FLUORIDE ACTION NETWORK PESTICIDE
PROJECT
Return to FAN's Pesticide Homepage
Return to Flumioxazin Index Page
Flumioxazin (Valent). December 31, 2002. Pesticide tolerance petitions. Federal Register.
[Federal Register: December 31, 2002 (Volume 67, Number 251)]
[Notices]
[Page 79918-79927]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr31de02-57]
-----------------------------------------------------------------------
ENVIRONMENTAL PROTECTION AGENCY
[OPP-2002-0349; FRL-7285-6]
Flumioxazin; Notice of Filing a Pesticide Petition to Establish a
Tolerance for a Certain Pesticide Chemical in or on Food
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
-----------------------------------------------------------------------
SUMMARY: This notice announces the initial filing of pesticide
petitions proposing the establishment of regulations for residues of a
certain pesticide chemical in or on various food commodities.
DATES: Comments, identified by docket ID number OPP-2002-0349, must be
received on or before January 30, 2003.
ADDRESSES: Comments may be submitted electronically, by mail, or
through hand delivery/courier. Follow the detailed instructions as
provided in Unit I. of the SUPPLEMENTARY INFORMATION.
FOR FURTHER INFORMATION CONTACT: Joanne I. Miller, Registration
Division (7505C), Office of Pesticide Programs, Environmental
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460-
0001; telephone number: (703) 305-6224; e-mail address:
Miller.Joanne@epamail.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:
• Crop production (NAICS 111)
• Animal production (NAICS 112)
• Food manufacturing (NAICS 311)
• Pesticide manufacturing (NAICS 32532)
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 Copies of this Document and Other Related Information?
1. Docket. EPA has established an official public docket for this
action under docket identification (ID) number OPP-2002-0349. The
official public docket consists of the documents specifically
referenced in this action, any public comments received, and other
information related to this action. Although a part of the official
docket, the public docket does not include Confidential Business
Information (CBI) or other information whose disclosure is restricted
by statute. The official public docket is the collection of materials
that is available for public viewing at the Public Information and
Records Integrity Branch (PIRIB), Rm. 119, Crystal Mall #2,
1921 Jefferson Davis Hwy., Arlington, VA. This docket facility is open
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal
holidays. The docket telephone number is (703) 305-5805.
2. Electronic access. You may access this Federal Register document
electronically through the EPA Internet under the ``Federal Register''
listings at http://www.epa.gov/fedrgstr/.
An electronic version of the public docket is available through
EPA's electronic public docket and comment system, EPA Dockets. You may
use EPA Dockets at http://www.epa.gov/edocket/ to submit or view public
comments,
[[Page 79919]]
access the index listing of the contents of the official public docket,
and to access those documents in the public docket that are available
electronically. Although not all docket materials may be available
electronically, you may still access any of the publicly available
docket materials through the docket facility identified in Unit I.B.1.
Once in the system, select ``search,'' then key in the appropriate
docket ID number.
Certain types of information will not be placed in the EPA Dockets.
Information claimed as CBI and other information whose disclosure is
restricted by statute, which is not included in the official public
docket, will not be available for public viewing in EPA's electronic
public docket. EPA's policy is that copyrighted material will not be
placed in EPA's electronic public docket but will be available only in
printed, paper form in the official public docket. To the extent
feasible, publicly available docket materials will be made available in
EPA's electronic public docket. When a document is selected from the
index list in EPA Dockets, the system will identify whether the
document is available for viewing in EPA's electronic public docket.
Although not all docket materials may be available electronically, you
may still access any of the publicly available docket materials through
the docket facility identified in Unit I.B. EPA intends to work towards
providing electronic access to all of the publicly available docket
materials through EPA's electronic public docket.
For public commenters, it is important to note that EPA's policy is
that public comments, whether submitted electronically or in paper,
will be made available for public viewing in EPA's electronic public
docket as EPA receives them and without change, unless the comment
contains copyrighted material, CBI, or other information whose
disclosure is restricted by statute. When EPA identifies a comment
containing copyrighted material, EPA will provide a reference to that
material in the version of the comment that is placed in EPA's
electronic public docket. The entire printed comment, including the
copyrighted material, will be available in the public docket.
Public comments submitted on computer disks that are mailed or
delivered to the docket will be transferred to EPA's electronic public
docket. Public comments that are mailed or delivered to the docket will
be scanned and placed in EPA's electronic public docket. Where
practical, physical objects will be photographed, and the photograph
will be placed in EPA's electronic public docket along with a brief
description written by the docket staff.
