[Federal Register Volume 66, Number 31 (Wednesday, February 14, 2001)]
[Notices]
[Pages 10292-10301]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-3620]


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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: 
<a href="/cdn-cgi/l/email-protection#79141015151c0b5713161817171c391c0918571e160f"><span class="__cf_email__" data-cfemail="432e2a2f2f26316d292c222d2d26032633226d242c35">[email protected]</span></a>.

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: <a href="/cdn-cgi/l/email-protection#b7d8c7c79ad3d8d4dcd2c3f7d2c7d699d0d8c1"><span class="__cf_email__" data-cfemail="68071818450c070b030d1c280d1809460f071e">[email protected]</span></a>, 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 <SUP>14</SUP>C-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 <SUP>14</SUP>C-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 LD<INF>50</INF> 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 LD<INF>50</INF> 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 LC<INF>50</INF> 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<SUP>-4</SUP> 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-<SUP>14</SUP>C) flumioxazin. The systemic 
absorption ranged from 3.8% at 2 hours to 6.9% of the recovered 
<SUP>14</SUP>C 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:
    <bullet> Flumioxazin interferes with normal heme biosynthesis 
resulting in sidroblastic anemia and porphyria in adult rats.
    <bullet> <SUP>14</SUP>C-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.
    <bullet> No clear pattern of adsorption, distribution, metabolism, 
or excretion was evident which could account for the species-specific 
development toxicity in rats.
    <bullet> 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.
    <bullet> 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.
    <bullet> 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.
    <bullet> 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.
    <bullet> 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.
    <bullet> 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 (F<INF>1</INF> females); decreased body weight/weight w/w gain 
(F<INF>0</INF> and F<INF>1</INF> females during gestation, 
F<INF>1</INF> males during premating) and decreased food consumption 
(F<INF>0</INF> and F<INF>1</INF> 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 F<INF>1</INF> 
males); decreased gestation index (F<INF>0</INF> females); decreased

[[Page 10297]]

mating and fertility indices (F<INF>1</INF> males) and increased 
clinical signs (F<INF>1</INF> 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-<SUP>14</SUP>C-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 <SUP>14</SUP>C-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:
    <bullet> Hydroxylation of the tetrahydrophthalimide moiety.
    <bullet> Incorporation of the sulfonic acid group into the 
tetrahydrophthalimide moiety.
    <bullet> Cleavage of the imide linkage.
    <bullet> Cleavage of the benzoxazinoneamide.
    <bullet> 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         95<SUP>th</SUP> Percentile    99.9<SUP>th</SUP> 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)<SUP>*</SUP>
Females 13 +          0.000053                                                                              2.94
 (nursing) (0.0018)<SUP>*</SUP>
Females 13 + (preg/   0.000070                                                                              3.89
 not nursing)
 (0.0018)<SUP>*</SUP>
Children 7-12 yrs     0.000132                                                                              0.73
 (0.018)<SUP>*</SUP>
Children 1-6 yrs      0.000163                                                                              9.06
 (0.0018)<SUP>*</SUP>
All infants (<1       0.000190                                                                             10.56
 year) (0.0018)<SUP>*</SUP>
Non-nursing infants   0.000229                                                                             12.72
 (0.0018)<SUP>*</SUP>
Nursing infants       0.000058                                                                              3.22
 (0.0018)<SUP>*</SUP>
----------------------------------------------------------------------------------------------------------------

    <SUP>*</SUP> 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 
K<INF>OC</INF> could not be measured directly in adsorption-desorption 
studies because of chemical stability, GENEEC values representative of 
a range of K<INF>OC</INF> values were modeled. The simulation that was 
selected for these exposure estimates used a K<INF>OC</INF> 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 99.9<SUP>th</SUP> 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 
99.9<SUP>th</SUP> 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 (99.9<SUP>th</SUP> 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-<SUP>14</SUP>C) flumioxazin. The systemic 
absorption ranged from 3.8% at 2 hours to 6.9% of the recovered 
<SUP>14</SUP>C 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:
    <bullet> Flumioxazin interferes with normal heme biosynthesis 
resulting in sidroblastic anemia and porphyria in adult rats.
    <bullet> <SUP>14</SUP>C-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.
    <bullet> No clear pattern of adsorption, distribution, metabolism, 
or excretion was evident which could account for the species-specific 
development toxicity in rats.
    <bullet> 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.
    <bullet> 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.
    <bullet> 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.
    <bullet> 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.
    <bullet> 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.
    <bullet> 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 (F<INF>1</INF> females); decreased body weight/
weight gain (F<INF>0</INF> and F<INF>1</INF> females during gestation, 
F<INF>1</INF> males during premating) and decreased food consumption 
(F<INF>0</INF> and F<INF>1</INF> 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:
    <bullet> Decreased pup body weight (both generations).
    <bullet> Decreased number of live pups/litter and viability index 
(both generations).
    <bullet> Increased incidence of abnormalities of the reproductive 
organs (predominately atrophied or hypoplastic testes and/or 
epididymides in F<INF>1</INF> males).
    <bullet> Decreased gestation index (F<INF>0</INF> females).
    <bullet> Decreased mating and fertility indices (F<INF>1</INF> 
males) and increased clinical signs (F<INF>1</INF> 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 99.9<SUP>th</SUP> 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 
99.9<SUP>th</SUP> 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


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