[Federal Register Volume 68, Number 237 (Wednesday, December 10, 2003)]
[Notices]
[Pages 68904-68908]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E3-00489]


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ENVIRONMENTAL PROTECTION AGENCY

[OPP-2003-0385; FRL-7337-6]


Spiroxamine; 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 ID number OPP-2003-0385, must be 
received on or before January 8, 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: Mary L. Waller, Registration Division 
(7505C), Office of Pesticide Programs, Environmental Protection Agency, 
1200 Pennsylvania Ave., NW., Washington, DC 20460-0001; telephone 
number: (703) 308-9354; e-mail address:[email protected].

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, pesticide manufacturer or 
formulator. Potentially affected entities may include, but are not 
limited to:
    [sbull] Crop production (NAICS 1111)
    [sbull] Food manufacturing (NAICS 311)
    [sbull] 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 identification (ID) number OPP-2003-0385. The 
official public docket consists of the documents specifically 
referenced in this action, any public comments received, and other 
information related to this action. Although a part of the official 
docket, the public docket does not include Confidential Business 
Information (CBI) or other information whose disclosure is restricted 
by statute. The official public docket is the collection of materials 
that is available for public viewing at the Public Information and 
Records Integrity Branch (PIRIB), Rm. 119, Crystal Mall 2, 
1921 Jefferson Davis Hwy., Arlington, VA. This docket facility is open 
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal 
holidays. The docket telephone number is (703) 305-5805.
    2. Electronic access. You may access this Federal Register document 
electronically through the EPA Internet under the ``Federal Register'' 
listings at http://www.epa.gov/fedrgstr/.
    An electronic version of the public docket is available through 
EPA's electronic public docket and comment system, EPA Dockets. You may 
use EPA Dockets at http://www.epa.gov/edocket/ to submit or view public 
comments, 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

[[Page 68905]]

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-2003-0385. 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 [email protected], 
Attention: Docket ID Number OPP-2003-0385. 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-2003-0385.
    3. By hand delivery or courier. Deliver your comments to: Public 
Information and Records Integrity Branch (PIRIB), Office of Pesticide 
Programs (OPP), Environmental Protection Agency, Rm. 119, Crystal Mall 
2, 1921 Jefferson Davis Hwy., Arlington, VA, Attention: Docket 
ID Number OPP-2003-0385. Such deliveries are only accepted during the 
docket's normal hours of operation as identified in Unit I.B.1.

D. How Should I Submit CBI to the Agency?

    Do not submit information that you consider to be CBI 
electronically through EPA's electronic public docket or by e-mail. You 
may claim information that you submit to EPA as CBI by marking any part 
or all of that information as CBI (if you submit CBI on disk or CD ROM, 
mark the outside of the disk or CD ROM as CBI and then identify 
electronically within the disk or CD ROM the specific information that 
is CBI). Information so marked will not be disclosed except in 
accordance with procedures set forth in 40 CFR part 2.
    In addition to one complete version of the comment that includes 
any information claimed as CBI, a copy of the comment that does not 
contain the information claimed as CBI must be submitted for inclusion 
in the public docket and EPA's electronic public docket. If you submit 
the copy that does not contain CBI on disk or CD ROM, mark the outside 
of the disk or CD ROM clearly that it does not contain CBI. 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.

[[Page 68906]]

List of Subjects

    Environmental protection, Agricultural commodities, Feed additives, 
Food additives, Pesticides and pests, Reporting and recordkeeping 
requirements.

    Dated: November 26, 2003.
Peter Caulkins,
Acting 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.

