10292 Federal Register / Vol. 66, No. 31 / Wednesday, February 14, 2001 / Notices

care) and receptor subpopulation (i.e.,

adults, children 1-6 years and infants

<1–year) are compared to the systemic

absorbed dose NOAEL for bifenthrin to

provide estimates of the MOEs. Based

on the toxicity endpoints selected by

EPA for bifenthrin, inhalation and

incidental oral ingestion absorbed doses

were combined and compared to the

relevant systemic NOAEL for estimating

MOEs.

In the case of potential aggregate

health risks, the above mentioned

conservative point estimates of

inhalation and incidental ingestion nondietary exposure (expressed as systemic

absorbed dose) are combined with

estimates (arithmetic mean values) of

chronic average dietary (oral) absorbed

doses. These aggregate absorbed dose

estimates are also provided for adults,

children 1-6 years and infants <1–year.

The combined or aggregated absorbed

dose estimates (summed across nondietary and chronic dietary) are then

compared with the systemic absorbed

dose NOAEL to provide estimates of

aggregate MOEs.

The non-dietary and aggregate (nondietary + chronic dietary) MOEs for

bifenthrin indicate a substantial degree

of safety. The total non-dietary

(inhalation + incidental ingestion)

MOEs for post-application exposure for

the lawn care product evaluated was

estimated to be 194,000 for adults,

52,400 for children 1-6 years old and

56,700 for infants <1–year. The

aggregate MOE (inhalation + incidental

oral + chronic dietary, summed across

all product use categories) was

estimated to be 4,878 for adults, 1,117

for children 1-6 years old and 1,361 for

infants (<1–year). It can be concluded

that the potential non-dietary and

aggregate (non-dietary + chronic dietary)

exposures for bifenthrin are associated

with substantial margins of safety.

D. Cumulative Effects

In consideration of potential

cumulative effects of bifenthrin and

other substances that may have a

common mechanism of toxicity, to our

knowledge there are currently no

available data or other reliable

information indicating that any toxic

effects produced by bifenthrin would be

cumulative with those of other chemical

compounds; thus only the potential

risks of bifenthrin have been considered

in this assessment of its aggregate

exposure. FMC Corporation intends to

submit information for the EPA to

consider concerning potential

cumulative effects of bifenthrin

consistent with the schedule established

by EPA in the Federal Register at 62 FR

42020 (August 4, 1997), FRL–5734–6

and other EPA publications pursuant to

the Food Quality Protection Act.

E. Safety Determination

1. U.S. population. For the overall

U.S. population, the calculated MOE at

the 95th percentile was estimated to be

650, 359 at the 99th percentile; and 181

at the 99.9th percentile. For all infants

<1–year old, the calculated MOE at the

95th percentile was estimated to be 540;

241 at the 99th percentile; and 171 at the

99.9th percentile. For nursing infants

<1–year old, the calculated MOE at the

95th percentile was estimated to be

1,311; 451 at the 99th percentile; and 246

at the 99.9th percentile. For non-nursing

infants <1–year old, the calculated

margins of exposure MOE at the 95th

percentile was estimated to be 476, 197

at the 99th percentile; and 169 at the

99.9th percentile. For the most highly

exposed population subgroup, children

1-6 years old, the calculated MOE at the

95th percentile was estimated to be 330,

214 at the 99th percentile; and 102 at the

99.9th percentile. Therefore, FMC

Corporation concludes that there is

reasonable certainty that no harm will

result from acute exposure to bifenthrin.

2. Infants and children—a. General. In

assessing the potential for additional

sensitivity of infants and children to

residues of bifenthrin, FMC Corporation

considered data from developmental

toxicity studies in the rat and rabbit,

and a 2–generation reproductive study

in the rat. The developmental toxicity

studies are designed to evaluate adverse

effects on the developing organism

resulting from pesticide exposure

during prenatal development to one or

both parents. Reproduction studies

provide information relating to effects

from exposure to the pesticide on the

reproductive capability of mating

animals and data on systemic toxicity.

FFDCA section 408 provides that EPA

may apply an additional margin of

safety for infants and children in the

case of threshold effects to account for

prenatal and postnatal toxicity and the

completeness of the data base.

b. Developmental toxicity studies. In

the rabbit developmental study, there

were no developmental effects observed

in the fetuses exposed to bifenthrin. The

maternal NOAEL was 2.67 mg/kg/day

based on head and forelimb twitching at

the LOAEL of 4 mg/kg/day. In the rat

developmental study, the maternal

NOAEL was 1 mg/kg/day, based on

tremors at the LOAEL of 2 mg/kg/day.

The developmental (pup) NOAEL was

also 1 mg/kg/day, based upon increased

incidence of hydroureter at the LOAEL

2 mg/kg/day. There was 5/23 (22%)

litters affected (5/141 fetuses since each

litter only had one affected fetus) in the

2 mg/kg/day group, compared with zero

in the control, 1, and 0.5 mg/kg/day

groups. According to recent historical

data (1992–1994) for this strain of rat,

incidence of distended ureter averaged

11% with a maximum incidence of

90%.

c. Reproductive toxicity study. In the

rat reproduction study, parental toxicity

occurred as decreased bwt at 5.0 mg/kg/

day with a NOAEL of 3.0 mg/kg/day.

There were no developmental (pup) or

reproductive effects up to 5.0 mg/kg/day

HDT.

d. Prenatal and postnatal sensitivity—

i. Prenatal. Since there was not a doserelated finding of hydroureter in the rat

developmental study and in the

presence of similar incidences in the

recent historical control data, the

marginal finding of hydroureter in rat

fetuses at 2 mg/kg/day (in the presence

of maternal toxicity) is not considered a

significant developmental finding. Nor

does it provide sufficient evidence of a

special dietary risk (either acute or

chronic) for infants and children which

would require an additional safety

factor. Based on the absence of pup

toxicity up to dose levels, which

produced toxicity in the parental

animals, there is no evidence of special

postnatal sensitivity to infants and

children in the rat reproduction study.

e. Conclusion. Based on the above,

FMC Corporation concludes that

reliable data support use of the standard

100–fold UF, and that an additional UF

is not needed to protect the safety of

infants and children. As stated above,

aggregate exposure assessments utilized

less than 10% of the RfD for either the

entire U. S. population or any of the 26

population subgroups including infants

and children. Therefore, it may be

concluded that there is reasonable

certainty that no harm will result to

infants and children from aggregate

exposure to bifenthrin residues.

