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http://www.epa.gov/fedrgstr/EPA-PEST/2004/October/Day-27/p24039.htm

[Federal Register: October 27, 2004 (Volume 69, Number 207)]
[Notices]
[Page 62680-62688]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr27oc04-60]
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ENVIRONMENTAL PROTECTION AGENCY
[OPP-2004-0273; FRL-7676-1]

BAS 320 I; Notice of Filing a Pesticide Petition to Establish a
Tolerance for a Certain Pesticide Chemical in or on Food
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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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 identification (ID) number OPP-
2004-0273, must be received on or before November 26, 2004.
ADDRESSES: Comments may be submitted electronically, by mail, or
through hand delivery/courier. Follow the detailed instructions as
provided in Unit I. of the SUPPLEMENTARY INFORMATION.
FOR FURTHER INFORMATION CONTACT: Ann Hanger, Registration Division
(7505C), Office of Pesticide Programs, Environmental Protection Agency,
1200 Pennsylvania Ave., NW., Washington, DC 20460-0001; telephone
number: (703) 306-0395; e-mail address: hanger.ann@epa.gov.
SUPPLEMENTARY INFORMATION:
I. General Information
A. Does this Action Apply to Me?
You may be potentially affected by this action if you are an
agricultural producer, food manufacturer, or pesticide manufacturer.
Potentially affected entities may include, but are not limited to:
• Crop production (NAICS 111)
• Animal production (NAICS 112)
• Food manufacturing (NAICS 311)
• Pesticide manufacturing (NAICS 32532)
This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in this unit could also be
affected. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether this action might apply to certain entities. 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 Copies of this Document and Other Related Information?
1. Docket. EPA has established an official public docket for this
action under docket ID number OPP-2004-0273. The official public docket
consists of the documents specifically referenced in this action, any
public comments received, and other information related to this action.
Although a part of the official docket, the public docket does not
include Confidential Business Information (CBI) or other information
whose disclosure is restricted by statute. The official public docket
is the collection of materials that is available for public viewing at
the Public Information and Records Integrity Branch (PIRIB), Rm. 119,
Crystal Mall #2, 1801 South Bell St., Arlington, VA. This
docket facility is open from 8:30 a.m. to 4 p.m., Monday through
Friday, excluding legal holidays. The docket telephone number is (703)
305-5805.
2. Electronic access. You may access this Federal Register document
electronically through the EPA Internet under the ``Federal Register''
listings at http://www.epa.gov/fedrgstr/.
An electronic version of the public docket is available through
EPA's electronic public docket and comment
[[Page 62681]]
system, EPA Dockets. You may use EPA Dockets at http://www.epa.gov/
edocket/ to submit or view public comments, access the index listing
of the contents of the official public docket, and to access those
documents in the public docket that are available electronically.
Although not all docket materials may be available electronically, you
may still access any of the publicly available docket materials through
the docket facility identified in Unit I.B.1. Once in the system,
select ``search,'' then key in the appropriate docket ID number.
Certain types of information will not be placed in the EPA Dockets.
Information claimed as CBI and other information whose disclosure is
restricted by statute, which is not included in the official public
docket, will not be available for public viewing in EPA's electronic
public docket. EPA's policy is that copyrighted material will not be
placed in EPA's electronic public docket but will be available only in
printed, paper form in the official public docket. To the extent
feasible, publicly available docket materials will be made available in
EPA's electronic public docket. When a document is selected from the
index list in EPA Dockets, the system will identify whether the
document is available for viewing in EPA's electronic public docket.
Although not all docket materials may be available electronically, you
may still access any of the publicly available docket materials through
the docket facility identified in Unit I.B. EPA intends to work towards
providing electronic access to all of the publicly available docket
materials through EPA's electronic public docket.
For public commenters, it is important to note that EPA's policy is
that public comments, whether submitted electronically or in paper,
will be made available for public viewing in EPA's electronic public
docket as EPA receives them and without change, unless the comment
contains copyrighted material, CBI, or other information whose
disclosure is restricted by statute. When EPA identifies a comment
containing copyrighted material, EPA will provide a reference to that
material in the version of the comment that is placed in EPA's
electronic public docket. The entire printed comment, including the
copyrighted material, will be available in the public docket.
Public comments submitted on computer disks that are mailed or
delivered to the docket will be transferred to EPA's electronic public
docket. Public comments that are mailed or delivered to the docket will
be scanned and placed in EPA's electronic public docket. Where
practical, physical objects will be photographed, and the photograph
will be placed in EPA's electronic public docket along with a brief
description written by the docket staff.
C. How and To Whom Do I Submit Comments?
You may submit comments electronically, by mail, or through hand
delivery/courier. To ensure proper receipt by EPA, identify the
appropriate docket ID number in the subject line on the first page of
your comment. Please ensure that your comments are submitted within the
specified comment period. Comments received after the close of the
comment period will be marked ``late.'' EPA is not required to consider
