology. Metabolism studies of flumioxazin in
rats, goats, hens, soybeans, and peanuts, as well as the fish
bioaccumulation study demonstrate that the parent is very rapidly
metabolized and, in animals, eliminated. The metabolites detected and
quantified from plants and animals show that there are no significant
aglycones in plants which are not also present in the excreta or
tissues of animals. Because parent and metabolites are not retained in
the body, the potential for acute toxicity from in situ formed
metabolites is low. The potential for chronic toxicity is adequately
tested by chronic exposure to the parent at the MTD and consequent
chronic exposure to the internally formed metabolites.
8. Endocrine disruption. No special studies to investigate the
potential for estrogenic or other endocrine effects of flumioxazin have
been performed. However, as summarized above, a large and detailed
toxicology data base exists for the compound including studies in all
required categories. These studies include acute, sub-chronic, chronic,
developmental, and reproductive toxicology studies including detailed
histology and histopathology of numerous tissues, including endocrine
organs, following repeated or long term exposures. These studies are
considered capable of revealing endocrine effects. The results of all
of these studies show no evidence of any endocrine-mediated effects and
no pathology of the
[[Page 10298]]
endocrine organs. Consequently, it is concluded that flumioxazin does
not possess estrogenic or endocrine disrupting properties.
C. Aggregate Exposure
1. Dietary exposure. A full battery of toxicology testing including
studies of acute, chronic, oncogenicity, developmental, mutagenicity,
and reproductive effects is available for flumioxazin. EPA has not had
the opportunity to review all of the toxicity studies on flumioxazin
and has not established toxic endpoints. Thus, in these risk
assessments Valent proposes as chronic oral toxic endpoint the NOAEL
for males from the rat chronic/oncogenicity feeding study, 1.8 mg/kg/
day; and as the acute oral toxic endpoint the NOAEL (proposed by EPA)
from the rat oral developmental toxicity study of 3.0 mg/kg/day.
Because the acute oral endpoint is for fetal toxicity to rats, Valent
has chosen to use the full, extra 10X uncertainty factor for
appropriate sub-groups of the population as mandated by FQPA.
i. Food. a. Acute dietary exposure to flumioxazin residues was
calculated for the U.S. population, women 13 years and older, and 5
children subgroups. The calculated exposure values are very
conservative because tolerance-level residues and 100% of the crop
treated are assumed. The calculated exposures and margins of exposure
(MOE) for the higher exposed proportions of the subgroups are listed
below. In all cases, margins of exposure relative to the acute endpoint
from the rat oral developmental toxicity study exceed 1-thousand.
Tier I Calculated Acute Dietary Exposures to the Total U.S.
Population and Selected Sub-Populations to Flumioxazin Residues in
Food.
----------------------------------------------------------------------------------------------------------------
Population
subgroup 95th Percentile 99.9th Percentile
----------------------------------------------------------------------------------------------------------------
Exposure (mg/kg/ MOE Exposure (mg/kg/ MOE
day) day)
Total U.S. population 0.000226 13,260 0.000791 3,791
Women 13 years and older 0.000146 20,592 0.000379 7,916
Children 7 to 12 years 0.000295 10,165 0.000758 3,956
Children 1 to 6 years 0.000397 7,559 0.000937 3,202
All infants 0.000801 3,744 0.001414 2,121
Non-nursing infants (<1-year 0.000861 3,483 0.001417 2,117
old)
Nursing infants (<1-year old) 0.000338 8,877 0.001244 2,411
----------------------------------------------------------------------------------------------------------------
b. Chronic dietary exposures to flumioxazin residues was calculated
for the U.S. population and 25 population subgroups. This Tier I
analysis assumes tolerance-level residues and 100% of the crops
treated. The results from several representative subgroups are listed
below. All calculated chronic dietary exposures were below 13% of the
c-PAD. The c-PAD was defined as the NOAEL from the rat oral 2-year
combined chronic toxicity oncogenicity study (1.8 mg/kg/day for males)
divided by the 100X UF for the adult exposures (0.018 mg/kg/day), or
divided by 1,000 to include the extra 10X uncertainty factor for adult
females of child-bearing age and infant and children population
subgroups (0.0018 mg/kg/day). Generally speaking, the Agency has no
cause for concern if total residue contribution for published and
proposed tolerances is less than 100% of the c-PAD.