F. International Tolerances

There are no Codex, Canadian, or

Mexican residue limits for residues of

bifenthrin in or on bananas.

[FR Doc. 01–3621 Filed 2–13–01; 8:45 am]

BILLING CODE 6560–50–S

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).

Federal Register / Vol. 66, No. 31 / Wednesday, February 14, 2001 / Notices 10293

ACTION: Notice.

SUMMARY: This notice announces the

initial filing of a pesticide petition

proposing the establishment of

regulations for residues of a certain

pesticide chemical in or on various food

commodities.

DATES: Comments, identified by docket

control number PF–996, must be

received on or before March 16, 2001.

ADDRESSES: Comments may be

submitted by mail, electronically, or in

person. Please follow the detailed

instructions for each method as

provided in Unit I.C. of the

SUPPLEMENTARY INFORMATION. To ensure

proper receipt by EPA, it is imperative

that you identify docket control number

PF–996 in the subject line on the first

page of your response.

FOR FURTHER INFORMATION CONTACT: By

mail: Joanne Miller, Registration

Division (7505C), Office of Pesticide

Programs, Environmental Protection

Agency, 1200 Pennsylvania Ave., NW.,

Washington, DC 20460; telephone

number: (703) 305–6224; e-mail address:

miller.joanne@epa.gov.

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this Action Apply to Me?

You may be affected by this action if

you are an agricultural producer, food

manufacturer or pesticide manufacturer.

Potentially affected categories and

entities may include, but are not limited

to:

Categories NAICS

codes

Examples of potentially affected

entities

Industry 111 Crop production

112 Animal production

311 Food manufacturing

32532 Pesticide manufacturing

This listing is not intended to be

exhaustive, but rather provides a guide

for readers regarding entities likely to be

affected by this action. Other types of

entities not listed in the table could also

be affected. The North American

Industrial Classification System

(NAICS) codes have been provided to

assist you and others in determining

whether or not this action might apply

to certain entities. If you have questions

regarding the applicability of this action

to a particular entity, consult the person

listed under FOR FURTHER INFORMATION

CONTACT.

B. How Can I Get Additional

Information, Including Copies of this

Document and Other Related

Documents?

1. Electronically. You may obtain

electronic copies of this document, and

certain other related documents that

might be available electronically, from

the EPA Internet Home Page at http://

www.epa.gov/. To access this

document, on the Home Page select

‘‘Laws and Regulations’’ and then look

up the entry for this document under

the ‘‘Federal Register—Environmental

Documents.’’ You can also go directly to

the Federal Register listings at http://

www.epa.gov/fedrgstr/.

2. In person. The Agency has

established an official record for this

action under docket control number PF–

996. The official record consists of the

documents specifically referenced in

this action, any public comments

received during an applicable comment

period, and other information related to

this action, including any information

claimed as confidential business

information (CBI). This official record

includes the documents that are

physically located in the docket, as well

as the documents that are referenced in

those documents. The public version of

the official record does not include any

information claimed as CBI. The public

version of the official record, which

includes printed, paper versions of any

electronic comments submitted during

an applicable comment period, is

available for inspection in the Public

Information and Records Integrity

Branch (PIRIB), Rm. 119, Crystal Mall

#2, 1921 Jefferson Davis Highway,

Arlington, VA, from 8:30 a.m. to 4 p.m.,

Monday through Friday, excluding legal

holidays. The PIRIB telephone number

is (703) 305–5805.

C. How and to Whom Do I Submit

Comments?

You may submit comments through

the mail, in person, or electronically. To

ensure proper receipt by EPA, it is

imperative that you identify docket

control number PF–996 in the subject

line on the first page of your response.

1. By mail. Submit your comments to:

Public Information and Records

Integrity Branch (PIRIB), Information

Resources and Services Division

(7502C), Office of Pesticide Programs

(OPP), Environmental Protection

Agency, 1200 Pennsylvania Ave., NW.,

Washington, DC 20460.

2. In person or by courier. Deliver

your comments to: Public Information

and Records Integrity Branch (PIRIB),

Information Resources and Services

Division (7502C), Office of Pesticide

Programs (OPP), Environmental

Protection Agency, Rm. 119, Crystal

Mall #2, 1921 Jefferson Davis Highway,

Arlington, VA. The PIRIB is open from

8:30 a.m. to 4 p.m., Monday through

Friday, excluding legal holidays. The

PIRIB telephone number is (703) 305–

5805.

3. Electronically. You may submit

your comments electronically by e-mail

to: opp-docket@epa.gov, or you can

submit a computer disk as described

above. Do not submit any information

electronically that you consider to be

CBI. Avoid the use of special characters

and any form of encryption. Electronic

submissions will be accepted in

Wordperfect 6.1/8.0 or ASCII file

format. All comments in electronic form

must be identified by docket control

number PF–996. Electronic comments

may also be filed online at many Federal

Depository Libraries.

D. How Should I Handle CBI That I

Want to Submit to the Agency?

Do not submit any information

electronically that you consider to be

CBI. You may claim information that

you submit to EPA in response to this

document as CBI by marking any part or

all of that information as CBI.

Information so marked will not be

disclosed except in accordance with

procedures set forth in 40 CFR part 2.

In addition to one complete version of

the comment that includes any

information claimed as CBI, a copy of

the comment that does not contain the

information claimed as CBI must be

submitted for inclusion in the public

version of the official record.

Information not marked confidential

will be included in the public version

of the official record without prior

notice. If you have any questions about

CBI or the procedures for claiming CBI,

please consult the person identified

under FOR FURTHER INFORMATION

CONTACT.

E. What Should I Consider as I Prepare

My Comments for EPA?

You may find the following

suggestions helpful for preparing your

comments:

1. Explain your views as clearly as

possible.

2. Describe any assumptions that you

used.

3. Provide copies of any technical

information and/or data you used that

support your views.

4. If you estimate potential burden or

costs, explain how you arrived at the

estimate that you provide.

5. Provide specific examples to

illustrate your concerns.