these late comments. If you wish to submit CBI or information that is
otherwise protected by statute, please follow the instructions in Unit
I.D. Do not use EPA Dockets or e-mail to submit CBI or information
protected by statute.
1. Electronically. If you submit an electronic comment as
prescribed in this unit, EPA recommends that you include your name,
mailing address, and an e-mail address or other contact information in
the body of your comment. Also include this contact information on the
outside of any disk or CD ROM you submit, and in any cover letter
accompanying the disk or CD ROM. This ensures that you can be
identified as the submitter of the comment and allows EPA to contact
you in case EPA cannot read your comment due to technical difficulties
or needs further information on the substance of your comment. EPA's
policy is that EPA will not edit your comment, and any identifying or
contact information provided in the body of a comment will be included
as part of the comment that is placed in the official public docket,
and made available in EPA's electronic public docket. If EPA cannot
read your comment due to technical difficulties and cannot contact you
for clarification, EPA may not be able to consider your comment.
i. EPA Dockets. Your use of EPA's electronic public docket to
submit comments to EPA electronically is EPA's preferred method for
receiving comments. Go directly to EPA Dockets at http://www.epa.gov/
edocket/, and follow the online instructions for submitting comments.
Once in the system, select ``search,'' and then key in docket ID number
OPP-2004-0273. The system is an ``anonymous access'' system, which
means EPA will not know your identity, e-mail address, or other contact
information unless you provide it in the body of your comment.
ii. E-mail. Comments may be sent by e-mail to opp-docket@epa.gov,
Attention: Docket ID Number OPP-2004-0273. In contrast to EPA's
electronic public docket, EPA's e-mail system is not an ``anonymous
access'' system. If you send an e-mail comment directly to the docket
without going through EPA's electronic public docket, EPA's e-mail
system automatically captures your e-mail address. E-mail addresses
that are automatically captured by EPA's e-mail system are included as
part of the comment that is placed in the official public docket, and
made available in EPA's electronic public docket.
iii. Disk or CD ROM. You may submit comments on a disk or CD ROM
that you mail to the mailing address identified in Unit I.C.2. These
electronic submissions will be accepted in WordPerfect or ASCII file
format. Avoid the use of special characters and any form of encryption.
2. By mail. Send your comments to: Public Information and Records
Integrity Branch (PIRIB) (7502C), Office of Pesticide Programs (OPP),
Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,
Washington, DC 20460-0001, Attention: Docket ID Number OPP-2004-0273.
3. By hand delivery or courier. Deliver your comments to: Public
Information and Records Integrity Branch (PIRIB), Office of Pesticide
Programs (OPP), Environmental Protection Agency, Rm. 119, Crystal Mall
#2, 1801 South Bell St., Arlington, VA, Attention: Docket ID
Number OPP-2004-0273. Such deliveries are only accepted during the
docket's normal hours of operation as identified in Unit I.B.1.
D. How Should I Submit CBI to the Agency?
Do not submit information that you consider to be CBI
electronically through EPA's electronic public docket or by e-mail. You
may claim information that you submit to EPA as CBI by marking any part
or all of that information as CBI (if you submit CBI on disk or CD ROM,
mark the outside of the disk or CD ROM as CBI and then identify
electronically within the disk or CD ROM the specific information that
is CBI). Information so marked will not be disclosed except in
accordance with procedures set forth in 40 CFR part 2.
In addition to one complete version of the comment that includes
any information claimed as CBI, a copy of the comment that does not
contain the information claimed as CBI must be submitted for inclusion
in the public docket and EPA's electronic public docket. If you submit
the copy that does
[[Page 62682]]
not contain CBI on disk or CD ROM, mark the outside of the disk or CD
ROM clearly that it does not contain CBI. Information not marked as CBI
will be included in the public docket and EPA's electronic public
docket without prior notice. If you have any questions about CBI or the
procedures for claiming CBI, please consult the person listed under FOR
FURTHER INFORMATION CONTACT.
E. What Should I Consider as I Prepare My Comments for EPA?
You may find the following suggestions helpful for preparing your
comments:
1. Explain your views as clearly as possible.
2. Describe any assumptions that you used.
3. Provide copies of any technical information and/or data you used
that support your views.
4. If you estimate potential burden or costs, explain how you
arrived at the estimate that you provide.
5. Provide specific examples to illustrate your concerns.
6. Make sure to submit your comments by the deadline in this notice.
7. To ensure proper receipt by EPA, be sure to identify the docket
ID number assigned to this action in the subject line on the first page
of your response. You may also provide the name, date, and Federal
Register citation.
II. What Action is the Agency Taking?
EPA has received a pesticide petition as follows proposing the
establishment and/or amendment of regulations for residues of a certain
pesticide chemical in or on various food commodities under section 408
of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a.
EPA has determined that this petition contains data or information
regarding the elements set forth in FFDCA section 408(d)(2); however,
EPA has not fully evaluated the sufficiency of the submitted data at
this time or whether the data support granting of the petition.
Additional data may be needed before EPA rules on the petition.
List of Subjects
Environmental protection, Agricultural commodities, Feed additives,
Food additives, Pesticides and pests, Reporting and recordkeeping
requirements.
Dated: October 19, 2004.
Lois Rossi,
Director, Registration Division, Office of Pesticide Programs.