Bayer CropScience

PP 3E6783

    EPA has received a pesticide petition (PP 3E6783) from Bayer 
CropScience, 2 T.W. Alexander Drive, P.O. Box 12014, Research Triangle 
Park, NC 27709roposing, 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 Spiroxamine, 8-(1,1-
Dimethylethyl)-N-ethyl-N-propyl-1,4-dioxaspiro[4,5]decane-2-methanamine 
in or on the raw agricultural commodity hop, dried cone - import at 
50.0 parts per million (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. A hop plant metabolism study has been 
conducted, and the nature of the residue is adequately understood. An 
animal metabolism study is not required since the proposed crop to be 
treated with Spiroxamine is not fed to livestock.
    2. Analytical method. A method to determine the total residues of 
Spiroxamine using gas chromatography has been submitted to the EPA. In 
addition, Spiroxamine has been evaluated using the multi-residue 
methodologies as published in the FDA Pesticide Analytical Manual, 
Volume I.
    3. Magnitude of residues. Eight field trials were conducted on 
fields in typical hop-growing regions in Germany to assess the residue 
levels of Spiroxamine, 8-(1,1-dimethylethyl)-N-ethyl-N-propyl-1,4-
dioxaspiro[4,5]decane-2-methanamine, in/on hops following foliar 
applications. A formulation containing Spiroxamine (KWG 4168 500 EC) 
was applied in two spray applications as an emulsifiable concentrate 
formulation containing 500 grams (g) active ingredient/liter(L), with 
an application rate of 1.5 liters/hectare (L/ha) and 3,000 L of water/
ha. This corresponded to a total applied amount of the active 
ingredient of 0.750 kilograms (kg)/ha. The applications were carried 
out at growth stages 75-79 and 77-81, respectively (corresponding to a 
9-10 day interval between applications).
    Duplicate composite samples of hop cones were collected at a 10-day 
preharvest interval (PHI) from each plot. In addition, single samples 
were collected on day 0 and, in four of the trials, on days 6 and 13 
after treatment. Hop cones were analyzed both fresh and, on days 10 and 
13, after kiln drying. The highest total residue value of Spiroxamine 
(defined as parent and metabolites converted to aminodiol equivalents) 
in dried hop cones was 30 ppm (highest individual value)/24.5 ppm 
(highest average value [HAFT] from two samples in a single trial) at a 
10-day PHI. The total Spiroxamine residues in hop cones appeared to 
decline with time. Note: The residue trials submitted with this 
petition are being submitted as a national submission in Germany in the 
European Union (EU). The European procedure for calculating a maximum 
residue limit (MRL) differs from the procedure used in the USA. 
Although no final decision has yet been made by the European 
authorities at the present time, an evaluation of the dried hop cone 
data according to EU principles leads to an MRL proposal equivalent to 
50 ppm total residues of Spiroxamine. In order to avoid possible trade 
conflicts, it is proposed that the U.S. tolerances be harmonized with 
the expected EU-MRL.
    Samples from two of the above field trials were also processed into 
beer (four individual processing trials). Average total residues for 
the dried hop cones prior to processing in these trials were 9.5 and 16 
ppm, respectively. In beer, the total residues of Spiroxamine were 
below the level of detection (i.e., <0.05 ppm) in all four trials.

B. Toxicological Profile

    1. Acute toxicity--KWG 4168 (Spiroxamine) Technical. The acute oral 
LD50 in male rats was 595 milligrams/kilogram (mg/kg) and in 
female rats was >500 but <560 mg/kg. The acute dermal LD50 
in rats was >1,600 and 1,068 mg/kg for males and females, respectively. 
The 4-hour inhalation LC50 in rats was 2.772 and 1.982 
milligrams/liter (mg/L) for males and females, respectively. Irritation 
studies in rabbits revealed Spiroxamine was severely irritating to the 
skin while not irritating to the eye. Spiroxamine exhibited a skin-
sensitizing potential in guinea pigs in both the Magnusson/Kligman 
maximization test and the Buehler patch test.
    2. Genotoxicty. The genotoxic action of Spiroxamine was studied in 
bacteria and mammalian cells with the aid of various in vitro test 
systems (Salmonella microsome test, forward mutation assay, cytogenetic 
study with Chinese hamster ovary cells and unscheduled DNA synthesis 
test) and in one in vivo test (micronucleus test). None of the tests 
revealed any evidence of a mutagenic or genotoxic potential of 
Spiroxamine. The compound did not induce point mutations, DNA damage or 
chromosome aberrations.
    3.Reproductive and developmental toxicity. In a reproduction study 
using rats, Spiroxamine was administered for two generations at dietary 
concentrations of 20, 80 or 300 ppm. Reproductive effects such as 
reduced litter size at birth and clinical signs of toxicity occurred at 
the high dose in conjunction with maternal toxicity. The parental and 
reproductive NOAELs were 20 ppm (equal to 2.13 milligrams per kilogram 
of bodyweight per day (mg/kg bw/day)) and 80 ppm (equal to 9.19 mg/kg 
bw/day), respectively.
    In a developmental toxicity study in rats, Spiroxamine was 
administered by oral gavage at dose levels of 0, 10 and 25 mg/kg bw/day 
and in a supplemental study at doses of 0 and 150 mg/kg bw/day. Severe 
maternal toxicity occurred at 150 mg/kg bw/day resulting in the deaths 
of 21 of 25 animals. Embryotoxicity (palatoschisis and omphalocele) was 
observed at the high dose in conjunction with the severe maternal 
toxicity. The two lower dose levels did not reveal any maternal or 
developmental toxicity. The results of these studies showed that the 
dose of 150 mg/kg bw/day was too high to obtain unequivocal results 
with respect to embryotoxicity and teratogenicity.
    In another oral developmental toxicity study in rats, Spiroxamine 
was administered by gavage during gestation