Tier I Calculated Chronic Dietary Exposures to the Total U.S.
Population and Selected Sub-Populations to Flumioxazin Residues in
Food.
Results of Chronic Dietary Exposure Estimate
----------------------------------------------------------------------------------------------------------------
Population Subgroup Exposure (mg/kg/day) Percent of c-PAD
----------------------------------------------------------------------------------------------------------------
Total U.S. 0.000075 0.42
population (total)
(0.018)*
Females 13 + 0.000053 2.94
(nursing) (0.0018)*
Females 13 + (preg/ 0.000070 3.89
not nursing)
(0.0018)*
Children 7-12 yrs 0.000132 0.73
(0.018)*
Children 1-6 yrs 0.000163 9.06
(0.0018)*
All infants (<1 0.000190 10.56
year) (0.0018)*
Non-nursing infants 0.000229 12.72
(0.0018)*
Nursing infants 0.000058 3.22
(0.0018)*
----------------------------------------------------------------------------------------------------------------
* C-PAD value used to calculate percent of occupancy.
ii. Drinking water. Since flumioxazin is applied outdoors to
growing agricultural crops, the potential exists for the parent or its
metabolites to reach ground or surface water that may be used for
drinking water. Because of the physical properties of flumioxazin, it
is unlikely that flumioxazin or its metabolites can leach to potable
groundwater. To quantify potential exposure from drinking water,
surface water concentrations for flumioxazin were estimated using
generic expected environmental concentration (GENEEC) 1.2. Because
KOC could not be measured directly in adsorption-desorption
studies because of chemical stability, GENEEC values representative of
a range of KOC values were modeled. The simulation that was
selected for these exposure estimates used a KOC of 150,
indicating high mobility. The peak GENEEC concentration predicted in
the simulated pond water was 12.59 parts per billion (ppb). Using
standard assumptions about body weight and water consumption, the acute
exposure from this drinking water would be 0.00036 and 0.0013 mg/kg/day
for adults and children, respectively. The 56-day GENEEC concentration
predicted in the simulated pond water was 0.45 ppb. Chronic exposure
from this drinking water would be 0.0000129 and 0.000045 mg/kg/day for
adults and children, respectively; 2.5% of the c-PAD of 0.0018 mg/kg/
day for children.
[[Page 10299]]
Based on this worse case analysis, the contribution of drinking water
to the dietary exposure is comparable to that from food, but the risk
is still negligible.
2. Non-dietary exposure. Flumioxazin is proposed only for
agricultural uses and no homeowner, turf, or industrial uses. Thus, no
non-dietary risk assessment is needed.
D. Cumulative Effects
Section 408(b)(2)(D)(v) requires that the Agency must consider
``available information'' concerning the cumulative effects of a
particular pesticide's residues and ``other substances that have a
common mechanism of toxicity.'' Available information in this context
include not only toxicity, chemistry, and exposure data, but also
scientific policies and methodologies for understanding common
mechanisms of toxicity and conducting cumulative risk assessments. For
most pesticides, although the Agency has some information in its files
that may turn out to be helpful in eventually determining whether a
pesticide shares a common mechanism of toxicity with any other
substances, EPA does not at this time have the methodologies to resolve
the complex scientific issues concerning common mechanism of toxicity
in a meaningful way.
There are other pesticidal compounds that are structurally related
to flumioxazin and have similar effects on animals. In consideration of
potential cumulative effects of flumioxazin and other substances that
may have a common mechanism of toxicity, there are currently no
available data or other reliable information indicating that any toxic
effects produced by flumioxazin would be cumulative with those of other
chemical compounds. Thus, only the potential risks of flumioxazin have
been considered in this assessment of aggregate exposure and effects.
Valent will submit information for EPA to consider concerning
potential cumulative effects of flumioxazin consistent with the
schedule established by EPA in the Federal Register at 62 FR 42020
(August 4, 1997), FRL-5734-6 and other subsequent EPA publications
pursuant to the Food Quality Protection Act (FQPA).