10294 Federal Register / Vol. 66, No. 31 / Wednesday, February 14, 2001 / Notices

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-fluoro3,4-dihydro-3-oxo-4-(2-propynyl)-2H1,4-benzoxazin-6-yl]-4,5,6,7-tetrahydro1H-isoindole-1,3(2H)-dione, in or on the

raw agricultural commodities (RACs)

soybean seed and peanut nutmeat at

0.01 parts per million (ppm), and on

sugar cane at 0.2 ppm. EPA has

determined that the petitions contains

data or information regarding the

elements set forth in section 408(d)(2) of

the FFDCA; however, EPA has not fully

evaluated the sufficiency of the

submitted data at this time or whether

the data support granting of the

petitions. Additional data may be

needed before EPA rules on the

petitions.

A. Residue Chemistry

Summary. Radiocarbon plant and

animal metabolism studies have

demonstrated that the residue of

concern is adequately understood for

the purposes of these tolerances and is

best defined as parent, flumioxazin.

Practical, validated residue

methodology is available to analyze all

appropriate matrices for flumioxazin

residue with a limit of quantification

(LOQ) of 0.01 ppm, adequate to enforce

all proposed tolerances. The potential

magnitude of residues of flumioxazin

has been evaluated in peanuts,

soybeans, and sugarcane and in

appropriate processed products and

animals. These studies are adequate to

support appropriate tolerances and

dietary risk analyses.

1. Plant metabolism. Metabolism of 14C-flumioxazin labelled in the phenylor tetrahydrophthalimido-rings has been

studied in soybeans and peanuts.

Flumioxazin was rapidly and

extensively metabolized to many

metabolites in both plants. Even with

exaggerated treatment, individual

metabolites and parent were only found

at very low concentrations.

Comparisons of metabolites detected

and quantified from plants and animals

show that there are no significant

aglycones in plants which are not also

present in the excreta or tissues of

animals. The residue of concern is best

defined as the parent.

2. Analytical method. Practical

analytical methods for detecting and

measuring levels of flumioxazin have

been developed and validated in/on all

appropriate agricultural commodities

and respective processing fractions. The

extraction methodology has been

validated using aged radiochemical

residue samples from 14C-metabolism

studies. The enforcement method has

been validated in soybean at an

independent laboratory and by EPA.

The LOQ of flumioxazin in the methods

is 0.01 ppm which will allow

monitoring of food with residues at the

levels proposed for the tolerances.

3. Magnitude of residues—i. Soybean.

Forty-two (42) field trials in soybeans

were conducted in 1989 through 1993 in

EPA regions II (2 trials), IV (9 trials, and

V (31 trials), representing approximately

99% of the U.S. soybean growing region.

Treatments ranged from 0.09 to 0.47

pounds active per acre, 1–to 5–times the

proposed application rate. No residues

of flumioxazin were detected in soybean

seed from any of the trials, even when

application rates were 5 times the

proposed label rate. Analysis for the

major plant metabolite, 1–OH-HPA, was

conducted on seed samples from 13

residue trials. In all cases no residues of

the degradate were found, including 2

trials which at a 5X treatment rate.

No residues of flumioxazin were

found in any of the processed

commodities in 2 processing studies of

soybeans treated at 5 times the proposed

label rate. In 1 of the processing studies,

no residue of 1–OH-HPA was found in

any processed fraction. All the data

support a proposed tolerance for

flumioxazin in/on soybean seed at 0.01

ppm, the LOQ of the enforcement

method. No separate tolerances are

needed for soybean processed

commodities.

ii. Peanut. Sixteen (16) field trials in

peanuts were conducted in 1992, 1993,

and 1996 in EPA regions II (8 trials), III

(3 trials), IV (3 trials), and VIII (2 trials),

representing virtually all of the U.S.

peanut growing regions. Treatments

ranged from 0.09 to 0.47 pounds active

per acre, 1–to 5–times the proposed

application rate. No residues of

flumioxazin were detected in any

peanut seed sample from any of the

trials, even when application rates were

5 times the proposed label rate. Analysis

for the major plant metabolite, 1–OHHPA, 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

Federal Register / Vol. 66, No. 31 / Wednesday, February 14, 2001 / Notices 10295

regions. Treatments ranged from 0.37 to

1.12 pounds active per acre, 1–to 3–

times the proposed application rate for

high organic soils. Finite residues of

flumioxazin were detected in fourteen

(14) of eighteen (18) duplicate samples.

Residues of flumioxazin averaged 0.039

ppm (standard deviation = 0.033 ppm)

from the trials conducted at the

proposed maximum application rate.

Analysis for the major plant metabolite,

1–OH-HPA, was conducted on all cane

samples including those from the 2 3X

processing trials. No residues of the

degradate were found in any cane

sample.

No residues of flumioxazin or its

degradate were found in the processed

commodity refined sugar. In molasses,

produced from cane treated at 3 times

the proposed label rate, flumioxazin was

detected (0.055 ppm) at approximately

half of the concentration in the starting

sugarcane. The degradate, 1–OH-HPA,

was also detected in molasses (0.036

ppm). Because these detections were in

a processed sample from cane treated at

3X, and are still less than the proposed

RAC tolerance, no separate processed

product tolerances are necessary.

All the data support a proposed

tolerance for flumioxazin in/on

sugarcane at 0.2 ppm. No separate

tolerances for parent or degradate are

needed for processed commodities.

iv. Secondary residues. Using

proposed tolerances to calculate the

maximum feed exposure to fed animals,

and using the very low potential for

residue transfer demonstrated in the

goat and hen metabolism studies,

detectable secondary residues in animal

tissues, milk, and eggs are not expected.

Therefore, no cow or hen residue

feeding studies were performed,and

tolerances are not proposed for these

commodities.

v. Rotational crops. The results of a

confined rotational crop accumulation

study indicate that no rotational crop

planting restrictions or rotational crop

tolerances are required.

B. Toxicological Profile

Summary. A full battery of toxicology

testing has been performed on

flumioxazin including acute, chronic,

oncogenicity, developmental,

mutagenicity, and reproductive effects.

