[Federal Register Volume 69, Number 14 (Thursday, January 22, 2004)]
[Notices]
[Pages 3138-3144]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 04-1237]


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ENVIRONMENTAL PROTECTION AGENCY

[OPP-2003-0409; FRL-7339-3]


Amicarbazone; 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-2003-0409, must be 
received on or before February 23, 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: Joanne I. Miller, Registration 
Division (7505C), Office of Pesticide Programs, Environmental 
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460-
0001; telephone number: (703) 305-6224; e-mail address: 
[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, or pesticide manufacturer. 
Potentially affected entities may include, but are not limited to:
    [sbull] Crop production (NAICS 111)
    [sbull] Animal production (NAICS 112)
    [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 ID number OPP-2003-0409. 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 
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

[[Page 3139]]

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-2003-0409. 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-2003-0409. 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-2003-0409.
    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-2003-0409. 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.

List of Subjects

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

    Dated: January 12, 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 represent the views 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.

PP 0F6131

Arvesta Corporation

    EPA has received a pesticide petition (0F6131) from Arvesta 
Corporation, 100 First Street, Suite 1700, San Francisco, CA 94105 
proposing, pursuant to

[[Page 3140]]

section 408(d) of the FFDCA, 21 U.S.C. 346a(d), to amend 40 CFR part 
180, by establishing a tolerance for residues of amicarbazone (4-amino-
4,5-dihydro-N-(1,1-dimethylethyl)-3-(1-methylethyl)-5-oxo-1H-1,2,4-
triazole-1-carboxamide, DA amicarbazone (N-(1,1-dimethylethyl)-4,5-
dihydro-3-(1-methylethyl)-5-oxo-1H-1,2,4-triazole-1-carboxamide) and 
iPr-2-OH DA amicarbazone (N-(1,1-dimethylethyl)-4,5-dihydro-3-(1-
hydroxy-1-methylethyl)-5-oxo-1H-1,2,4-triazole-1-carboxamide) in or on 
the raw agricultural commodities corn grain, at 0.05 parts per million 
(ppm); corn forage at 0.8 ppm; corn stover at 0.5 ppm; alfalfa forage 
at 0.04 ppm; alfalfa hay at 0.06 ppm; cotton undelinted seed at 0.04 
ppm; cotton gin by-product at 0.2 ppm; cottonseed meal at 0.01 ppm; 
cottonseed refined oil at 0.01 ppm; cottonseed hulls at 0.01 ppm; 
soybean forage at 2.5 ppm; soybean hay at 7.0 ppm, soybean seed at 0.6 
ppm, soybean meal at 0.25 ppm; soybean hulls at 0.2 ppm; soybean oil at 
0.01 ppm; wheat forage at 0.6 ppm; wheat hay at 0.9 ppm; wheat grain at 
0.09 ppm; wheat straw at 0.4 ppm; wheat bran at 0.08 ppm; wheat shorts 
at 0.06 ppm; wheat flour at 0.05 ppm; wheat middlings at 0.05 ppm; 
wheat germs at 0.05 ppm; sugarcane at 0.15 ppm; sugarcane molasses at 
0.8 ppm; meat (cattle, sheep, goats, horses, hogs) at 0.01 ppm; meat 
byproducts (cattle, sheep, goats, horses, hogs) at 0.2 ppm; and milk at 
0.01 ppm respectively. 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. The major metabolic pathway of amicarbazone 
involved the deamination of the triazole amino group followed by 
hydroxylation at the tertiary carbon of the isopropyl group to give 
iPr-2-OH DA amicarbazone. The iPr-2-OH DA amicarbazone was the major 
metabolite in all three corn matrices. Hydroxylation of the isopropyl 
methyl gave iPr-1-OH DA amicarbazone, which under went O-glucosidation. 
Another pathway involved hydroxylation of the t-butyl and isopropyl 
groups to give tBu-iPr-2-diOH DA amicarbazone. In addition, DA 
amicarbazone formed an glucoside. The hydroxylated DA amicarbazone 
formed several minor O-glucosides.
    2. Analytical method--i. Plant. An analytical method was developed 
to determine the residues of amicarbazone in plant matrices. The method 
was validated in corn forage, corn fodder, corn grain, and corn 
processed commodities. The corn matrices were extracted with water 
containing 0.05% H3PO4 using a Dionex Accelerated Solvent Extractor 
(ASETM) at 150 [deg]C and 1,500 psi. Following the addition of a 
mixture of deuterated internal standards, the material was purified by 