E. Safety Determination
The FQPA of 1996 introduced a new standard of safety, a reasonable
certainty of no harm. To make this determination, at this time the
Agency should consider only the incremental risk of flumioxazin in its
exposure assessment. Since the potential chronic and acute exposures to
flumioxazin are small (<<100% of c-PAD, MOE >>1,000) the provisions of
the FQPA of 1996 will not be violated.
1. U.S. population--i. Acute risk: The potential acute exposure
from food to the U.S. population and various non-child/infant
population subgroups (shown above) provide MOE values exceeding 1,000.
Addition of the worse case, but small ``background'' dietary exposure
from water reduces the MOE value at the 99.9th percentile
from 3,791 to 2,606. In a conservative policy, the Agency has no cause
for concern if total acute exposure to adults calculated for the
99.9th percentile yields a MOE of 100 or larger. For Women
of child bearing age where a MOE of 1,000 or larger is appropriate, the
addition of water to the diet of women, 13 years and older, reduces the
MOE (99.9th percentile) from 20,592 to 7,916. It can be
concluded that there is a reasonable certainty that no harm will result
to the overall U.S. population and many non-child/infant subgroups from
aggregate, acute exposure to flumioxazin residues.
ii. Chronic risk. Using the dietary exposure assessment procedures
described above for flumioxazin, calculated chronic dietary exposure
resulting from residue exposure from proposed uses of flumioxazin is
minimal. The estimated chronic dietary exposure from food for the
overall U.S. Population and many non-child/infant subgroups is 0.42 to
3.89% of the appropriate c-PAD. Addition of the small but worse case
potential exposure from drinking water (calculated above) increases
exposure by 0.000013 mg/kg /day and the maximum occupancy of the c-PAD
from 3.89% to 5.22% (women 13 +). Generally, the Agency has no cause
for concern if total residue contribution is less than 100% of the
appropriate c-PAD. It can be concluded that there is a reasonable
certainty that no harm will result to the overall U.S. Population and
many non-child/infant subgroups from aggregate, chronic exposure to
flumioxazin residues.
2. Infants and children--Safety factor for infants and children. In
assessing the potential for additional sensitivity of infants and
children to residues of flumioxazin, FFDCA section 408 provides that
EPA shall apply an additional margin of safety, up to ten-fold, for
added protection for infants and children in the case of threshold
effects unless EPA determines that a different margin of safety will be
safe for infants and children.
i. Children. The toxicological data base for evaluating prenatal
and postnatal toxicity for flumioxazin is complete with respect to
current data requirements. Developmental toxicity was observed by both
oral and dermal routes in rats. Therefore, reliable data support use of
the standard 100-fold UF and an additional UF of 10X for flumioxazin to
be further protective of infants and children.
ii. Developmental toxicity studies. Flumioxazin shows developmental
toxicity in the absence of maternal toxicity in rats. Mechanistic
studies demonstrate that the effect is specifically related to the
inhibition of heme synthesis, that the effect shows considerable
species specificity, and that the rat is a conservative surrogate
species for the potential for developmental toxicity in man. No
developmental toxicity was observed in rabbits. Developmental toxicity
to the pups was seen in the rat reproduction study at doses that were
not toxic to the parental animals.
a. Rats. In the definitive rat oral developmental toxicity study,
pregnant rats were administered oral doses of 0, 1, 3, 10, or 30 mg/kg/
day of flumioxazin technical on days 6 through 15 of gestation. No
maternal deaths were observed at any dosage and no treatment-related
effects on clinical signs or food consumption were noted. A decrease in
maternal body weight gain was found at 30 mg/kg/day. The number of live
fetuses and fetal body weights were decreased in the 30 mg/kg/day group
and the incidence of embryo mortality tended to be higher but was not
statistically significant. No effects on the number of implantations,
sex ratios, or external abnormalities were found. The incidence of
fetuses with cardiovascular abnormalities, primarily VSD, was increased
in the 30 mg/kg/day group. Other developmental effects observed at 30
mg/kg/day included an increase in the incidence of wavy ribs and
curvature of the scapula, and a decrease in the number of ossified
sacrococcygeal vertebral bodies. Based on these findings, a maternal
NOAEL of 30 mg/kg/day and a developmental NOAEL of 3 mg/kg/day are
proposed.