Summary of Petition

The petitioner summary of the pesticide petition is printed below
as required by FFDCA section 408(d)(3). The summary of the petition was
prepared by the petitioner and represents the view of the petitioner.
The petition summary announces the availability of a description of the
analytical methods available to EPA for the detection and measurement
of the pesticide chemical residues or an explanation of why no such
method is needed.

BASF Corporation
Pesticide Petition 4F6839
EPA has received a pesticide petition (PP 4F6839) from BASF
Corporation, P.O. Box 13528, Research Triangle Park, NC 27709
proposing, pursuant to section 408(d) of the Federal Food, Drug, and
Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by
establishing a tolerance for residues of BAS 320 I, a mixture
comprising 4-{(2E)-2-({[4-(trifluoromethoxy)anilino]
carbonyl{time}
hydrazono)-2-[3-(trifluoromethyl)phenyl]ethyl{time} benzonitrile and
4-{(2Z)-2-({[4-(trifluoromethoxy)anilino]
carbonyl{time} hydrazono)-2-
[3-(trifluoromethyl) phenyl]ethyl{time} benzonitrile in or on the raw
agricultural commodity tuberous and corm vegetables (crop subgroup 1-C)
at 0.05 parts per million (ppm), leafy vegetables (crop group 4) at 35
ppm, head and stem brassica (crop subgroup 5-A) at 5 ppm, leafy
brassica greens (crop subgroup 5-B) at 25 ppm, fruiting vegetables
(crop group 8) at 1.0 ppm. EPA has determined that the petition
contains data or information regarding the elements set forth in
section 408(d)(2) of the FFDCA; however, EPA has not fully evaluated
the sufficiency of the submitted data at this time or whether the data
supports granting of the petition. Additional data may be needed before
EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism. In three plant metabolism studies (cabbage,
tomato and cotton), the major component of the residue was BAS 320 I
(E- and Z-isomers). The major degradate was the ketone, M320I04 and an
oxidized and cyclized metabolite, M320I23, was present in lesser
amounts. These four compounds were defined as the residues of concern
and were incorporated into an analytical method. In the confined
rotational crop studies plant uptake was very limited and the residues
were a mixture of minor and polar components.

2. Analytical method. BASF Analytical Method No. 531/0 was
developed to determine residues of BAS 320 I (E- and Z-Isomer) and its
metabolites M320I04 and M320I23, the residues of concern in plants, in
crop matrices. In this method, residues of BAS 320 I are extracted from
plant matrices with methanol/water (70:30; v/v) and then partitioned
into dichloromethane. For oily matrices, the residues are extracted
with a mixture of isohexane/acetonitrile (1:1; v/v). The final
determination of BAS 320I and its metabolites is performed by LC/MS/MS.

3. Magnitude of residues. Field trials were carried out in order to
determine the magnitude of residue in the following crops: Broccoli,
cabbage, celery, head lettuce, leaf lettuce, mustard greens, pepper
(bell and non-bell), potato, spinach, and tomato. Field trials were
conducted in the required regions. Field trials were carried out using
the maximum label rate, the maximum number of applications and the
minimum preharvest interval. In addition, processing studies were
conducted on potatoes and tomatoes to determine the concentration
factor during normal processing of the raw agricultural commodities. No
animal feeding studies were conducted.

B. Toxicological Profile
1. Acute toxicity. Based on the available acute toxicity data BAS
320 I and its formulated product do not pose acute toxicity risks.