[[Page 68907]]

at doses of 0, 10, 30 or 100 mg/kg bw/day. Developmental toxicity 
occurred in conjunction with distinct maternal toxicity at the highest 
dose tested. The maternal NOAEL was 30 mg/kg bw/day based on reduced 
body weight gain and feed intake at 100 mg/kg bw/day. The NOAEL for 
developmental toxicity was 30 mg/kg bw/day based on delayed 
ossification, slightly reduced fetal weights and three cases of 
palatoschisis at 100 mg/kg bw/day.
    In oral developmental toxicity studies in rabbits, Spiroxamine was 
administered by gavage during gestation at doses of 0, 5, 20 or 80 mg/
kg bw/day and in a supplemental study at doses of 0 and 80 mg/kg bw/
day. The maternal NOAEL was 20 mg/kg bw/day based on clinical findings, 
reduced body weight gain, reduced food intake and lethality at 80 mg/kg 
bw/day. The NOAEL for developmental toxicity was 20 mg/kg bw/day based 
on marginal developmental toxicity (reduced fetal weight and a slight 
increased rate of spontaneous malformations) at the highest dose level.
    In a dermal developmental toxicity study in rats, Spiroxamine was 
administered for 6 hours/day during gestation at doses of 0, 5, 20 or 
80 mg/kg. Reduced body weight gain occurred in dams at 20 mg/kg and 
greater. Dose-related skin reactions were observed at all treated 
doses. Developmental toxicity, such as wavy ribs, occurred in 
conjunction with maternal toxicity at the highest dose tested. The 
NOAELs for systemic and local maternal toxicity were 5 and <5 mg/kg, 
respectively. The NOAEL for developmental toxicity was 20 mg/kg. 
Spiroxamine did not reveal any teratogenic potential associated with 
dermal application.
    4. Subchronic toxicity.In subacute dermal toxicity studies, rabbits 
were treated with Spiroxamine at doses ranging from 0.05 to 5 mg/kg bw/
day for 6 hours/day over a period of 3 weeks. Systemic effects were not 
observed in these studies. Local irritation, increased skin fold 
thickness, and histopathological findings of the skin occurred in these 
studies. The overall NOAELs for local and systemic effects were 0.2 and 
5 mg/kg bw/day, respectively.
    In a 90-day feeding study, mice were administered Spiroxamine at 
dietary concentrations of 0, 20, 80, 320 or 1,280 ppm. Effects observed 
included clinical signs of toxicity, decreased body weight and food 
consumption, changes in hematological parameters, hyperplastic changes 
in the epidermis of the auricles and/or tail, and effects on the liver, 
kidney, and urinary bladder. The NOAEL was 20 ppm (equal to 6.2 mg/kg 
bw/day) for male mice based on marginally reduced body weight 
development at 80 ppm. The NOAEL for female mice was 80 ppm (equal to 
28.5 mg/kg bw/day) based on slight morphological findings in the liver 
at 320 ppm.
    In another subchronic mouse study, Spiroxamine was administered by 
oral gavage at doses of 0, 60, 180 or 240 mg/kg. Effects observed 
included clinical signs of toxicity, and effects of the liver, urinary 
bladder and hyperplastic changes in the epidermis of the auricles and 
tails. Evidence of liver enzyme induction was seen in all treatment 
groups. The NOAEL was <60 mg/kg bw/day for both males and females.
    Spiroxamine was administered to rats in a subchronic feeding study 
at dietary concentrations of 0, 25, 125 or 625 ppm over a period of 13 
weeks. Effects included clinical signs of toxicity, reduced body weight 
gains, changes in hematological parameters, and effects on the liver, 
urinary bladder, esophagus and forestomach. The NOAEL for both male and 
female was 25 ppm (equal to 1.9 and 2.7 mg/kg bw/day, respectively) 
based on histopathological findings in the esophagus and forestomach at 
125 ppm.
    In two subchronic feeding studies in dogs, Spiroxamine was 