Flumioxazin has low toxicity via oral

and dermal routes and is not

carcinogenic. Overall, it does not

present a genetic hazard. Although

developmental and reproductive effects

were observed in rats, acute and chronic

dietary assessments and worker

exposure assessments demonstrate large

margins of safety when worst case

exposures are compared to the proposed

toxic endpoints, along with appropriate

uncertainty factors (UF). Valent

proposes a chronic population adjusted

dose (c-PAD) of 0.018 milligram/

kilogram (mg/kg)/day for adults and

0.0018 mg/kg/day for women of child

bearing age and infants and children

based on the no observed adverse effect

level (NOAEL) of 1.8 mg/kg/day for

males in the rat 2 year chronic toxicity

oncogenicity study. Valent also

proposes 3.0 mg/kg/day as the acute oral

endpoint based on the developmental

toxicity NOAEL from the rat oral

developmental toxicity study.

1. Acute toxicity. The acute toxicity of

technical grade flumioxazin is low by

all routes. The battery of acute toxicity

studies place flumioxazin in toxicity

category III.

i. No abnormal clinical signs, body

weight (bwt) changes, or gross

pathological findings were observed and

no rats died following administration of

an oral dose of 5 gram/kilogram (g/kg)

of flumioxazin technical. The LD50 was

greater than 5 g/kg.

ii. No deaths, abnormal clinical signs,

bwt changes, or gross pathological

findings were observed in rats exposed

to a 2.0 g/kg dermal dose of flumioxazin

technical. The LD50 was greater than 2.0

g/kg.

iii. Rats were exposed to a dust

aerosol of flumioxazin technical for 4

hours at measured concentrations of

1.55 or 3.93 milligrams/Liter (mg/L), the

maximum attainable concentration.

Irregular respiration, bradypnea and a

decrease in spontaneous activity were

observed in many of the rats, but these

effects disappeared within 2 hours after

termination of the exposure. No deaths,

bwt changes, gross pathological findings

or histopathological changes in the

respiratory organs were observed. The

LC50 for flumioxazin technical was

determined to be greater than 3.93 mg/

L.

iv. Flumioxazin technical produced

minimal eye irritation in rabbits which

cleared within 48 hours.

v. Flumioxazin technical did not

produce any signs of skin irritation in

abraded or intact skin of rabbits.

vi. Flumioxazin technical was not a

skin sensitizer when tested in guinea

pigs using the Magnussen and Kligman

maximization test methodology.

2. Genotoxicity. Flumioxazin does not

present a genetic hazard. Flumioxazin

was evaluated in the following tests for

mutagenicity:

i. A reverse gene mutation assay in

Salmonella typhimurium and

Escherichia coli was negative with or

without metabolic activation.

ii. An in vitro chromosome aberration

assay using chinese hamster ovary

(CHO) cells was negative in the absence

of metabolic activation. However, an

increase in cells with aberrations was

observed at doses of 1X10-4 M and

higher in the presence of S9.

iii. An in vivo chromosomal

aberration study in the rat was negative.

No significant increase in the incidence

of chromosomal aberrations in bone

marrow cells was observed following

treatments as high as 5,000 mg/kg.

iv. An in vitro unscheduled DNA

synthesis (UDS) assay with rat

hepatocytes was negative.

v. A mouse micronucleus assay was

negative following intraperitoneal

injection of 5,000 mg/kg.

3. Reproductive and developmental

toxicity. Flumioxazin shows

developmental toxicity in the absence of

maternal toxicity in rats. Mechanistic

studies demonstrate that the effect is

specifically related to the inhibition of

heme synthesis, that the effect shows

considerable species specificity, and

that the rat is a conservative surrogate

species for the potential for

developmental toxicity in man. No

developmental toxicity was observed in

rabbits. Developmental toxicity to the

pups was seen in the rat reproduction

study at doses that were not toxic to the

parental animals.

i. Rat—Developmental toxicity. A

pilot dose range-finding study was

conducted to determine appropriate

doses for the definitive oral

developmental toxicity study.

Flumioxazin technical was

administered by oral gavage at dosages

of 0, 30, 100, 200, and 500 mg/kg/day

to pregnant rats on days 6 through 15 of

gestation. No animals died during the

course of this study and maternal

toxicity was limited to decreased weight

gain associated with high

embryolethality observed in all dose

groups. Fetuses obtained from the 30

mg/kg/day dams had significantly

reduced bwts and were found to have

both skeletal and visceral abnormalities

primarily wavy ribs and ventricular

septal defects (VSD). Because of the

high degree of embryolethality at doses

of 100 mg/kg/day and greater, the

highest dose selected for the definitive

study was 30 mg/kg/day.

In the definitive study, pregnant rats

were administered oral doses of 0, 1, 3,

10, or 30 mg/kg/day of flumioxazin

technical on days 6 through 15 of

gestation. No maternal deaths were

observed at any dosage and no

treatment-related effects on clinical

signs or food consumption were noted.

A decrease in maternal bwt gain was

found at 30 mg/kg/day. The number of

live fetuses and fetal bwts were

decreased in the 30 mg/kg/day group

10296 Federal Register / Vol. 66, No. 31 / Wednesday, February 14, 2001 / Notices

and the incidence of embryo mortality

tended to be higher but was not

statistically significant. No effects on the

number of implantations, sex ratios, or

external abnormalities were found. The

incidence of fetuses with cardiovascular

abnormalities, primarily VSD, was

increased in the 30 mg/kg/day group.

Other developmental effects observed at

30 mg/kg/day included an increase in

the incidence of wavy ribs and

curvature of the scapula, and a decrease

in the number of ossified sacrococcygeal

vertebral bodies. Based on these

findings, a maternal NOAEL of 30 mg/

kg/day and a developmental NOAEL of

3 mg/kg/day are proposed.

In a range-finding dermal

developmental toxicity study

flumioxazin technical was administered

dermally at levels of 100, 200, 400, and

800 mg/kg/day in corn oil. No adverse

effects on the dams were observed at

doses up to 800 mg/kg/day. Because of

the high degree of embryolethality at

doses of 400 mg/kg/day and greater, the

highest dose selected for the definitive

study was 300 mg/kg/day.