[[Page 62683]]

2. Genotoxicty. In a battery of three in vitro and two in vivo
mutagenicity assays consisting of all required end-points (point
mutation, chromosomal damage, and DNA damage and repair), the weight of
the evidence for BAS 320 I indicates a lack of potential genotoxicity.

Specifically, for the battery of three in vitro mutagenicity assays
with BAS 320 I, no positive responses were observed for increased
revertant frequencies with and without metabolic activation bacterial
reverse mutation assay or for increased mutant frequencies with and
without metabolic activation Hypoxanthine guanine phophoribosyl
transferase (HGPRT) locus assay. Although there was a positive result
for a statistically increased number of structurally aberrant
metaphases in the chromosomes, which indicates clastogenic potential
under in vitro conditions, this result was only observed without
metabolic activation cytogenicity study with V79 cells.

Importantly, the potential biological significance of this apparent
chromosome damage observed in vitro only without metabolic activation,
was evaluated in vivo using the mouse micronucleus assay. Testing in
the in vivo micronucleus study with NMRI mice was conducted at a high
dose level (2,000 mg/kg b.w.) that demonstrated clinical symptoms of
toxicity, including piloerection and poor general state, in 5 of 5
animals. No significant or dose-related increases in chromosomal damage
were observed in this in vivo test, indicating that BAS 320 I does not
cause chromosomal aberrations in intact animals.

Moreover, it has also been recognized by EPA that more weight
should be placed on in vivo systems than in vitro systems as expressed
in the Agency's weight of evidence for genotoxic evaluation of a
chemical included in the ``Guidelines for Mutagenicity Risk
Assessment'' (Federal Register, September 24, 1986, Vol. 51: 34006-
34012). Thus, the negative in vivo results (non-clastogenicity for
chromosomal aberrations) observed in the mouse micronucleus assay and
the rat hepatocytes assay, should override the positive results
obtained in the in vitro assay only without metabolic activation.
Furthermore, it has been noted that in vitro systems may simulate
abnormal physiological conditions from prolonged exposure to a chemical
in the absence of S-9 metabolic activation (Brusick, D.J. (editor)
1987. Genotoxicity Produced in Cultured Mammalian Cell Assay by
Treatment Conditions. Mutation Research, Vol. 189, No.1: 1-69 and
Sofuni, T. 1993. Japanese Guidelines for Mutagenicity Testing.
Environmental and Molecular Mutagenesis, Vol. 21, No.1: 2-7).
Consequently, based on the weight of the evidence presented above, BAS
320 I does not pose a genotoxic concern.

3. Reproductive and developmental toxicity. Potential reproductive
toxicity of BAS 320 I was investigated in a 2-generation reproduction
toxicity study in Wistar rats by oral gavage administration.
Originally, the highest dose tested (HDT) by oral gavage was 75 mg/kg
b.w./day, which induced both excessive maternal toxicity (very high
incidences of poor general health in females during premating,
gestation, and lactation; and statistically decreased food consumption,
body weights, and body weight gain) as well as excessive developmental
toxicity (statistically impaired pup body weights and body weight
gain), which altogether resulted in high pup mortality. Consequently, a
meaningful assessment of the potential reproductive toxicity of the
test compound at this excessively toxic dose level was not possible.
Thereafter, for the next two successive parental generations of rats,
which were originally derived from the parents treated at 75 mg/kg
b.w./day, the HDT was 50 mg/kg b.w./day.

Subsequently, the no observable adverse effect level (NOAEL) for
parental toxicity was 20 mg/kg b.w./day, based on the following effects
for females at 50 mg/kg b.w./day (HDT for two consecutive generations)

[[Page 62684]]

increased incidences of poor general health in females during
premating, gestation, and lactation; 3 of 25 dams with complete litter
losses; and statistically significantly reduced body weights during
premating, gestation, and lactation.

The NOAEL for offspring/pup toxicity was 20 mg/kg b.w./day, based
on a slight increased incidence of pup mortality at 50 mg/kg b.w./day.
Whereas the NOAEL for fertility in this study was 50 mg/kg b.w./day
(HDT for two generations), the NOAEL for reproductive performance was
considered to be 20 mg/kg b.w./day, based on 3 of 25 dams with complete
litter losses, of which 2 of these 3 dams had indications of poor
nursing for their first generation of pups. It is noteworthy that
because most of the pup mortality was due to poor nursing in only 2 of
25 dams, this finding may be considered to be incidental. Importantly,
no comparable impairment of reproductive performance occurred for the
succeeding parental generation treated by oral gavage administration at
50 mg/kg b.w./day.