administered at dietary concentrations of 0, 25, 750 or 1,500 ppm and 
at 0, 150, 250 or 500 ppm over a period of 13 weeks. Toxicological 
effects included changes in clinical chemistries, increased relative 
liver weights, and histopathological findings in the liver. The overall 
NOAELs from these studies were 500 ppm (equal to 16.9 mg/kg bw/day) and 
750 ppm (equal to 21.29 mg/kg bw/day) for males and females, 
respectively, based on liver effects.
    5.Chronic toxicity. In a chronic dog study, Spiroxamine was 
administered at dietary concentrations of 0, 25, 75, 1,000 or 2,000 ppm 
for a period of 52 weeks. Effects included opthalmological findings, 
changes in clinical chemistries, mild anemia, and histopathological 
findings (eye and liver). The NOAEL for both sexes was 75 ppm (equal to 
2.47 and 2.48 mg/kg bw/day for males and females, respectively) based 
on eye and liver effects.
    Rats were administered Spiroxamine for 2 years at dietary 
concentrations of 0, 10, 70 or 490 ppm. Effects included reduced body 
weight gains, a slight increase in mortality and histopathological 
findings in the esophagus and urinary bladder. The NOAEL for both sexes 
was 70 ppm (equal to 4.22 and 5.67 mg/kg bw/day for males and females, 
respectively) based on esophagus and urinary bladder effects.
    The carcinogenicity potential of Spiroxamine was investigated in 
rats and mice at maximum dietary concentrations of 490 ppm (equal to 
32.81 mg/kg bw/day) and 600 ppm (equal to 149.8 mg/kg bw/day), 
respectively. No evidence of an oncogenic potential of Spiroxamine was 
found in the long-term studies in rats and mice.
    6. Animal metabolism. Rats were gavaged with 1 or 100 mg/kg radio-
labeled technical Spiroxamine. Seventy percent of the oral low dose was 
absorbed. Within 48 hours of dosing, over 97% of the dose was excreted 
in urine and feces. At sacrifice (48 hours post dosing), the 
radioactivity remaining in the body was below 1% in the low dose groups 
and approximately 1% and 2% in the male and female rats, respectively, 
from the high dose group. Concentrations found in tissues and organs 
were relatively low: i.e., they do not exceed 0.04 mirograms/gram 
([mu]g/g). The highest concentrations were found in liver, thymus and 
adrenals. Slightly smaller concentrations were observed in the thyroid, 
spleen, fat, ovaries and uterus. The main metabolite in all dose groups 
is Spiroxamine oxidized to the carboxylic acid in the t-butyl-moiety. 
The identification rate was approximately 77% of the recovered 
radioactivity in all dose groups.
    7. Metabolite toxicology. Toxicological studies have been conducted 
on KWG 4168 N-oxide, a plant and animal metabolite of Spiroxamine. In 
an acute oral toxicity study on KWG 4168 N-oxide using female rats, the 
LD50 was 707 mg/kg. In a subacute toxicity study, rats were 
administered KWG 4168 N-oxide at dietary concentrations of 0, 30, 150 
and 1,000 ppm. The highest concentration resulted in treatment-related 
effects. The main targets were the epithelia of the digestive tract and 
the urinary bladder. A mild liver enzyme induction was observed without 
any correlating gross- or micropathological findings. In a subchronic 
study, rats were administered KWG 4168 N-oxide at dietary 
concentrations of 0, 25, 125 and 625 ppm, and KWG 4168 at 625 ppm. 
Toxic effects were observed at 625 ppm for both test substances. 
Similar effects included delayed body weight development, changes in 
clinical chemistries and micropathological findings of the esophagus 
and stomach. The effects were less pronounced for KWG 4168 N-oxide when 
compared to KWG 4168 (parent). Effects noted only in animals treated 
with KWG 4168 included changes in hematological