On days 6–15 of gestation, pregnant

rats were exposed dermally to dose

levels of 30, 100, or 300 mg/kg/day of

flumioxazin technical in corn oil. No

adverse effects were observed in the

dams throughout the study. Increased

fetal mortality was accompanied by

decreases in the number of live fetuses

and fetal bwts at doses of 300 mg/kg/

day. No external abnormalities were

observed at any dose level. An increase

in cardiovascular abnormalities,

primarily VSD, an increase in wavy ribs

and a decrease in the number of ossified

sacrococcygeal vertebral bodies was

observed at 300 mg/kg/day. Based on

these results, a maternal NOAEL of 300

mg/kg/day and a developmental NOAEL

of 30 mg/kg/day are proposed.

To measure the dermal penetration of

flumioxazin under the conditions of the

dermal teratology study, 13–day

pregnant rats were dermally exposed to

(phenyl-14C) flumioxazin. The systemic

absorption ranged from 3.8% at 2 hours

to 6.9% of the recovered 14C at 48 hours.

ii. Mechanistic studies. A series of

scientific studies were conducted to

examine the mechanism and species

differences in the production of

developmental toxicity by flumioxazin.

This research demonstrates clear species

differences between rats, rabbits, mice,

and (in vitro) humans and indicates a

high degree of correlation between the

interruption of heme synthesis and the

production of developmental toxicity in

rats. The data support that the rat is a

conservative model for use in the risk

assessment for humans. Specifically the

studies demonstrate that:

• Flumioxazin interferes with normal

heme biosynthesis resulting in

sidroblastic anemia and porphyria in

adult rats.

• 14C-Flumioxazin administered to

pregnant rats on day 12 of gestation

crosses the placenta and reaches the rat

fetus at maximum levels of radiocarbon

(and flumioxazin), 4 hours later.

• No clear pattern of adsorption,

distribution, metabolism, or excretion

was evident which could account for

the species-specific development

toxicity in rats.

• The critical period of sensitivity to

the developmental effects of

flumioxazin in rats is day 12 of

gestation. This correlates with the peak

period of protoporphyrin IX (PPIX)

accumulation in maternal rat liver and

the rat fetus.

• A histological examination of rat

fetus indicated signs of fetal anemia

within 6 hours after dosing, but no

histological changes in the fetal rat heart

were observed until 36 or 48 hour after

treatment. No effects were observed in

rabbit fetus treated in the same manner

as the rats.

• Other observations in the

pathogenesis of the developmental

effects of flumioxazin in rat fetuses

included; enlarged heart, edema,

anemia, (decreased red blood cell count,

and hemoglobin), delayed closure of the

interventricular foramen, reduced serum

protein, and incomplete/delayed

ossification of the ribs.

• The observation of enlarged heart,

edema, and anemia preceding the

occurrence of fetal mortality suggest

these effects may be instrumental in the

cause of fetal deaths.

• The occurrence of an enlarged heart

preceding the failure of interventricular

foramen closure could be related to the

pathogenesis rather than a direct toxic

effect of flumioxazin on cardiac tissue.

• A strong correlation exists between

PPIX accumulation, an indicator of

disrupted heme synthesis, and

developmental toxicity. Evidence of this

correlation exists on the basis of species

differences between rats and rabbits; the

critical period of sensitivity in the rat;

and compound-specific differences with

two chemicals structurally related to

flumioxazin, one which produces

developmental effects in rats and one

which does not.

iii. Rabbits. In a pilot dose rangefinding 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 rangefinding rat reproduction studies were

conducted with flumioxazin technical at

dosages from 100 to 5,000 ppm in the

diet. In the definitive 2–generation

reproduction study in the rat dietary

levels of 0, 50, 100, 200, and 300 ppm

established a systemic NOAEL of 200

ppm based on increased clinical signs

(both sexes and generations); mortality,

gross, and histopathology findings in

the liver (F1 females); decreased body

weight/weight w/w gain (F0 and F1

females during gestation, F1 males

during premating) and decreased food

consumption (F0 and F1 females during

lactation). The reproductive NOAEL of

100 ppm was mainly based on

developmental toxicity at 200 ppm.

Observed at 200 ppm were a decreased

number of liveborn pups and reduced

pup bwts. At 300 ppm the following

effects were observed: decreased pup

bwt (both generations); decreased

number of live pups/litter and viability

index (both generations); increased

incidence of abnormalities of the

reproductive organs (predominately

atrophied or hypoplastic testes and/or

epididymides in F1 males); decreased

gestation index (F0 females); decreased

Federal Register / Vol. 66, No. 31 / Wednesday, February 14, 2001 / Notices 10297

mating and fertility indices (F1 males)

and increased clinical signs (F1 pups).

4. Subchronic toxicity. Subchronic

toxicity studies conducted with

flumioxazin technical in the rat (oral

and dermal), mouse and dog indicate a

low level of toxicity. Effects observed at

high dose levels consisted primarily of

anemia and histological changes in the

spleen, liver and bone marrow related to

the anemia.

i. Rats. A 90–day subchronic toxicity

study was conducted in rats, with

dietary intake levels of 0, 30, 300, 1,000

and 3,000 ppm flumioxazin technical

(98.4% purity). The NOAEL of 300 ppm

was based on decreased bwts; anemia;

increases in absolute and/or relative

liver, kidney, brain, heart, and thyroid

weights, and histological changes in the

spleen, liver, and bone marrow related

to the anemia.

A second 90–day subchronic toxicity

study was conducted with a sample of

flumioxazin technical of typical purity

(94.8%) at dietary concentrations of 0,

30, 300, 1,000, and 3,000 ppm. The

NOAEL was 30 ppm based on anemia

and related hematological changes;

increases in liver, heart, kidney, and

thyroid weights; and histological

changes in the spleen, liver, and bone

marrow related to the anemia.

ii. Mice. Dose levels for the mouse

oncogenicity study were selected on the

basis of results from a 4–week study of

flumioxazin in the diets of mice at

levels of 0, 1,000, 3,000, and 10,000

ppm. In this range-finding study,

increases in absolute and/or relative

liver weights were noted for males at

10,000 ppm, and at 3,000, and 10,000

ppm for females.

iii. Dogs. A 90–day study was

conducted in dogs given gelatin

capsules containing 0, 10, 100, or 1,000

mg/kg/day. The NOAEL of 10 mg/kg/

day for this study was based on a slight

prolongation of activated partial

thromboplastin time; increased total

cholesterol and phospholipid and

elevated alkaline phosphatase activity;

increased absolute and relative liver

weights; and histological changes in the

liver.

iv. A 21–day dermal toxicity study

was conducted in rats at dose levels of

0, 100, 200, or 1,000 mg/kg/day. The

NOAEL was determined to be 300 mg/

kg/day based on significantly decreased

hemoglobin and hematocrit values for

females.