C. How and To Whom Do I Submit Comments?
You may submit comments electronically, by mail, or through hand
delivery/courier. To ensure proper receipt by EPA, identify the
appropriate docket ID number in the subject line on the first page of
your comment. Please ensure that your comments are submitted within the
specified comment period. Comments received after the close of the
comment period will be marked ``late.'' EPA is not required to consider
these late comments. If you wish to submit CBI or information that is
otherwise protected by statute, please follow the instructions in Unit
I.D. Do not use EPA Dockets or e-mail to submit CBI or information
protected by statute.
1. Electronically. If you submit an electronic comment as
prescribed in this unit, EPA recommends that you include your name,
mailing address, and an e-mail address or other contact information in
the body of your comment. Also include this contact information on the
outside of any disk or CD ROM you submit, and in any cover letter
accompanying the disk or CD ROM. This ensures that you can be
identified as the submitter of the comment and allows EPA to contact
you in case EPA cannot read your comment due to technical difficulties
or needs further information on the substance of your comment. EPA's
policy is that EPA will not edit your comment, and any identifying or
contact information provided in the body of a comment will be included
as part of the comment that is placed in the official public docket,
and made available in EPA's electronic public docket. If EPA cannot
read your comment due to technical difficulties and cannot contact you
for clarification, EPA may not be able to consider your comment.
i. EPA Dockets. Your use of EPA's electronic public docket to
submit comments to EPA electronically is EPA's preferred method for
receiving comments. Go directly to EPA Dockets at http://www.epa.gov/edocket
, and follow the online instructions for submitting comments.
Once in the system, select ``search,'' and then key in docket ID number
OPP-2002-0349. The system is an ``anonymous access'' system, which
means EPA will not know your identity, e-mail address, or other contact
information unless you provide it in the body of your comment.
ii. E-mail. Comments may be sent by e-mail to opp-docket@epa.gov,
Attention: Docket ID Number OPP-2002-0349. In contrast to EPA's
electronic public docket, EPA's e-mail system is not an ``anonymous
access'' system. If you send an e-mail comment directly to the docket
without going through EPA's electronic public docket, EPA's e-mail
system automatically captures your e-mail address. E-mail addresses
that are automatically captured by EPA's e-mail system are included as
part of the comment that is placed in the official public docket, and
made available in EPA's electronic public docket.
iii. Disk or CD ROM. You may submit comments on a disk or CD ROM
that you mail to the mailing address identified in Unit I.C.2. These
electronic submissions will be accepted in WordPerfect or ASCII file
format. Avoid the use of special characters and any form of encryption.
2. By mail. Send your comments to: Public Information and Records
Integrity Branch (PIRIB) (7502C), Office of Pesticide Programs (OPP),
Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,
Washington, DC 20460-0001, Attention: Docket ID Number OPP-2002-0349.
3. By hand delivery or courier. Deliver your comments to: Public
Information and Records Integrity Branch (PIRIB), Office of Pesticide
Programs (OPP), Environmental Protection Agency, Rm. 119, Crystal Mall
#2, 1921 Jefferson Davis Hwy., Arlington, VA, Attention: Docket
ID Number OPP-2002-0349. Such deliveries are only accepted during the
docket's normal hours of operation as identified in Unit I.B.1.
D. How Should I Submit CBI To the Agency?
Do not submit information that you consider to be CBI
electronically through EPA's electronic public docket or by e-mail. You
may claim information that you submit to EPA as CBI by marking any part
or all of that information as CBI (if you submit CBI on disk or CD ROM,
mark the outside of the disk or CD ROM as CBI and then identify
electronically within the disk or CD ROM the specific information that
is 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 docket and EPA's electronic public docket. If you submit
the copy that does not contain CBI on disk or CD ROM, mark the outside
of the disk or CD ROM clearly that it does not contain CBI.
[[Page 79920]]
Information not marked as CBI will be included in the public docket
and EPA's electronic public docket without prior notice. If you have
any questions about CBI or the procedures for claiming CBI, please
consult the person listed 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.
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
ID 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 FFDCA 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: December 20, 2002.
Debra Edwards,
Acting Director, Registration Division, Office of Pesticide Programs.Summary of Petition
The petitioner summary of the pesticide petitions is printed below
as required by FFDCA section 408(d)(3). The summary of the petitions
was prepared by the petitioner and represents the view of the
petitioner. 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.Valent U.S.A. Corporation
1F6296 and 0F6171
EPA has received pesticide petitions (PP 1F6296, 0F6171) from
Valent U.S.A. Corporation, 1333 North California Boulevard, Suite 600,
Walnut Creek, California 94596-8025 proposing, pursuant to section
408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C.