On days 6-15 of gestation, pregnant rats were exposed dermally to
dose levels of 30, 100, or 300 mg/kg/day of flumioxazin technical in
corn oil. No adverse effects were observed in the dams throughout the
study. Increased fetal mortality was accompanied by decreases in the
number of live fetuses and fetal body weights at doses of 300 mg/kg/
day. No external abnormalities were observed at any dose level. An
increase in cardiovascular abnormalities, primarily VSD, an increase in
wavy ribs and a decrease in the number of ossified vertebral bodies was
observed at 300 mg/kg/day. Based on these results, a maternal NOAEL of
[[Page 10300]]
300 mg/kg/day and a developmental NOAEL of 30 mg/kg/day are proposed.
To measure the dermal penetration of flumioxazin under the
conditions of the dermal teratology study, 13-day pregnant rats were
dermally exposed to (phenyl-14C) flumioxazin. The systemic
absorption ranged from 3.8% at 2 hours to 6.9% of the recovered
14C at 48 hours.
b. Mechanistic studies. A series of scientific studies were
conducted to examine the mechanism and species differences in the
production of developmental toxicity by flumioxazin. This research
demonstrates clear species differences between rats, rabbits, mice, and
(in vitro) humans and indicates a high degree of correlation between
the interruption of heme synthesis and the production of developmental
toxicity in rats. The data support that the rat is a conservative model
for use in the risk assessment for humans. Specifically the studies
demonstrate that:
Flumioxazin interferes with normal heme biosynthesis
resulting in sidroblastic anemia and porphyria in adult rats.
14C-Flumioxazin administered to pregnant rats
on day 12 of gestation crosses the placenta and reaches the rat fetus
at maximum levels of radiocarbon (and flumioxazin), 4 hours later.
No clear pattern of adsorption, distribution, metabolism,
or excretion was evident which could account for the species-specific
development toxicity in rats.
The critical period of sensitivity to the developmental
effects of flumioxazin in rats is day 12 of gestation. This correlates
with the peak period of protoporphyrin IX (PPIX) accumulation in
maternal rat liver and the rat fetus.
A histological examination of rat fetus indicated signs of
fetal anemia within 6 hours after dosing, but no histological changes
in the fetal rat heart were observed until 36 or 48 hour after
treatment. No effects were observed in rabbit fetus treated in the same
manner as the rats.
Other observations in the pathogenesis of the
developmental effects of flumioxazin in rat fetuses included; enlarged
heart, edema, anemia, (decreased red blood cell count and hemoglobin),
delayed closure of the interventricular foramen, reduced serum protein
and incomplete/delayed ossification of the ribs.
The observation of enlarged heart, edema, and anemia
preceding the occurrence of fetal mortality suggest these effects may
be instrumental in the cause of fetal deaths.
The occurrence of an enlarged heart preceding the failure
of interventricular foramen closure could be related to the
pathogenesis rather than a direct toxic effect of flumioxazin on
cardiac tissue.
A strong correlation exists between PPIX accumulation, an
indicator of disrupted heme synthesis, and developmental toxicity.
Evidence of this correlation exists on the basis species differences
between rats and rabbits; the critical period of sensitivity in the
rat; and compound-specific differences with two chemicals structurally
related to flumioxazin, one which produces developmental effects in
rats and one which does not.
c. Rabbits. Pregnant rabbits were administered 0, 300, 1,000, or
3,000 mg/kg/day of flumioxazin technical on days 7-19 of gestation by
oral gavage. The highest dose was well in excess of the 1,000 mg/kg/day
limit dose for developmental toxicity studies. The 3,000 mg/kg/day
dosage tended to reduce maternal body weight gains and relative and
absolute feed consumption values. No gross lesions were produced at any
dose level. The 3,000 mg/kg/day dosage group litters tended to have
reduced fetal body weights but these differences were not statistically
different. No fetal external, soft tissue, or skeletal malformations or
variants were attributable to the test substance. Based on these data,
the maternal NOAEL was 1,000 mg/kg/day and the developmental NOAEL was
3,000 mg/kg/day.
iii. Reproductive toxicity study. In the 2-generation reproduction
study in the rat dietary levels of 0, 50, 100, 200, and 300 ppm
established a systemic NOAEL of 200 ppm based on increased clinical
signs (both sexes and generations); mortality, gross and histopathology
findings in the liver (F1 females); decreased body weight/
weight gain (F0 and F1 females during gestation,
F1 males during premating) and decreased food consumption
(F0 and F1 females during lactation). The
reproductive NOAEL of 100 ppm was mainly based on developmental
toxicity at 200 ppm. Observed at 200 ppm were a decreased number of
liveborn pups and reduced pup body weights. At 300 ppm the following
effects were observed:
Decreased pup body weight (both generations).