5. Chronic toxicity. Flumioxazin

technical has been tested in chronic

studies with dogs, rats and mice. Valent

proposes a chronic oral endpoint of 1.8

mg/kg bw/day, based on the NOAEL for

male rats in the 2–year chronic toxicity

oncogenicity feeding study.

i. Rats. In a 2–year study in rats,

flumioxazin technical administered in

the diet at levels of 0, 50, 500, and 1,000

ppm produced anemia and chronic

nephropathy in rats of the 500 and 1,000

ppm groups. The anemia lasted

throughout the treatment period,

however, it was not progressive nor

aplastic in nature. No evidence of an

oncogenic effect was observed in rats

and the NOAEL for this study was 50

ppm (1.8 mg/kg/day for males and 2.2

mg/kg/day for females).

ii. Mice. Flumioxazin technical was

administered to mice at doses of 0, 300,

3,000, and 7,000 ppm in diet for 78

weeks. An increased incidence of

hypertrophy of centrilobular

hepatocytes was observed in males of

the 3,000 and 7,000 ppm groups.

Increases in the incidence of diffuse

hypertrophy and single cell necrosis of

hepatocytes were observed in females of

the 3,000 and 7,000 ppm groups. There

was no evidence of any treatmentrelated 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. Treatmentrelated changes in blood biochemistry

included increased total cholesterol and

phospholipid values, elevated alpha-2-

globulin ratio at 1,000 mg/kg/day and

increased alkaline phosphatase activity

in the 100 and 1,000 mg/kg/day groups.

The absolute and/or relative liver

weights were elevated in one animal in

the 100 mg/kg/day group and four

animals of the 1,000 mg/kg/day group.

Minimal treatment-related histological

changes were noted in the livers of

animals at the 1,000 mg/kg/day group.

Based on these data the NOAEL was

determined to be 10 mg/kg/day.

iv. Carcinogenicity. Flumioxazin is

not a carcinogen. Adequately designed

studies with both rats and mice have

shown that repeated high dose

exposures produced anemia, liver

effects, and nephropathy, but did not

produce cancer in test animals. No

oncogenic response was observed in a

rat 2–year chronic feeding/oncogenicity

study or in a 78 week study on mice.

Valent anticipates that the oncogenicity

classification of flumioxazin will be ‘‘E’’

(no evidence of carcinogenicity for

humans).

6. Animal metabolism. The

absorption, tissue distribution,

metabolism and excretion of phenyl– 14C-labeled flumioxazin were studied in

rats after single oral doses of 1 or 100

mg/kg, and after a single oral dose of 1

mg/kg following 14 daily oral doses at

1 mg/kg of unlabelled material. For all

dose groups, most (97.9–102.3%) of the

administered radiolabel was excreted in

the urine and feces within seven days

after radiolabeled test material dosing.

Radiocarbon tissue residue levels were

generally low on the seventh day postdosing. Radiocarbon residues were

higher in blood cells than tissues.

Tissue 14C-residue levels, including

those for fat, were lower than blood

levels which suggests little potential for

bioaccumulation. Urinary radiocarbon

excretion was greater in females than

males in all dose groups.

Flumioxazin was extensively

metabolized by rats and 35 metabolites

were detected and quantitated. The

main metabolic reactions in rats were:

• Hydroxylation of the

tetrahydrophthalimide moiety.

• Incorporation of the sulfonic acid

group into the tetrahydrophthalimide

moiety.

• Cleavage of the imide linkage.

• Cleavage of the

benzoxazinoneamide.

• Acetylation of the aniline nitrogen

group.

7. Metabolite toxicology. Metabolism

studies of flumioxazin in rats, goats,

hens, soybeans, and peanuts, as well as

the fish bioaccumulation study

demonstrate that the parent is very

rapidly metabolized and, in animals,

eliminated. The metabolites detected

and quantified from plants and animals

show that there are no significant

aglycones in plants which are not also

present in the excreta or tissues of

animals. Because parent and metabolites

are not retained in the body, the

potential for acute toxicity from in situ

formed metabolites is low. The potential

for chronic toxicity is adequately tested

by chronic exposure to the parent at the

MTD and consequent chronic exposure

to the internally formed metabolites.

8. Endocrine disruption. No special

studies to investigate the potential for

estrogenic or other endocrine effects of

flumioxazin have been performed.

However, as summarized above, a large

and detailed toxicology data base exists

for the compound including studies in

all required categories. These studies

include acute, sub-chronic, chronic,

developmental, and reproductive

toxicology studies including detailed

histology and histopathology of

numerous tissues, including endocrine

organs, following repeated or long term

exposures. These studies are considered

capable of revealing endocrine effects.

The results of all of these studies show

no evidence of any endocrine-mediated

effects and no pathology of the

10298 Federal Register / Vol. 66, No. 31 / Wednesday, February 14, 2001 / Notices

endocrine organs. Consequently, it is

concluded that flumioxazin does not

possess estrogenic or endocrine

disrupting properties.

C. Aggregate Exposure

1. Dietary exposure. A full battery of

toxicology testing including studies of

acute, chronic, oncogenicity,

developmental, mutagenicity, and

reproductive effects is available for

flumioxazin. EPA has not had the

opportunity to review all of the toxicity

studies on flumioxazin and has not

established toxic endpoints. Thus, in

these risk assessments Valent proposes

as chronic oral toxic endpoint the

NOAEL for males from the rat chronic/

oncogenicity feeding study, 1.8 mg/kg/

day; and as the acute oral toxic endpoint

the NOAEL (proposed by EPA) from the

rat oral developmental toxicity study of

3.0 mg/kg/day. Because the acute oral

endpoint is for fetal toxicity to rats,

Valent has chosen to use the full, extra

10X uncertainty factor for appropriate

sub-groups of the population as

mandated by FQPA.

i. Food. a. Acute dietary exposure to

flumioxazin residues was calculated for

the U.S. population, women 13 years

and older, and 5 children subgroups.