346a(d), to amend 40 CFR part 180 by establishing a tolerance for
residues of the herbicide chemical 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 cotton at 0.02 parts per million (ppm), cotton, gin
byproducts at 0.60 ppm, grape at 0.02 ppm, almonds at 0.02 ppm, almond,
hulls at 0.70 ppm and sugarcane at 0.20 ppm. EPA has determined that
the petitions contain 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. Metabolism of 14C-flumioxazin
labeled in the phenyl- or tetrahydrophthalimido-rings has been studied
in soybeans, peanuts, grapes and corn. Flumioxazin was rapidly and
extensively metabolized to many metabolites in all 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 limit of quantitation (LOQ) of
flumioxazin in the method is 0.02 ppm which will allow monitoring of
food with residues at the levels proposed for the tolerances.
3. Magnitude of residues--i.Cotton. Thirteen field trials in cotton
were conducted in 1999 in EPA Regions II (1 trial), IV (4 trials), VI
(1 trial), VIII (4 trials), and X (3 trials), representing
approximately 97% of the U.S. cotton growing regions. Seasonal
treatment ranged from 0.190 to 0.375 pounds active ingredient per acre
[two applications of 0.095 lb. a.i./A each or two applications of 0.187
lb. a.i./A each], 1.5- to 3-times the proposed application rate for
high organic soils. Application of VALOR was done lay-by and post
direct to the soil and not over the top. Finite residues of flumioxazin
were detected in 7 of 26 duplicate samples cottonseed and in 14 of the
16 duplicate samples of gin trash. The LOQ of the residue method was
0.01 ppm, and the limit of detection (LOD) was 0.005 ppm. No residues
of 1-OH-HPA were detected (<0.005 ppm) in any cottonseed or gin trash
sample, including samples from trial treated at the 2X rate. The data
demonstrate that 1-OH-HPA is not a residue of concern in cottonseed or
cotton gin trash.
No residues of flumioxazin or its degradate were found in the
processed commodities treated ginned seed, hulls, solvent extracted
meal and refined oil.
All these data support proposed tolerance for flumioxazin in/on
cotton at 0.02 ppm, and in/on cotton, gin byproducts at 0.60 ppm. No
separate tolerances are needed for cotton processed commodities.
ii. Grapes. Twelve field trials in grapes were conducted in 1999 in
EPA Regions I (2 trials) Region X (9 trials) and Region XI (1 trial),
representing approximately 96% of the U.S. grapes growing regions.
Seasonal treatment ranged from 0.75 to 3.75 pounds active ingredient
per acre [two applications of 0.375 lb. a.i./A each or two applications
of 1.87 lb. a.i./A each]
1 to 5-times the proposed application rate.
Application on grapes was post direct and not over the top. At the
proposed maximum seasonal rate of 0.75 lb. a.i./A, no residues of
flumioxazin were found in/on grapes from all 12 trials. Residues of
flumioxazin were detected in only one of six samples treated at 2X
application rate (seasonal total of 1.5 lb. a.i./A). The residue found,
0.005 ppm, was below the LOQ of 0.01 ppm.
[[Page 79921]]
Grapes treated at 5X (seasonal total of 3.75 lb. a.i./A) the
proposed use rate were processed into grape juice and raisins. The RAC
grapes contained 0.006 ppm flumioxazin. No residues (<0.005 ppm) of
flumioxazin were found in grape juice. In raisins 0.007 ppm flumioxazin
was detected. These residues were below the LOQ of 0.01 ppm. The data
demonstrate no concentration of flumioxazin residues in juice and
raisins.
All these data support a proposed tolerance for flumioxazin in/on
grapes of 0.02 ppm. No separate tolerances are needed for grapes
processed commodities.
iii. Almond. Five field trials in almonds were conducted in 1999 in
EPA Regions X, representative of all U.S. almond growing regions.
Seasonal treatment ranged from 0.75 to 1.5 pounds active ingredient per
acre [two applications of 0.375 lb. a.i./A each or two applications of
0.75 lb. a.i./A each]
1 to 2-times the proposed application rate.