Decreased number of live pups/litter and viability index
(both generations).
Increased incidence of abnormalities of the reproductive
organs (predominately atrophied or hypoplastic testes and/or
epididymides in F1 males).
Decreased gestation index (F0 females).
Decreased mating and fertility indices (F1
males) and increased clinical signs (F1 pups).
iv. Prenatal and postnatal sensitivity. Flumioxazin interferes with
normal heme biosynthesis resulting in sidroblastic anemia and porphyria
in adult rats. Clear species differences between rats, rabbits, mice,
and (in vitro) humans were demonstrated. There is a high degree of
correlation between the interruption of heme synthesis, consequent PPIX
accumulation, and the production of developmental toxicity in rats. The
data support that the rat is a conservative model for use in the risk
assessment for humans.
v. Acute exposure and risk. The potential acute exposure from food
to the various child and infant population subgroups (shown above) all
provide MOE values exceeding 1,000. Addition of the worse case, but
small ``background'' dietary exposure from water (0.00126 mg/kg/day) to
the 99.9th percentile food exposure for infants reduces the
MOE value from 2,117 to 1,121. In a conservative policy with the
addition of the FQPA extra 10X UF, the Agency has no cause for concern
if total acute exposure to infants and children calculated for the
99.9th percentile yields a MOE of 1,000 or larger. It can be
concluded that there is a reasonable certainty that no harm will result
to infants and children from aggregate, acute exposure to flumioxazin
residues.
vi. Chronic exposure and risk. Using the conservative exposure
assumptions described above, the percentage of the c-PAD that will be
utilized by dietary (food only) exposure to residues of flumioxazin
ranges from 0.73% for children 7-12 years, to 12.72% for non-nursing
infants. Adding the worse case potential incremental exposure to
infants and children from flumioxazin in drinking water ( 0.000045 mg/
kg/day) increases the aggregate, chronic dietary exposure by 2.5%. The
addition of the exposure attributable to drinking water increases the
occupancy of the c-PAD for non-nursing infants to 15.22%. EPA generally
has no concern for exposures below 100% of the c-PAD because the c-PAD,
in this case including the extra 10X FQPA UF, represents the level at
or below which daily aggregate dietary exposure over a lifetime will
not pose appreciable risks to human health. It can be concluded that
there is a reasonable certainty that no harm will result to infants and
children from aggregate, chronic exposure to flumioxazin residues.
vii. Determination of safety--Safety determination summary.
Aggregate acute or chronic dietary exposure to various sub-populations
of children and adults demonstrate acceptable risk. Chronic dietary
exposures to flumioxazin occupy considerably less
[[Page 10301]]
than 100% of the appropriate c-PAD, and all acute dietary MOE values
exceed 1,000. Chronic and acute dietary risk to children from
flumioxazin should not be of concern. Further, flumioxazin has only
agricultural uses and no other uses, such as indoor pest control,
homeowner or turf, that could lead to unique, enhanced exposures to
vulnerable sub-groups of the population. It can be concluded that there
is a reasonable certainty that no harm will result to the U.S.
population or to any sub-group of the U.S. population, including
infants and children, from aggregate chronic or aggregate acute
exposures to flumioxazin residues resulting from proposed uses.
F. International Tolerances
Flumioxazin has not been evaluated by the JMPR and there are no
Codex maximum residue limits (MRL) for flumioxazin. MRL values have
been established to allow the following uses of flumioxazin in the
following countries.
------------------------------------------------------------------------
Country Crop MRL (ppm)
------------------------------------------------------------------------
Brazil Soybean 0.05
Argentina Soybean 0.015
Sunflower 0.02
Paraguay Soybean 0.015
South Africa Soybean 0.02
Groundnut 0.02
------------------------------------------------------------------------
[FR Doc. 01-3620 Filed 2-13-01; 8:45 am]
BILLING CODE 6560-50-S