The calculated exposure values are very

conservative because tolerance-level

residues and 100% of the crop treated

are assumed. The calculated exposures

and margins of exposure (MOE) for the

higher exposed proportions of the

subgroups are listed below. In all cases,

margins of exposure relative to the acute

endpoint from the rat oral

developmental toxicity study exceed 1–

thousand.

Tier I Calculated Acute Dietary

Exposures to the Total U.S. Population

and Selected Sub-Populations to

Flumioxazin Residues in Food.

Population subgroup 95th Percentile 99.9th Percentile

Exposure (mg/kg/day) MOE Exposure (mg/kg/day) MOE

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

old)

0.000861 3,483 0.001417 2,117

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. population (total) (0.018)* 0.000075 0.42

Females 13 + (nursing) (0.0018)* 0.000053 2.94

Females 13 + (preg/not nursing) (0.0018)* 0.000070 3.89

Children 7–12 yrs (0.018)* 0.000132 0.73

Children 1–6 yrs (0.0018)* 0.000163 9.06

All infants (<1 year) (0.0018)* 0.000190 10.56

Non-nursing infants (0.0018)* 0.000229 12.72

Nursing infants (0.0018)* 0.000058 3.22

* C-PAD value used to calculate

percent of occupancy.

ii. Drinking water. Since flumioxazin

is applied outdoors to growing

agricultural crops, the potential exists

for the parent or its metabolites to reach

ground or surface water that may be

used for drinking water. Because of the

physical properties of flumioxazin, it is

unlikely that flumioxazin or its

metabolites can leach to potable

groundwater. To quantify potential

exposure from drinking water, surface

water concentrations for flumioxazin

were estimated using generic expected

environmental concentration (GENEEC)

1.2. Because KOC could not be measured

directly in adsorption-desorption

studies because of chemical stability,

GENEEC values representative of a

range of KOC values were modeled. The

simulation that was selected for these

exposure estimates used a KOC of 150,

indicating high mobility. The peak

GENEEC concentration predicted in the

simulated pond water was 12.59 parts

per billion (ppb). Using standard

assumptions about body weight and

water consumption, the acute exposure

from this drinking water would be

0.00036 and 0.0013 mg/kg/day for

adults and children, respectively. The

56–day GENEEC concentration

predicted in the simulated pond water

was 0.45 ppb. Chronic exposure from

this drinking water would be 0.0000129

and 0.000045 mg/kg/day for adults and

children, respectively; 2.5% of the cPAD of 0.0018 mg/kg/day for children.

Federal Register / Vol. 66, No. 31 / Wednesday, February 14, 2001 / Notices 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 cPAD, 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 nonchild/infant population subgroups

(shown above) provide MOE values

exceeding 1,000. Addition of the worse

case, but small ‘‘background’’ dietary

exposure from water reduces the MOE

value at the 99.9th percentile from 3,791

to 2,606. In a conservative policy, the

Agency has no cause for concern if total

acute exposure to adults calculated for

the 99.9th percentile yields a MOE of

100 or larger. For Women of child

bearing age where a MOE of 1,000 or

larger is appropriate, the addition of

water to the diet of women, 13 years and

older, reduces the MOE (99.9th

percentile) from 20,592 to 7,916. It can

be concluded that there is a reasonable

certainty that no harm will result to the

overall U.S. population and many nonchild/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 tenfold, 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

10300 Federal Register / Vol. 66, No. 31 / Wednesday, February 14, 2001 / Notices

300 mg/kg/day and a developmental

NOAEL of 30 mg/kg/day are proposed.

To measure the dermal penetration of

flumioxazin under the conditions of the

dermal teratology study, 13–day

pregnant rats were dermally exposed to

(phenyl-14C) flumioxazin. The systemic

absorption ranged from 3.8% at 2 hours

to 6.9% of the recovered 14C at 48 hours.

b. Mechanistic studies. A series of

scientific studies were conducted to

examine the mechanism and species

differences in the production of

developmental toxicity by flumioxazin.

This research demonstrates clear species

differences between rats, rabbits, mice,

and (in vitro) humans and indicates a

high degree of correlation between the

interruption of heme synthesis and the

production of developmental toxicity in

rats. The data support that the rat is a

conservative model for use in the risk

assessment for humans. Specifically the

studies demonstrate that:

• Flumioxazin interferes with normal

heme biosynthesis resulting in

sidroblastic anemia and porphyria in

adult rats.

• 14C-Flumioxazin administered to

pregnant rats on day 12 of gestation

crosses the placenta and reaches the rat

fetus at maximum levels of radiocarbon

(and flumioxazin), 4 hours later.

• No clear pattern of adsorption,

distribution, metabolism, or excretion

was evident which could account for

the species-specific development

toxicity in rats.

• The critical period of sensitivity to

the developmental effects of

flumioxazin in rats is day 12 of

gestation. This correlates with the peak

period of protoporphyrin IX (PPIX)

accumulation in maternal rat liver and

the rat fetus.

• A histological examination of rat

fetus indicated signs of fetal anemia

within 6 hours after dosing, but no

histological changes in the fetal rat heart

were observed until 36 or 48 hour after

treatment. No effects were observed in

rabbit fetus treated in the same manner

as the rats.

• Other observations in the

pathogenesis of the developmental

effects of flumioxazin in rat fetuses

included; enlarged heart, edema,

anemia, (decreased red blood cell count

and hemoglobin), delayed closure of the

interventricular foramen, reduced serum

protein and incomplete/delayed

ossification of the ribs.

• The observation of enlarged heart,

edema, and anemia preceding the

occurrence of fetal mortality suggest

these effects may be instrumental in the

cause of fetal deaths.

• The occurrence of an enlarged heart

preceding the failure of interventricular

foramen closure could be related to the

pathogenesis rather than a direct toxic

effect of flumioxazin on cardiac tissue.