Application on almonds was done post direct and not over the top. At
the proposed maximum seasonal rate of 0.75 lb. a.i./A, no residues of
flumioxazin were found in/on almond nutmeat greater than the LOQ (0.01
ppm). The highest average field Trial for residues of flumioxazin in/on
almond hulls was 0.552 ppm. Residues of 1-OH-HPA were not detected in
any sample of almond hulls (<0.05 ppm).The LOQ and LOD of the residue
method for 1-OH-HPA in/on almond hulls were 0.1 ppm and 0.05 ppm,
respectively.
All these data support a proposed tolerance for flumioxazin in/on
almond of 0.02 ppm, and in/on almond hulls of 0.6 ppm.
iv. Sugarcane. Nine 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
regions. Treatments ranged from 0.37 to 1.12 pounds active ingredient
per acre, 1- to 3-times the proposed application rate for high organic
soils. Finite residues of flumioxazin were detected in 14 of 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 two
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 three 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 these data support a proposed tolerance for flumioxazin in/on
sugarcane at 0.20 ppm. No separate tolerances for parent or degradate
are needed for processed commodities.B. Toxicological Profile
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 changes, or gross
pathological findings were observed and no rats died following
administration of an oral dose of 5 g/kg of flumioxazin technical. The
LD50 was greater than 5 g/kg.
ii. No deaths, abnormal clinical signs, body weight 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 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, body weight 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. Genotoxicty. 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
1 x 10-4 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 body weights 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.
[[Page 79922]]
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 NOEL of 30 mg/kg/day and a developmental NOEL 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 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 sacrococcygeal
vertebral bodies was observed at 300 mg/kg/day. Based on these results,
a maternal NOEL of 300 mg/kg/day and a developmental NOEL 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 body weight 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 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 NOEL was 1,000 mg/kg/day
and the developmental NOEL 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 two-generation reproduction study in
the rat dietary levels of 0, 50, 100, 200 and 300 ppm established a
systemic NOEL 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 NOEL of 100 ppm was mainly based on developmental toxicity
at 200 ppm. Observed at 200 ppm were a decreased number of live-born
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
[[Page 79923]]
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).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 no-observed-effect-level
(NOEL) of 300 ppm was based on decreased body weights; 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 NOEL 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 NOEL 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. Rats. A 21-day dermal toxicity study was conducted in rats at
dose levels of 0, 100, 200 or 1,000 mg/kg/day. The NOEL 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 NOEL for male rats in
the two-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 NOEL 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 NOEL 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 bw/day for 1
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 NOEL 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 7 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 (1) hydroxylation of the tetrahydrophthalimide moiety; (2)
incorporation of the sulfonic acid group into the tetrahydrophthalimide
moiety; (3) cleavage of the imide linkage; (4) cleavage of the
benzoxazinoneamide and;(5) 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 database 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
[[Page 79924]]
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 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. In these risk
assessments Valent has chosen as the chronic oral toxic endpoint the
NOEL for males from the rat chronic/oncogenicity feeding study, 1.8 mg/
kg/day; and as the acute oral toxic endpoint the NOEL (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 exposures to flumioxazin residues were
calculated for the U.S. population, Women 13 years and older, and five
children subgroups. The calculated exposure values are very
conservative because tolerance-level residues and 100% of the crop
treated are assumed. For refined sugar from sugarcane and juice from
grapes for which processing is required, concentration factors were
considered. 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 1,000.Table 1.--Tier I Calculated Acute Dietary Exposures to the Total U.S. Population and Selected Sub-Populations to Flumioxazin Residues in Food
95th percentile 99.9th percentile Population Subgroup Exposure (mg/kg/ day) MOE Exposure (mg/kg/ day) MOE Total U.S. Population 0.000063 47,737 0.000287 10,442 Women 13 Years and Older 0.000040 74,350 0.000128 23,527 Children 7 to 12 Years 0.000076 39,620 0.000310 9,675 Children 1 to 6 Years 0.000153 19,583 0.000599 5,008 All Infants 0.000205 14,608 0.000800 3,750 Non-Nursing Infants (<1 yr old) 0.000217 13,807 0.000799 3,753 Nursing Infants (<1 yr old) 0.000106 28,357 0.000283 10,612
b. Chronic dietary exposures to flumioxazin residues were
calculated for the U.S. population and 25 population subgroups. This
modified Tier I analysis assumes tolerance-level residues, processing
factors for grape and cane sugar, and 100 percent of the crops treated.