In a developmental (teratology) toxicity study in the Wistar rat,
the results indicated that the NOAEL for maternal toxicity was 40 mg/kg
b.w./day, based on statistically decreased food consumption and body
weight gains at 120 mg/kg b.w./day (HDT). The NOAEL for fetal
(prenatal)/developmental toxicity was 120 mg/kg b.w./day (HDT). In
addition, there were no indications of any teratogenic effects in the
rat fetuses at 120 mg/kg b.w./day (HDT). Therefore, BAS 320 I is
considered to be neither a developmental toxicant nor a teratogenic
agent in the rat.

In a developmental (teratology) toxicity study in the Himalayan
rabbit, the results indicated that the NOAEL for maternal toxicity was
100 mg/kg b.w./day, based on several clinical symptoms of toxicity
(including ataxia and poor general state) occurring in 4 of 25 does at
300 mg/kg b.w./day, for which 2 of these 4 does had abortions prior to
being sacrificed early, with a third doe at 300 mg/kg b.w./day being
sacrificed moribund. Similarly, the NOAEL for fetal (prenatal)/
developmental toxicity was 100 mg/kg b.w./day, based on slightly
decreased mean fetal body weights as well as an increased rate for a
certain skeletal variation, namely incomplete ossification of
sternabrae. Because developmental toxicity was only observed at dose
levels that were maternally toxic, BAS 320 I is not selectively toxic
to the fetal rabbit.

Lastly, in this rabbit developmental toxicity study, there were no
indications of any teratogenic effects in the rabbit fetuses at 300 mg/
kg b.w./day (HDT). Therefore, BAS 320 I is not teratogenic in the rabbit.

4. Subchronic toxicity. In the Sprague-Dawley rat, treatment by
oral gavage with BAS 320 I for a subchronic duration (90-day timepoint
in the chronic toxicity/carcinogenicity study) resulted in reduced food
consumption and/or decreased mean body weight and/or body weight gains
in males and females at 300 mg/kg b.w./day and in increased incidences
of hepatocellular centrilobular hypertrophy in the livers of males at
300 mg/kg b.w./day. Under the conditions of the study, the NOAEL for
oral administration of BAS 320 I for 90 days was 60 mg/kg b.w./day.
In the beagle dog, treatment by oral gavage with BAS 320 I for a
subchronic duration (90-day timepoint in the chronic toxicity study)
resulted in reduced body weight gain and/or decreased food consumption
in several dogs at 30 mg/kg b.w./day and slightly decreased mean cell
hemoglobin concentration (MCHC) at 30 mg/kg b.w./day. Under the
conditions of the study, the NOAEL for oral administration of BAS 320 I
for 90 days was 12 mg/kg b.w./day.

Lastly, in a subchronic (90-day) dermal toxicity study conducted
with BAS 320 I technical in Wistar rats, the results support a NOAEL of
100 mg/kg b.w./day, based on decreased food consumption (females) and
decreased body weight change in males and females at 300 mg/kg b.w./
day, the next HDT.

5. Chronic toxicity. In the Sprague-Dawley rat, treatment by oral
gavage with BAS 320 I for a 2-year chronic duration resulted in dose-
related increased incidences of hepatocellular centrilobular
hypertrophy in the livers of males and females at 60 mg/kg b.w./day and
at 300/200 mg/kg b.w./day and hepatocellular basophilic alteration in
males at 60 and 300 mg/kg b.w./day. (Note: Beginning the first day of
Week 3, the dose level of the high-dose females was lowered from 300 to
200 mg/kg b.w./day, due to an adverse effect of -71% decreased body
weight gain as compared to controls.)

Therefore, the NOAEL for systemic toxicity following oral
administration of BAS 320 I for 24 months to Sprague-Dawley rats was 30
mg/kg b.w./day for males and females. Importantly, treatment with BAS
320 I to rats for 2 years resulted in no test substance-related
neoplastic findings, and therefore, the NOAEL for oncogenicity was 300/
200 mg/kg b.w./day (HDT).

In the CD-1 mouse, treatment by oral gavage with BAS 320 I for an
18-month chronic duration resulted in a treatment-related increased
incidence of increased brown pigment in the spleens of male and female
animals administered 1,000 mg/kg b.w./day (HDT), as compared to
controls. Under the conditions of the study, the NOAEL for systemic
toxicity following oral administration of BAS 320 I for 18 months to
CD-1 mice was 250 mg/kg b.w./day (the next HDT) for males and females.
Importantly, treatment with BAS 320 I to mice for 18 months resulted in
no test substance-related neoplastic findings, and therefore, the NOAEL
for oncogenicity was 1,000 mg/kg b.w./day (HDT).