solid phase extraction (spe). The purified analytes were analyzed by 
high performance liquid chromatography-electrospray ionization/
massspectrometry (LC-ES/MS/MS). The limit of quantitation (LOQ) of the 
method was 0.010 ppm. The recoveries from the various crop matrices 
fortified at 0.01 ppm with amicarbazone and related plant metabolites 
ranged from 70% to 119%. The recoveries from the various crop matrices 
fortified at 0.05 ppm with amicarbazone and related plant metabolites 
ranged from 74% to 97%. The limit of detection (LOD) in corn matrices 
(forage and grain) was 0.001 ppm. The LOD in corn fodder was 0.006 ppm. 
An alternative method was developed and validated in mustard green 
leaves, turnip tops, wheat forage, wheat hay, wheat grain, wheat straw, 
alfalfa, cotton, and soybean. The matrices were extracted in 0.1% 
acetic acid in acetonitrile/water (4:1), filtered and diluted using 
additional in acetonitrile/water (4:1). An aliquot of the extract was 
purified by solid-phase extraction and concentrated to an aqueous 
remainder. Methanol was added and the extract diluted with aqueous 5 mM 
ammonium bicarbonate. The samples were analyzed using LC-MS/MS in 
positive-ion selected reaction monitoring (+SRM) mode and quantified 
using a known amount of deuterated internal standard which was added to 
the initial sample extract.
    The LOQ of the method was 0.010 ppm. The recoveries from the 
various crop matrices fortified at 0.01 ppm with amicarbazone and 
related plant metabolites ranged from 79% to 104%. The recoveries from 
the various crop matrices fortified at 0.10 ppm with amicarbazone and 
related plant metabolites ranged from 106% to 119%. The LOD in matrices 
ranged from 0.0011 to 0.0097 ppm.
    ii. Animal. An analytical method was developed to measure the 
residues of amicarbazone in cattle tissue and milk. The amicarbazone 
residues were extracted from the tissue samples by accelerated solvent 
extraction (ASE). The extract was treated with potassium permanganate 
which oxidized the residues of interest to a common moiety, iPr-2-OH DA 
amicarbazone. The iPr-2-OH DA amicarbazone was removed from the 
reaction mixture by using C-18 solid-phase extraction (spe). The 
isolated analyte was detected by liquid chromatography/tandem mass 
spectroscopy (lc/ms/ms) and quantified against a known amount of a 
deuterated internal standard. Recoveries of a mixture of amicarbazone, 
DA amicarbazone, and iPr-2-OH DA amicarbazone from all tissues and milk 
(0.010 ppm and 0.100 ppm fortifications) were measured. For animal 
matrices, recoveries of 0.010 ppm of the amicarbazone component mixture 
ranged from 62% to 93%. The recoveries of 0.100 ppm of the amicarbazone 
component mixture from animal matrices ranged from 69% to 87%. For 
milk, the recoveries of 0. 010 ppm and 0.100 ppm of the amicarbazone 
component mixture ranged from 79% to 103%. The method LOQ is 0.010 ppm. 
The method LOD is 0.005 ppm.
    3. Magnitude of residues. A total of 24 field trials were conducted 
in two different growing seasons to evaluate the quantity of 
amicarbazone residues in corn forage, fodder, and grain following a 
single application of amicarbazone. The residues of amicarbazone and 
two metabolites DA and iPr-2-OH DA, were quantitated by lc/ms/ms. The 
LOQ was 0.01 ppm for all RACs. The highest average field trial 
amicarbazone residues in corn were 0.55 ppm in forage, 0.43 ppm in 
fodder, and 0.02 ppm in grain. In decline trials, amicarbazone residues 
did not vary appreciably with time. Twelve trials each for alfalfa and 
cotton and 20 trials each for soybean and wheat were conducted to 
evaluate the quantity of amicarbazone residues in these rotational 
crops, following plant back intervals of 0 month (wheat), 1 month 
(soybean), 4 months (alfalfa, and 12 months (cotton). The LOQ was 0.01 
ppm for all RACs. The highest average field trial amicarbazone residues 
were 0.02 and 0.04 ppm (alfalfa forage and hay), 0.03 and 0.16 ppm 
(cotton undelinted seed and gin byproduct), and 1.18, 4.35 and 0.57 ppm 
(soybean forage, hay and seed), 0.47, 0.87, 0.07, and 0.39 (wheat 
forage, hay, grain and straw).
    One field trial was conducted to evaluate the quantity of 
amicarbazone residues in sugarcane, molasses, bagasse, and refined 
sugar in support of an import tolerance. Following an application at 5x 
the maximum expected rate for amicarbazone on sugarcane, the highest 
average field trial amicarbazone residues in sugarcane