• A strong correlation exists between

PPIX accumulation, an indicator of

disrupted heme synthesis, and

developmental toxicity. Evidence of this

correlation exists on the basis species

differences between rats and rabbits; the

critical period of sensitivity in the rat;

and compound-specific differences with

two chemicals structurally related to

flumioxazin, one which produces

developmental effects in rats and one

which does not.

c. Rabbits. Pregnant rabbits were

administered 0, 300, 1,000, or 3,000 mg/

kg/day of flumioxazin technical on days

7–19 of gestation by oral gavage. The

highest dose was well in excess of the

1,000 mg/kg/day limit dose for

developmental toxicity studies. The

3,000 mg/kg/day dosage tended to

reduce maternal body weight gains and

relative and absolute feed consumption

values. No gross lesions were produced

at any dose level. The 3,000 mg/kg/day

dosage group litters tended to have

reduced fetal body weights but these

differences were not statistically

different. No fetal external, soft tissue,

or skeletal malformations or variants

were attributable to the test substance.

Based on these data, the maternal

NOAEL was 1,000 mg/kg/day and the

developmental NOAEL was 3,000 mg/

kg/day.

iii. Reproductive toxicity study. In the

2–generation reproduction study in the

rat dietary levels of 0, 50, 100, 200, and

300 ppm established a systemic NOAEL

of 200 ppm based on increased clinical

signs (both sexes and generations);

mortality, gross and histopathology

findings in the liver (F1 females);

decreased body weight/weight gain (F0

and F1 females during gestation, F1

males during premating) and decreased

food consumption (F0 and F1 females

during lactation). The reproductive

NOAEL of 100 ppm was mainly based

on developmental toxicity at 200 ppm.

Observed at 200 ppm were a decreased

number of liveborn pups and reduced

pup body weights. At 300 ppm the

following effects were observed:

• Decreased pup body weight (both

generations).

• Decreased number of live pups/litter

and viability index (both generations).

• Increased incidence of abnormalities

of the reproductive organs

(predominately atrophied or hypoplastic

testes and/or epididymides in F1 males).

• Decreased gestation index (F0

females).

• Decreased mating and fertility

indices (F1 males) and increased clinical

signs (F1 pups).

iv. Prenatal and postnatal sensitivity.

Flumioxazin interferes with normal

heme biosynthesis resulting in

sidroblastic anemia and porphyria in

adult rats. Clear species differences

between rats, rabbits, mice, and (in

vitro) humans were demonstrated. There

is a high degree of correlation between

the interruption of heme synthesis,

consequent PPIX accumulation, and the

production of developmental toxicity in

rats. The data support that the rat is a

conservative model for use in the risk

assessment for humans.

v. Acute exposure and risk. The

potential acute exposure from food to

the various child and infant population

subgroups (shown above) all provide

MOE values exceeding 1,000. Addition

of the worse case, but small

‘‘background’’ dietary exposure from

water (0.00126 mg/kg/day) to the 99.9th

percentile food exposure for infants

reduces the MOE value from 2,117 to

1,121. In a conservative policy with the

addition of the FQPA extra 10X UF, the

Agency has no cause for concern if total

acute exposure to infants and children

calculated for the 99.9th percentile

yields a MOE of 1,000 or larger. It can

be concluded that there is a reasonable

certainty that no harm will result to

infants and children from aggregate,

acute exposure to flumioxazin residues.

vi. Chronic exposure and risk. Using

the conservative exposure assumptions

described above, the percentage of the cPAD 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 nonnursing 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

Federal Register / Vol. 66, No. 31 / Wednesday, February 14, 2001 / Notices 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 subgroups 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 AfricaSoybean 0.02

Groundnut 0.02

[FR Doc. 01–3620 Filed 2–13–01; 8:45 am]

BILLING CODE 6560–50–S

ENVIRONMENTAL PROTECTION

AGENCY

[OPP–50879; FRL–6765–2]

Experimental Use Permit; Cry1Ac

Soybean Receipt of Application for

Extension

AGENCY: Environmental Protection

Agency (EPA).

ACTION: Notice.

SUMMARY: This notice announces receipt

of an application 524–EUP–91 from

Monsanto Company requesting an

extension for an experimental use

permit (EUP) for the Bacillus

thuringiensis Cry1Ac protein and the

genetic material necessary for its

production (vectors PV-GMBT01 and

PV-GMBT02) in soybean. The Agency

has determined that the application may

be of regional and national significance.

Therefore, in accordance with 40 CFR

172.11(a), the Agency is soliciting

comments on this application.

DATES: Comments, identified by docket

control number OPP–50879, must be

received on or before April 2, 2001.

ADDRESSES: Comments and data may be

submitted by mail, electronically, or in

person. Please follow the detailed

instructions for each method as

provided in Unit I. of the

SUPPLEMENTARY INFORMATION. To ensure

proper receipt by EPA, it is imperative

that you identify docket control number

OPP–50879 in the subject line on the

first page of your response.

FOR FURTHER INFORMATION CONTACT: By

mail: Alan Reynolds, Biopesticides and

Pollution Prevention Division (7511C),

Office of Pesticide Programs,

Environmental Protection Agency, 1200

Pennsylvania Ave., NW., Washington,

DC 20460; telephone number: (703)

605–0515; e-mail address:

reynolds.alan@epa.gov.

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this Action Apply to Me?

This action is directed to the public

in general. This action may, however, be

of interest to those persons interested in

plant-pesticides or who are or may be

required to conduct testing of chemical

substances under the Federal Food,

Drug and Cosmetic Act (FFDCA), or the

Federal Insecticide, Fungicide, and

Rodenticide Act (FIFRA). Since other

entities may also be interested, the

Agency has not attempted to describe all

the specific entities that may be affected

by this action. If you have any 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,’’ ‘‘Regulations

and Proposed Rules,’’ 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

OPP–50879. The official record consists

of the documents specifically referenced

in this action, 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 Hwy.,

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 OPP–50879 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 Hwy.,

Arlington, VA. The PIRIB is open from

8:30 a.m. to 4 p.m., Monday through

Friday, excluding legal holidays. The

PIRIB telephone number is (703) 305–

5805.

3. Electronically. You may submit

your comments electronically by e-mail

to: opp-docket@epa.gov, or you can

submit a computer disk as described

above. Do not submit any information

electronically that you consider to be

CBI. Avoid the use of special characters

and any form of encryption. Electronic

submissions will be accepted in

WordPerfect 6.1/8.0 or ASCII file

format. All comments in electronic form

must be identified by docket control

number OPP–50879. Electronic

comments may also be filed online at

many Federal Depository Libraries.