The results from several representative subgroups are listed below. All
calculated chronic dietary exposures were below 5% of the c-PAD. The c-
PAD was defined as the NOEL from the rat oral two-year combined chronic
toxicity oncogenicity study (1.8 mg/kg/day for males) divided by the
100X uncertainty factor 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 percent 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
Population Subgroup Exposure (mg/kg/day) Percent of cPAD Total U.S. Population (total) (0.018)* 0.000020 0.11 Females 13+ (nursing) (0.0018)* 0.000016 0.89 Females 13+ (pregnant/not nursing) (0.0018)* 0.000015 0.83 Children 7-12 yrs (0.018)* 0.000030 0.17 Children 1-6 yrs (0.0018)* 0.000052 2.89 All Infants (<1 year) (0.0018)* 0.000067 3.72 Non-Nursing Infants (0.0018)* 0.000082 4.56 Nursing Infants (0.0018)* 0.000016 0.89
* 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
GENEEC 1.2. Because KOC could not be measured
[[Page 79925]]
directly in adsorption- desorption studies because of chemical
stability, GEEC values representative of a range of KOC
values were modeled. The simulation that was selected for these
exposure estimates used an average KOC of 385, indicating
high mobility. The peak GEEC concentration predicted in the simulated
pond water was 9.8 ppb. Using standard assumptions about body weight
and water consumption, the acute exposure from this drinking water
would be 0.00028 and 0.00098 mg/kg/day for adults and children,
respectively. The 56-day GEEC concentration predicted in the simulated
pond water was 0.34 ppb. Chronic exposure from this drinking water
would be 0.0000097 and 0.000034 mg/kg/day for adults and children,
respectively; 1.9 percent of the c-PAD of 0.0018 mg/kg/day for
children. 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 or turf 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 at 62 FR 42020 (Aug. 4, 1997) and other
subsequent EPA publications pursuant to the Food Quality Protection
Act.
E. Safety Determination
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 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 10,442 to 5,291. In
a conservative policy, the Agency has no cause for concern if total
acute exposure to adults calculated for the 95th percentile (for the
Tier I calculated acute dietary exposure using tolerance level residues
and 100% crops treated) yields a MOE of 100 or larger. For women of
child bearing age where an 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 23,527 to 7,353. 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 0.11 to
0.89% of the appropriate c-PAD. Addition of the small but worse case
potential exposure from drinking water (calculated above) increases
exposure by 0.0000097 mg/kg /day and the maximum occupancy of the c-PAD
from 0.89 to 1.43% (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 database for evaluating pre- and
post-natal 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 uncertainty factor and an additional uncertainty
factor 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
NOEL of 30 mg/kg/day and a developmental NOEL 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
[[Page 79926]]
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 sacrococcygeal vertebral
bodies was observed at 300 mg/kg/day. Based on these results, a
maternal NOEL of 300 mg/kg/day and a developmental NOEL 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 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.
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 NOEL was 1,000 mg/kg/day and the developmental NOEL was
3,000 mg/kg/day.
iii. Reproductive toxicity study. In the two-generation
reproduction study in the rat dietary levels of 0, 50, 100, 200 and 300
ppm established a systemic NOEL 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 NOEL of 100 ppm was mainly based on developmental toxicity
at 200 ppm. Observed at 200 ppm were a decreased number of live-born
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 all provide MOE
values exceeding 1,000. Addition of the worse case, but small
``background'' dietary exposure from water (0.00098 mg/kg/day) to the
99.9th percentile food exposure for infants reduces the MOE value from
3,753 to 1,686. In a conservative policy with the addition of the FQPA
extra 10X uncertainty factor, the Agency has no cause for concern if
total acute exposure to infants and children calculated for the 95th
percentile for the Tier I acute dietary exposure 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 0.17% for children 7-12 years, to 4.6% for Non-Nursing
Infants. Adding the worse case potential incremental exposure to
infants and children from flumioxazin in drinking water (0.000034 mg/
kg/day) increases the aggregate, chronic dietary exposure by 1.9%. The
addition of the exposure attributable to drinking water increases the
occupancy of the c-PAD for Non-Nursing Infants to 6.44%. 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 uncertainty factor,
represents the level at or below which daily
[[Page 79927]]
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--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 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 World Health
Organization, Joint Meeting on Pesticide Residues (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
Sunflower0.015
0.02Paraguay Soybean 0.015 South Africa Soybean
Groundnut0.02
0.02
[FR Doc. 02-32990 Filed 12-30-02; 8:45 am]
BILLING CODE 6560-50-S