[[Page 3141]]

were 0.11 ppm in cane, 0.78 ppm in molasses, 0.44 ppm in bagasse, and 
<0.01 ppm in refined sugar.
    A processing study was conducted to evaluate the quantity of 
amicarbazone in corn processed products. The residues of amicarbazone 
and two metabolites DA and iPr-2-OH DA, were quantitated by LC/MS/MS. 
The LOQ was 0.01 ppm for corn grain and all corn processed commodities. 
Total amicarbazone residues in corn grain were <0.01 ppm. Except for 
the residue (0.01 ppm) in meal, which showed a slight concentration 
(1.1x), amicarbazone residues in all other processed commodities 
(starch, grits, flour, and refined oil) were less than the residue in 
corn grain.
    Processing studies on the rotational crops cottonseed, soybean, and 
wheat were also conducted following an application at 5x (cottonseed) 
or 1x (soybean and wheat) the maximum expected labeled rate on corn. 
Total amicarbazone residues in all cotton seed fractions (meal refined 
oil and hulls) were <0.01 ppm. Amicarbazone residues in soybean grain 
hulls and deodorized oil were less than the residue in soybean grain. 
The residues in soybean grain meal (0.21 ppm), showed a slight 
concentration (1.2x). Amicarbazone residues in wheat grain flour, 
middlings and germs were less than the residue in grain. The residue in 
wheat bran (0.06 ppm) and shorts (0.05 ppm), showed a slight 
concentration (1.5x and 1.2x, respectively).