In the beagle dog, treatment via gelatin capsules with BAS 320 I
for a 12-month chronic duration resulted in reduced body weight gain
and/or decreased food consumption in several dogs at 30 mg/kg b.w./day
and slightly decreased mean MCHC at 30 mg/kg b.w./day. Under the
conditions of the study, the NOAEL for oral administration of BAS 320 I
for 12 months was 12 mg/kg b.w./day.

i. Threshold effect. For estimated chronic exposure, the
calculation of the chronic reference dose (chronic RfD) is based on the
results of the chronic toxicity studies in the rat, mouse, and dog, and
the two-generation reproduction study in the rat. For BAS 320 I, the
lowest NOAEL for chronic toxic effects is 12 mg/kg b.w./day from the
12-month dog study. A safety factor of 100 is applied to the NOAEL of
12 mg/kg b.w./day, which results in a chronic RfD of 0.12 mg/kg b.w./day.

ii. Non threshold effect. Since there were no test substance-
related neoplastic findings following long-term treatment with BAS 320
I to mice for 18 months or to rats for 24 months, the NOAEL for
oncogenicity in both studies was established at the respective HDT.
Therefore, BAS 320 I should be classified as ``not likely to be a human
carcinogen.''

6. Animal metabolism. In the rat and goat metabolism studies, the
majority of the dose was rapidly excreted in the feces. The low levels
that were absorbed were distributed throughout various tissues. BAS 320
I was the major component of the extractable residues in all tissues
and milk and is the only residue of concern. Metabolism of BAS 320 I
occurs by hydroxylation and conjugation on either of the phenyl rings
or at the ethylene bridge and are the major routes of detoxification.
Cleavage of the semicarbazide bond to yield M320I04 also occurs,
usually with accompanying conjugation. The only residue of concern is
BAS 320 I.

[[Page 62685]]

7. Metabolite toxicology. Toxicity of the metabolites of BAS 320 I
with potential exposure to humans was concurrently evaluated during
toxicity testing of the parent except for the metabolite M320I23 that
was not observed in the rat metabolism study. The Z-isomer (M320I02) of
BAS 320 I was evaluated in additional toxicity tests to confirm no
differences between the minor Z-isomer component and BAS 320 I
technical with a 9 to 1 E-isomer to Z-isomer ratio, respectively. The
results show no toxicological concerns:
i. Toxicity studies with the metabolite M320I23.
• Acute toxicity study with metabolite M 320I023
• The metabolite M 320I023 of BAS 320 I technical
demonstrates low acute toxicity via the oral route of exposure in the rat.
• Oral LD50 > 2,000 mg/kg b.w. (category III).

ii. Subchronic toxicity study with metabolite M 320I023.
In the Sprague-Dawley rat, treatment by oral gavage with metabolite
M 320I023 of BAS 320 I technical for a subchronic (90-day) duration
resulted in systemic toxicity effects of increased relative liver
weights (females) and increased incidences of liver hepatocellular
centrilobular hypertrophy in males and females at 1,000 mg/kg b.w./day
(HDT), as compared to controls. Under the conditions of the study, the
NOAEL for oral administration of the metabolite M 320I023 of BAS 320 I
for 90 days was 200 mg/kg b.w./day (next HDT) in males and females.

iii. Mutagenicity/Genotoxicity studies with metabolite M 320I023.
In a battery of three in vitro and one in vivo mutagenicity assays
consisting of all required end-points (point mutation, chromosomal
damage, and DNA damage and repair), the weight of the evidence for the
metabolite M 320I023 (parent ketone) of BAS 320 I technical indicates a
lack of potential genotoxicity.

Specifically, for the battery of three in vitro mutagenicity assays
with metabolite M 320I023 of BAS 320 I technical, no positive responses
were observed for increased revertant frequencies with and without
metabolic activation bacterial reverse mutation assay or for increased
mutant frequencies with and without metabolic activation HGPRT locus
assay. Although there was a positive result for a statistically
increased number of structurally aberrant metaphases in the
chromosomes, which indicates clastogenic potential under in vitro
conditions, this result was only observed with metabolic activation
cytogenicity study with V79 cells.