[[Page 68908]]

parameters and micropathological findings of the urinary bladder 
(females). The mutagenic potential of KWG 4168 N-oxide was studied in 
vitro in bacteria and mammalian cells. It did not cause mutations in 
vitro in the Ames assay, the V-79-HPRT gene mutation assay, or produce 
clastogenicity in the chromosome aberration assay with or without 
metabolic activation.
    8. Endocrine disruption. The toxicology data base for Spiroxamine 
is current and complete. Studies in this data base include evaluation 
of the potential effects on reproduction and development, and an 
evaluation of the pathology of the endocrine organs following short- or 
long-term exposure. These studies revealed no primary endocrine effects 
due to Spiroxamine.

C. Aggregate Exposure

    1. Dietary exposure. An aggregate risk assessment was conducted for 
all pending uses (grape, hop (domestic and imported) and banana 
(imported)) to assess the potential acute and chronic dietary exposure 
resulting from applications of Spiroxamine to these crops. Novigen 
Sciences, Inc.'s Dietary Exposure Evaluation Model (DEEM[reg]) was used 
to estimate the chronic and acute dietary exposure.
    For the acute dietary analysis, the proposed acute reference dose 
(aRfD) of 0.1 mg/kg/day was used. This aRfD is based on NOELs of 10 mg/
kg from an acute oral toxicity and an acute neurotoxicity screening 
study and applying a 100-fold uncertainty factor.
    For the chronic dietary analysis, the proposed chronic reference 
dose (cRfD) of 0.02 mg/kg/day was used. This cRfD is based on a 
parental toxicity NOEL of 2.13 mg/kg/day from the two-generation 
reproduction study and the application of a 100-fold uncertainty 
factor.
    Results from the acute and chronic dietary exposure analyses 
described below demonstrate a reasonable certainty that no harm to the 
overall U.S. population or any population subgroup will result from the 
use of Spiroxamine on grape, hop and banana.
    i. Food. An acute, Tier 1 dietary (food) risk assessment was 
conducted using the highest residue values and 100% crop treated. The 
estimated percent of the aRfD for the overall U.S. population (all 
seasons) at the 95 percentile is 8.5%. The most highly exposed 
population subgroup, non-nursing infants, had an exposure equal to 
33.3% of the aRfD at the 95 percentile. These exposure estimates in are 
within EPA's criteria of acceptability.
    A chronic, Tier 1 dietary (food) risk assessment was conducted 
using average residue values and 100% crop treated. The estimated 
percent of the cRfD for the overall U.S. population (all seasons) is 
9.1%. For the most highly exposed population subgroup, children 1 to 6) 
years old, the exposure consumed 30.6% of the cRfD. These exposure 
estimates are within EPA's criteria of acceptability.
    ii. Drinking water. No monitoring data are available for residues 
of Spiroxamine in ground water, and EPA has established no health 
advisory levels or maximum contaminant levels for residues of 
Spiroxamine in drinking water.
    Studies show low to no soil mobility for Spiroxamine and its 
primary metabolites. In addition, field studies show that Spiroxamine 
and its degradates do not leach below the 6-inch depth level, and show 
very low potential to leach into ground water. Therefore, it can be 
concluded with reasonable certainty that no harm will result from acute 
or chronic aggregate exposure to Spiroxamine residues in drinking 
water.
    2. Non-dietary exposure. Spiroxamine is not registered nor are 
registrations pending for uses that would result in non-dietary 
exposure.

D. Cumulative Effects

    Spiroxamine belongs to a new class of chemistry know as 
spiroketalamines. Therefore, for this tolerance petition, it is assumed 
that Spiroxamine does not have a common mechanism of toxicity with 
other substances and only the potential risks of Spiroxamine in its 
aggregate exposure are considered.

E. Safety Determination

    1. U.S. population. Based on the above aggregate food exposure 
estimates for the overall U.S. population (8.5% of the aRfD and 9.1% of 
the cRfD), the low potential for Spiroxamine and its degradates to 
leach into ground water, and the completeness of the toxicity data 
base, there is reasonable certainty that no harm to the U.S. population 
will result from aggregate exposure to Spiroxamine.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of Spiroxamine, data 
from developmental toxicity studies in mice, rats, rabbits and a two-
generation reproduction study in the rat are considered. The 
developmental toxicity studies are designed to evaluate adverse effects 
on the developing organism resulting from maternal pesticide exposure 
during gestation. Reproduction studies provide information relating to 
effects from exposure to the pesticide on the reproductive capability 
of mating animals and data on systemic toxicity.
    Based on the above, aggregate food exposure estimates for the most 
highly exposed population subgroups, i.e., non-nursing infants and 
children (1-6 years old), consumed 33.3% and 30.6% of the aRfD and 
cRfD, respectively. This, in combination with the low potential for 
Spiroxamine and its degradates to leach into ground water, and on the 
completeness of the toxicity data base, there is reasonable certainty 
that no harm to infants and children will result from aggregate 
exposure to Spiroxamine.

F. International Tolerances

    There are no established Codex, Canadian or Mexican MRLs for 
Spiroxamine.
[FR Doc. E3-00489 Filed 12-8-03; 8:45 am]
BILLING CODE 6560-50-S