B. Toxicological Profile

    1. Acute toxicity--i. Amicarbazone is minimally toxic to fasted 
rats following a single oral administration. The oral LD50 
is 1,300 and 1,015 milligrams/kilogram body weight (mg/kg/bwt) for 
males and females, respectively.
    ii. Amicarbazone is minimally toxic to rats following a single 
dermal application. The dermal LD50 is >2,000 mg/kg for both 
males and females.
    iii. An acute inhalation study with rats demonstrated minimal 
toxicity following a 4-hour exposure to the test compound as a 
respirable dust. The inhalation LC50 is >2.242 mg/L for both 
males and females.
    iv. A primary eye irritation study in rabbits showed no positive 
ocular effects, and only very slight, reversible irritation.
    v. A dermal irritation study in rabbits showed that amicarbazone is 
not irritating to the skin.
    vi. Amicarbazone has no skin sensitizing potential under the 
conditions of the buehler topical closed-patch technique in guinea 
pigs.
    2. Genotoxicity. The genotoxic potential of amicarbazone was 
studied in bacterium and mammalian cells with the aid of various in 
vitro test systems (salmonella microsome test, hypoxanthine guanine 
phophoribosyl transferase (HGPRT) test with Chinese Hamster V79 cells, 
and a cytogenetic study with Chinese hamster V79 cells) and one in vivo 
test (micronucleus test). None of the tests revealed any evidence of a 
mutagenic or genotoxic potential of amicarbazone. The compound did not 
induce point mutation, DNA damage, or chromosome aberration.
    3. Reproductive and developmental toxicity--i. In a two-generation 
reproduction toxicity study, Sprague-Dawley rats were administered 
dietary levels of amicarbazone at levels of 0, 100, 500, and 1,000 ppm. 
The no observed adverse effect levels (NOAELs) for reproductive 
parameters was established at 100 ppm (equivalent to 7 mg amicarbazone/
kg/ bwt day) based on a decrease in pup weight at 500 and 1,000 ppm. 
The systemic NOAELs established for both parental males and females was 
100 ppm based on decreased food consumption, decreased body weight, and 
increased liver/body weight observed in the 1,000 ppm group and to a 
lesser extent in the 500 ppm group.
    ii. Two developmental toxicity studies were conducted with 
amicarbazone in the Sprague-Dawley rat. In the first study, gravid dams 
were administered 0, 15, 100, or 300 mg/kg bwt/day on days 6 through 19 
of gestation. Maternal effects were observed at the 100 and 300 mg/kg 
dose levels, and included decreased food consumption, decreased body 
weight, and increased liver weight. No test compound-related maternal 
effects were noted in the 15 mg/kg dose group. An increase in nonviable 
fetuses and decreased fetal weight were observed in the 300 mg/kg dose 
level, and an increase in fetal skeletal variations was noted in the 
100 and 300 mg/kg dose groups. A supplemental study was conducted to 
substantiate the developmental NOAEL of 15 mg/kg from the initial 
study. In the subsequent study gravid Sprague-Dawley rats were 
administered amicarbazone at 0, 5, and 15 mg/kg bwt/day on gestation 
days 6 through 19. No test compound-related maternal or developmental 
effects were observed at any dose level. Based on the findings from 
both rodent studies, there is no teratogenic potential for amicarbazone 
in the rat, and both the maternal and developmental NOAELs were 
established at 15 mg/kg bwt/day.
    iii. Two developmental toxicity studies were conducted with 
amicarbazone in the himalayan rabbit. In the first study, gravid does 
were administered 0, 5, 20, or 70 mg/kg bwt/day on gestation days 6 
through 28 post-coitum. A maternal NOAEL of 5 mg/kg bwt/day was 
established based on decreased body weight at dose levels of 20 and 70 
mg/kg bwt/day. The NOAEL for developmental parameters was 20 mg/kg bwt/
day based on a marginal decrease in fetal weight and a corresponding 
marginal effect on fetal skeletal ossification. A supplemental 
developmental toxicity study was conducted in the rabbit to confirm the 
absence of treatment-related malformations. In this study gravid does 
were administered amicarbazone at 0 or 70 mg/kg bwt/day on gestation 
days 6 through 28. Decreased feed consumption, decreased water 
consumption, and decreased body weight were observed (as in the first 
study) in the 70 mg/kg bwt/day group. Also as noted in the previous 
study, fetal weight was decreased and an accompanying effect on fetal 
skeletal ossification was observed. Based on the findings from both 
rabbit studies, there is no teratogenic potential for amicarbazone in 
the rabbit, and thematernal and developmental NOAELs are 5 and 20 mg/kg 
bwt/day, respectively.
    4. Subchronic toxicity--i. A subchronic dermal toxicity study was 
conducted in the Sprague-Dawley rat in which doses of 0, 200, 500, or 
1,000 mg/kg bwt/day were applied to males (22 days) and females (21 
days). There were no effects at any dose level. The NOAEL was 1,000 mg/
kg bwt/day (the limit dose for this study type).
    ii. A 90-day feeding study was conducted in which Fischer 344 rats 
were exposed to 0,100, 250, 500, 1,000, 2,500, or 5,000 ppm 
amicarbazone in the diet for 13 weeks. Body weight gain was reduced at 
dietary levels of 1,000 ppm and greater in both males and females. 
Hematology and clinical chemistry parameters were affected in the males 
and females of the 1,000, 2,500, and 5,000 ppm groups. No gross 
pathological alterations were described in any group. Through 
approximately 13 weeks of continuous and repeated dietary exposure to 
amicarbazone, the toxicological response of the rat could be broadly 
characterized as involving structural and/or functional alterations in 
liver-, thyroid-, pancreatic-, and hematologic-related (spleen and bone 
marrow) endpoints. There were no adverse compound-related effects in 
the various parameters associated with these target organs at doses up 
to and including 500 ppm (equivalent to 33 mg