Importantly, the potential biological significance of this apparent
chromosome damage observed in vitro only with metabolic activation, was
evaluated in vivo using the mouse micronucleus assay. Testing in this
in vivo micronucleus study with NMRI mice was conducted at a high dose
level (2,000 mg/kg b.w.), that demonstrated no clinical symptoms of
toxicity but which represents the limit dose for this assay. No
significant or dose-related increases in in vivo chromosomal damage
were observed, indicating that the metabolite M 320I023 of BAS 320 I
technical does not cause chromosomal aberrations in intact animals.
Moreover, it has also been recognized by U.S. EPA that more weight
should be placed on in vivo systems than in vitro systems as expressed
in the Agency's weight of evidence for genotoxic evaluation of a
chemical included in the ``Guidelines for Mutagenicity Risk
Assessment'' ( Federal Register, September 24, 1986, Vol. 51: 34006-
34012). Thus, the negative in vivo results (non-clastogenicity for
chromosomal aberrations) observed in the mouse micronucleus assay
should override the positive results obtained in the in vitro assay
only with metabolic activation. Furthermore, it has been noted that in
vitro systems may simulate abnormal physiological conditions (Brusick,
D.J. (editor) 1987. Genotoxicity Produced in Cultured Mammalian Cell
Assay by Treatment Conditions. Mutation Research, Vol. 189, No.1: 1-
69). Additionally, it has been reported in the literature that S-9
metabolic activation does not often have adequate cofactors for
activating detoxifying mechanisms found in the whole animal system
Ashby, J. 1983. The Unique Role of Rodents in The Detection of Possible
Human Carcinogens and Mutagens. Mutation Research, Vol. 115: 117-213
Galloway, S.M. 1994. Chromosome Aberrations Induced In Vitro:
Mechanisms. Delayed Expression, and Intriguing Questions. Environmental
and Molecular Mutagenesis, Vol. 23, Supplement 24: 44-53. Consequently,
based on the weight of the evidence presented above, the metabolite M
320I023 of BAS 320 I technical does not pose a genotoxic concern.
Therefore, as indicated from the results of the mammalian toxicity
studies as well as the mutagenicity assays, metabolite M 320I023 of BAS
320 I does not demonstrate more adverse toxicity when compared to the
BAS 320 I.

iv. Toxicity studies with the Z-Isomer of technical BAS 320 I.
• Acute toxicity study with Z-Isomer. The Z-isomer of BAS
320 I technical demonstrates low acute toxicity via the oral route of
exposure in the rat.
• Oral LD50 > 5,000 mg/kg b.w. (category IV).
v. Subchronic toxicity study with Z-Isomer. In the Sprague-Dawley
rat, treatment by oral gavage with the Z-isomer of BAS 320 I for a
subchronic (90-day) duration resulted in impaired body weight gain only
in females at the mid-dose (300 mg/kg b.w./day) and the high-dose
(1,000 mg/kg b.w./day), as compared to controls. Several microscopic
changes were observed in female animals at these two dose levels, but
all morphologic changes were regarded to be indirect effects of the
impaired body weight gain. Under the conditions of the study, the NOAEL
for oral administration of the Z-isomer of BAS 320 I for 90 days was
1,000 mg/kg b.w./day (HDT) in males and 100 mg/kg b.w./day (lowest dose
tested) in females.

vi. Mutagenicity/Genotoxicity study with Z-Isomer. In an in vitro
mutagenicity assay with the Z-isomer of BAS 320 I, there were no
positive responses observed for increased revertant frequencies with
and without metabolic activation bacterial reverse mutation assay.
Therefore, as indicated from the results of the mammalian toxicity
studies as well as the mutagenicity assay, the minor isomer of BAS 320
I, namely the Z isomer, does not demonstrate more adverse toxicity when
compared to BAS 320 I. 8. Endocrine disruption. Data from the
reproduction / developmental toxicity and short- and long-term repeated
dose toxicity studies with BAS 320 I in the rat, rabbit, mouse, or dog,
do not suggest any endocrine disruption activity. This information is
based on the absence of any treatment-related effects from the
histopathological examination of reproductive organs as well as a low
level of concern for possible effects on fertility, reproductive
performance, or any other aspect of reproductive function, or on growth
and development of the offspring.

C. Aggregate Exposure

1. Dietary exposure--i. Food. Assessments were conducted to
evaluate the potential risk due to acute and chronic dietary exposure
of the U.S. population to residues of BAS 320 I. This insecticide and
its metabolites (M320I04, M320I23) were expressed as the parent
compound (BAS 320 I). The dietary analysis was conducted on all
proposed crops which include potatoes, sweet potatoes, yams, leafy
greens subgroup, leaf petioles subgroup, head &