[[Page 3142]]

amicarbazone/kg bwt/day) in both the males and females.
    iii. In a dose range-finding toxicity study, CD-1 mice were 
continuously exposed to 0, 25, 50, 100, 250, 500, 1,000, 2,500, 5,000, 
or 7,000 ppm amicarbazone in the diet for 6 weeks. Effects observed 
during the study included decreased body weight (7,000 ppm males only), 
affected clinical chemistry parameters (500-7,000 ppm, males and/or 
females, depending on endpoint), and alterations in hematology 
endpoints (2,500-7,000 ppm, males and/or females, depending on 
endpoint). Organ weight effects were limited to significantly increased 
liver weights, noted in both the males and females at 500 ppm and 
above. Compound-related histopathology included hepatocytomegaly (500-
7,000 ppm), thyroid follicular cell hypertrophy (5,000-7,000 ppm), and 
splenic pigmentation (5,000-7,000 ppm). No effects were noted in either 
the males or females of the 250 ppm level.
    iv. A 90-day feeding study in the dog at levels of 0, 200, 800, and 
2,000 ppm amicarbazone established a NOAEL of 200 ppm (equivalent to 
6.74 mg/kg bwt/day) in the males and a NOAEL of 200 ppm (equivalent to 
6.28 mg/kg bwt/day) in the females. Effects observed at 2,000 ppm and 
to a lesser extent in the 800 ppm group included elevated liver and 
thyroid weights, decreased thymus weight, and affected clinical 
chemistry and hematology parameters. Compound-related histopathology 
was noted in the liver, gall bladder, and thyroid of males and/or 
females (depending on endpoint) of the 2,000 ppm level. The NOAEL was 
established in the females based on a slight induction of hepatic 
enzymes at the 200 ppm dietary level. In contrast affected hepatic 
enzymes were only observed in the males of the 800 and 2,000 ppm 
groups.
    5. Chronic toxicity--i. A 2-year chronic/oncogenicity study was 
conducted with male and female Fischer 344 rats at dietary levels of 0, 
50, 500, and 1,250/1,000 ppm. Decreased body weight gain was noted in 
the males and females of the mid and high-dose groups. Also observed in 
these groups were affected clinical chemistry parameters, including 
increased serum cholesterol (males and females) and increased thyroxine 
and triiodothyronine (males only). At the interim sacrifice (1-year), 
an increase in liver weights was observed in the males (500 and 1,200 
ppm) and females (500 and 1,000 ppm). Evaluation of other organ/body 
weight ratios suggests that other organ weight changes were 
attributable to the decreases in body weight gain. Histopathological 
considerations included a decrease in the background incidence of 
hepatic vacuolation in the 1-year, 1,250 ppm, males. No other 
remarkable histopathology findings were noted and no evidence of any 
test compound-induced neoplastic response was noted in any tissue 
examined. Through approximately 2 years of continuous and repeated 
dietary exposure to the test substance, the toxicological response of 
the rat was principally characterized by alterations in body weight 
gain as well as structural and/or functional alterations in liver-
related endpoints. Based on the lack of an adverse compound-related 
effect in the liver at a dose of 50 ppm in males and females, a 
systemic chronic toxicity NOAEL of 2.3 mg amicarbazone/kg bwt/day was 
established for the rat (specifically, 2.3 and 2.7 mg amicarbazone/kg 
bwt/day for male and female rats, respectively).
    ii. In a chronic toxicity study in the mouse, CD-1 mice were 
continuously exposed to 0, 100, 1,500, or 4,000 ppm amicarbazone in the 
diet for 18-months. Compound-related effects were limited to organ 
weight changes, including pronounced increases in liver weights in the 
1,500 and 4,000 ppm males and females, and decreased kidney weights in 
4,000 ppm males and females. Histopathological considerations included 
an increased incidence of splenic pigmentation in 1,500 and 4,000 ppm 
males and 4,000 ppm males and females as well as hepatocellular 
hypertrophy in all doses tested. The hypertrophy was indicative of an 
adaptive response by the liver to an increased need to facilitate the 
metabolism and excretion of an exogenously administered test substance. 
While the response at 100 ppm (equivalent to 16 and 18 mg/kg bwt/day 
for the males and females, respectively) could be characterized as a 
slight physiologically adaptive response, morphological evidence 
demonstrated an increasingly severe response at 1,500 and 4,000 ppm, 
suggesting that the animals had been pushed near physiological limit. 
There was no evidence of a compound-induced neoplastic response in any 
tissue examined.
    iii. A 1-year feeding study in dogs at dietary levels of 0, 75, 
100, 300, and 1,200 ppm amicarbazone established a NOAEL of 75 ppm for 
both males and females (equivalent to 1.6 and 1.8 mg/kg bwt/day for the 
males and females, respectively). Mild neurological signs (described as 
secondary neuromuscular in nature) were noted in the 1,200 ppm females: 
Three at 6 months and one at 12 months. No other females, and no males 
were affected. Clinical pathology parameters, including triglyceride, 
cholesterol, albumin, globulin, and several hepatic enzymes,were, in 
general, affected in both the males and females of the 1,200 ppm group, 
to a lesser extent in the 300 ppm group, and in some cases in the 100 
ppm group. Hematology parameters, including platelets, hemoglobin, 
hematocrit, and eosinophils, were affected primarily in the 1,200 ppm 
group, and to a lesser extent in the 300 and 100 ppm groups. Terminal 
body weight was unaffected by treatment and there were no gross lesions 
ascribed to the test compound. Compound-related effects on organ 
weights were limited to the liver and thymus. Relative and absolute 
liver weights were increased in the 300 and 1,200 ppm males and the 
1,200 ppm females, and absolute and relative thymus weights were 
decreased in the 1,200 ppm males. Compound-related micropathology 
lesions were limited to minimal to slight diffuse thymic a trophy in 
all 1,200 ppm males and one 1,200 ppm female. There was no evidence of 
a compound-induced neoplastic response in any tissue examined.
    6. Animal metabolism. In a metabolism and disposition study, 
amicarbazone (MKH 3586); (4-amino-4,5-dihydro-N-(1,1-dimethylethyl)-3-
(1-methylethyl)-5-oxo-H-1,2,4-triazole-1-carboxamide), was administered 
as a single oral dose, 5 mg/kg/bwt, to four male Fischer rats. The test 
compound was radio-labeled at the 3-position of the triazolinone ring. 
After oral administration to rats, triazolinone-3-14C amicarbazone was 
rapidly absorbed and metabolized. Recovered radioactivity ranged from 
88% to 95% of the theoretical dose. The majority (54% to 68%) of the 
radioactive residue was excreted in the urine, and the remainder (20% 
to 38%) of the radioactive residue was excreted in feces. No 
appreciable portion of the TRR was found in the tissues, residual 
carcass, or respired gases. A total of 17 metabolites arising from 
amicarbazone were detected in excreta; 10 metabolites could be 
identified. Approximately 73% of the dose was identified in the urine 
and feces. All individual metabolites representing >1% of the dose were 
identified. All unidentified residues in excreta were characterized. 
The main pathways for degradation and excretion of amicarbazone were 
direct conjugation with glucuronic acid to form amicarbazone-GA, an N-
glucuronide, which was excreted mainly in the feces and deamination to 
form DA amicarbazone with subsequent