[[Page 62686]]

stem brassica subroup, leafy brassica greens subgroup, and fruiting
vegetables except cucurbits.
Secondary residues from meat, milk, and eggs were not included in
this assessment since the proposed crops are only considered for human
consumption with the exception of processed potato commodities being
potentially utilized in animal feed. Animal feeding studies were not
required on potatoes based on results of residues of BAS 320 I and its
metabolites (M320I04 and M320I23) in unwashed potatoes. Following an
application rate 18 times the proposed seasonal rate, residues in
potatoes were at or below the limit of quantitation (LOQ) and thus the
proposed tolerance level was set at the LOQ and no feeding studies were
needed.
The acute and chronic dietary exposure estimates were based on the
proposed tolerance values, 100 percent crop treated values,
concentration/processing factors and consumption data from the USDA
Continuing Survey of Food Intake by Individuals (CSFII 1994 - 1996,
1998) and the EPA Food Commodity Ingredient Database (FCID) using
Exponent's Dietary Exposure Evaluation Module (DEEM-FCID) software.
Result exposure estimates were compared against the BAS 320 I acute
Population Adjusted Dose (aPAD) and chronic Population Adjusted Dose
(cPAD) of 20 mg/kg b.w./day and 0.12 mg/kg b.w./day, respectively.
Exposure estimates for the BAS 320 I acute dietary assessment were well
under 100% of the aPAD at the 99.9\th\ percentile (see table below).
The overall U.S. population and the highest exposed subpopulation (all
infants) used only 1.16% and 3.26% of the aPAD, respectively.
Additional refinements including the use of anticipated residues and
predicted percent crop treated would further reduce the acute exposure
estimates.

Results of the chronic dietary assessments are listed in the table
below. The estimated chronic dietary exposure was less than 14.5% of
the cPAD for all subpopulations. Additional refinements such as the use
of anticipated residues and predicted percent crop treated would
further reduce the estimated chronic dietary exposure.

ii. Drinking water. Drinking water level of comparison (DWLOC)
calculation and comparison to surface water and ground water
estimations are given in the tables below. The expected environmental
concentrations (EEC) for both ground water and surface water are well
below the allowable level.

[[Page 62687]]

iii. Aggregate exposure (Diet + Water). The acute and chronic
aggregate exposure of BAS 320 I residues is summarized in the table below.

These results indicate the aggregate exposure of BAS 320 I from
potential residues in food and water, will not exceed the U.S. EPA's
level of concern (100% of PAD). The percent acute and chronic PAD were
< 4 and 14% for all subpopulations, respectively. Overall, considering
a ``worst-case'' scenario, we can conclude with reasonable certainty
that no harm will occur from either acute or chronic aggregate exposure
of BAS 320 I residues from the proposed uses.

D. Cumulative Effects
Section 408(b)(2)(D)(v) requires that, when considering whether to
establish, modify, or revoke a tolerance, the Agency consider
``available information'' concerning the cumulative effects of a
particular pesticide's residues and ``other substances that have a
common mechanism of toxicity.''
The EPA is currently developing methodology to perform cumulative
risk assessments. At this time, there is no available data to determine
whether BAS 320 I has a common mechanism of toxicity with other
substances or how to include this pesticide in a cumulative risk assessment

E. Safety Determination
1. U.S. population. Using the conservative exposure assumptions
described above and based on the completeness and the reliability of
the toxicity data, BASF has estimated the aggregate exposure to BAS 320
I will utilize less than 2% and 14% of the aPAD and cPAD for the U.S.
population, respectively. For the highest exposed age-related
subpopulation the maximum aggregate exposure is predicted to be less
than 3.5% of the aPAD (infants) and 15% of the cPAD (3-5 years).

2. Infants and children. All subpopulations based on age were
considered. Infants and children remained below 3.5 and 15% of the
aggregate aPAD and cPAD for food and water, respectively. BASF,
considering a worst-case situation, concludes with reasonable certainty
that no harm will result to infants or children from aggregate exposure
to BAS 320 I residues.

No additional FQPA safety factor(s) are considered to be
appropriate for BAS 320 I, for the following reasons: There is a
complete toxicity database for BAS 320 I and the exposure data are
complete or are estimated based on data that reasonably accounts for
potential exposures. There is no evidence of susceptibility following
in utero exposure to rats and there is a low level of concern for any
uncertainties in the developmental toxicity study in rabbits or the 2-
generation reproduction study,

[[Page 62688]]

after establishing toxicity endpoints and traditional uncertainty
factors to be used in the risk assessment. Based on these data and
conclusions, a FQPA safety factor of 1X appears to be appropriate for
BAS 320 I.
F. International Tolerances
No Maximum residue levels (MRLs) have been established for BAS 320
I by the Codex Alimentarius Commision (CODEX) or in Canada and Mexico.
[FR Doc. 04-24039 Filed 10-26-04; 8:45 am]
BILLING CODE 6560-50-S