[[Page 3143]]

oxidation to form a variety of hydroxylated metabolites which were 
excreted in the urine.
    7. Metabolite toxicology--i. Amicarbazone-triazolinone was tested 
for eye and dermal irritation, skin sensitization, and mutagenicity. In 
an acute eye irritation study in the rabbit, the test compound 
demonstrated corneal opacity (grade 1) in all animals at 1 and 24-hours 
with one animal demonstrating effects up to 4 days following exposure. 
No effects on the iris or conjunctiva were observed. The results of a 
dermal irritation study in the rabbit indicate that the test compound 
is not a dermal irritant. The guinea pig maximization test was utilized 
to test the skin sensitization potential of the test compound. No 
dermal effects were noted following the challenge dose indicating that 
the test compound exhibits no skin-sensitization potential. 
Mutagenicity was investigated using the salmonella/microsome plate 
incorporation test. Following incubation with five salmonella 
typhimurium LT2 mutants, no evidence of mutagenic activity of the test 
compound was seen.
    ii. In a similar battery of tests, amicarbazone-oxadiazolinone was 
evaluated as above. In the eye irritation study corneal opacity and 
irritation to the iris were observed up to 21 days after treatment. The 
conjunctiva were not affected by instillation of the test compound. 
Dermal irritation was observed up to 24-hours following exposure to the 
test compound. Based on the findings of the guinea pig maximization 
test, the test compound does not exhibit skin sensitizing properties. 
Similarly, the test compound did not demonstrate any mutagenic 
potential following evaluation using the salmonella/microsome plate 
incorporation test.
    8. Endocrine disruption. There is no evidence to suggest that 
amicarbazone has an effect on the endocrine system. Studies in this 
database include evaluation of the potential effects on reproduction 
and neonatal development, and an evaluation of the pathology of the 
endocrine organs following short-term and long-term exposure. These 
studies revealed no endocrine effects due to amicarbazone.

C. Aggregate Exposure

    1. Dietary exposure--i. Food. Estimates of chronic dietary exposure 
to residues of amicarbazone utilized the proposed tolerances in corn 
forage, corn grain, meat, meat byproducts, fat and milk (of cattle, 
sheep, goats, horses, hogs) of 0.8, 0.05, 0.01, 0.2, 0.01 and 0.01 ppm 
respectively. The assumption was made that 7% of the target crop would 
be treated with amicarbazone. Processing factors were used in 
estimating the residue levels of amicarbazone in processed commodities. 
Potential secondary residues in livestock tissues and milk were 
calculated by multiplying the tissue-to-feed ratios determined in the 
cattle feeding study by a calculated dietary burden based on actual 
field residue data. Potential exposures from field rotational crops 
were considered negligible compared to the above-mentioned exposures. 
For chronic exposures, an reference dose (RfD) of 0.016 mg/kg/day was 
assumed based on and NOAEL of 1.6 mg/kg bwt/day from the chronic 
toxicity feeding study in dogs. A safety factor of 100 was used based 
on interspecies extrapolation (10x) and intraspecies variability (10x). 
Using these assumptions, dietary residues of amicarbazone contribute 
0.000000 mg/kg/day (0.0% of the RfD for children 1 to 6 years old, and 
for the U.S. population. For acute dietary exposure, the same 
assumptions were made. A NOAEL of 5 mg/kg bwt/day from the behavioral 
and physiological toxicity study in rats with a safety factor of 100 
was used in the acute dietary assessment. The safety factor of 100 was 
based on interspecies extrapolation (10x) and intraspecies variability 
(10x) and the acute (aRfD) was 0.05 mg/kg bwt/day. At the 
95th percentile for the U.S. population, amicarbazone 
contributes 0.000023 mg/kg bwt/day (0.05% of the aRfD) toward the RfD. 
For children 1 to 6 years old (the most sensitive subpopulation) 
amicarbazone contributes 0.000042 mg/kg bwt/day (0.08% of the aRfD) 
toward the aRfD.
    ii. Drinking water. The Tier I screening models GENEEC and SCI-GROW 
were used to determine potential levels of human exposure from drinking 
water sources. Given the proposed application pattern and course soil 
use restriction, the risk of human exposure from ground water is 
predicted to be lower than that for surface water. The Tier I models 
predict residues of amicarbazone resulting from typical agricultural 
use would be higher in surface water than ground water. However, even 
when potential surface water exposure is evaluated using the Tier I 
screening model GENEEC, the risk via drinking water is very low. GENEEC 
was used to predict an acute surface water concentration of 
amicarbazone of 19.8 g/L assuming a 70 kg adult drinks 2 liters of 
water/day containing 19.8 g/L, the acute exposure would be 5.66E-04 mg/
kg/day for adults. Assuming a 10 kg child drinks 1 liter/day containing 
19.8 g/L, the exposure would be 1.98E-03 mg/kg/day. Based on the NOAEL 
of 5 mg/kg/day from the behavioral and physiological toxicity study in 
rats and assuming an uncertainty factor of 100, the acute population 
adjusted dose (aPAD) is 0.05 mg/kg/day. Therefore, based on the 
contribution from drinking water alone, 1.1% of the aPAD is consumed 
for adults and 4.0% of the aPAD for children. At the levels calculated 
here, acute exposure from amicarbazone via drinking water inadults or 
children is far below the level of concern. GENEEC predicted a chronic 
(average 56-day) surface water concentration of amicarbazone to be 15.4 
g/L. Assuming a 70 kg adult consumes 2 L of water per day containing 
15.4 g/L amicarbazone residues for a period of 70 years, the chronic 
exposure would be 4.40E-04. Assuming a chronic NOAEL of 1.6 mg/kg/day 
from the chronic toxicity feeding study in dogs and a 100-fold safety 
factor, residues of amicarbazone in surface water account for less than 
3.0% of the chronic population adjusted dose (cPAD) (0.016 mg/kg/day). 
For children (10 kg consuming 1 L/day with 15.5 g/L of amicarbazone) 
the same calculation translates to only 9.6% of the cPAD. Amicarbazone 
screening concentrations in ground water SCI-GROW were predicted to be 
much lower than in surface water generic expected environmental 
concentration (GENEEC). SCI-GROW predicted an amicarbazone 
concentration of less than 1 g/L at the maximum seasonal use rate. 
Therefore the potential contribution to human exposure from drinking 
water from ground water sources is even less than that from surface 
water. At the levels predicted by EPA's current Tier I screening 
models, both acute and chronic exposure from amicarbazone via drinking 
water in adults and children is predicted to be well below any 
reasonable level of concern.
    2. Non-dietary exposure. There are no current non-food uses for 
amicarbazone registered under the Federal Insecticide, Fungicide, and 
Rodenticide Act (FIFRA), as amended. No non-food uses are proposed for 
amicarbazone and no non-dietary exposures are expected for the general 
population.

D. Cumulative Effects

    Amicarbazone falls into the category of triazolinone herbicides. 
There is no information to suggest that any members of this class of 
herbicides has a common mechanism of mammalian toxicity or even produce 
similar effects, so it is not appropriate to combine exposures of 
amicarbazone with other herbicides. Arvesta Corporation is considering 
only the potential risk of amicarbazone.

[[Page 3144]]

E. Safety Determination

    1. U.S. population. As presented previously, the exposure of the 
U.S. general population to amicarbazone is low, and the risks, based on 
comparisons to the RfD, are minimal. The margins of safety from the use 
of amicarbazone are well within EPA's acceptable limits. Arvesta 
Corporation concludes that there is a reasonable certainty that no harm 
will result to the U.S. population from aggregate exposure to 
amicarbazone residues.
    2. Infants and children. The complete toxicological data base, 
including the developmental toxicity and two-generation reproduction 
studies were considered in assessing the potential for additional 
sensitivity of infants and children to residues of amicarbazone. The 
developmental toxicity studies in rats and rabbits did not indicate any 
increased sensitivity of rats or rabbits to in-utero exposure to 
amicarbazone. The two-generation reproduction study did not reveal any 
increased sensitivity of rats to prenatal or postnatal exposure to 
amicarbazone. Furthermore, none of the other toxicology studies 
indicated any data demonstrating that young animals were more sensitive 
to amicarbazone than adult animals. The data taken collectively clearly 
demonstrate that application of an FQPA uncertainty for increased 
sensitivity of infants and children is unnecessary for amicarbazone.

F. International Tolerances

    Amicarbazone is registered for use on corn and sugarcane in Brazil. 
The tolerance for these uses in 0.02 ppm.
[FR Doc. 04-1237 Filed 1-21-04; 8:45 am]
BILLING CODE 6560-50-S