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Trifloxysulfuron-sodium (Syngenta). March 21, 2003. Pesticide petition. Federal Register.


http://www.epa.gov/fedrgstr/EPA-PEST/2003/March/Day-21/p6822.htm

[Federal Register: March 21, 2003 (Volume 68, Number 55)]
[Notices]
[Page 13924-13930]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr21mr03-63]

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ENVIRONMENTAL PROTECTION AGENCY
[OPP-2003-0057; FRL-7296-6]
 
Trifloxysulfuron-sodium; 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-2003-0057, must be 
received on or before April 21, 2003.

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: James A. Tompkins, Registration 
Division (7505C), Office of Pesticide Programs, Environmental 
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460-
0001; telephone number: (703) 305-5697; e-mail address: 
tompkins.jim@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-2003-0057. 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

[[Page 13925]]

 #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 on 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-2003-0057. 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-2003-0057. 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-2003-0057.
    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-2003-0057. 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

[[Page 13926]]

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.

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: March 10, 2003.
Debra Edwards,
Acting Director, Registration Division, Office of Pesticide Programs.

 Summary of Petition

    The petitioner's summary of the pesticide petition is printed below 
as required by FFDCA section 408(d)(3). The summary of the petition was 
prepared by Syngenta Crop Protection, Inc, 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.

Syngenta Crop Protection, Inc.

PP 1F6280

    EPA has received a pesticide petition (1F6280) from Syngenta Crop 
Protection, Inc., Greensboro, NC 27419 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 trifloxysulfuron-sodium in or on the raw agricultural 
commodities sugarcane at 0.01 parts per million (ppm), cottonseed at 
0.05 ppm, cotton by-products at 1.0 ppm, citrus at 0.01, almond hulls 
at 0.01 ppm, almond nut meat at 0.01 ppm, and tomatoes at 0.01 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 support granting of the petition. Additional 
data may be needed before EPA rules on the petition.

A. Residue Chemistry

    1. Plant metabolism. The primary metabolic pathways of 
trifloxysulfuron-sodium in plants (cotton, sugarcane and citrus) were 
similar to those described for animals, with certain extensions of the 
pathway in plants. The metabolism of trifloxysulfuron-sodium is well 
characterized in plants and animals and the data is adequate for 
tolerance setting purposes.
    The metabolism profile in plants and animals supports the use of an 
analytical enforcement method that accounts for parent 
trifloxysulfuron-sodium. The multiple other metabolites formed in 
plants and animals are considered of equal or lesser toxicity than 
parent compound.
    2. Analytical method. Syngenta Crop Protection, Inc. has submitted 
practical analytical methodology for detecting and measuring levels of 
trifloxysulfuron-sodium in or on raw agricultural commodities. This 
method is based on crop specific cleanup procedures and determination 
by liquid chromatography with a ultraviolet (UV/Vis) detector. The 
limit of detection (LOD) for each analyte of this method is 2 nanograms 
of trifloxysulfuron-sodium. The limit of quantitation (LOQ), as 
demonstrated by acceptable recoveries from fortified control samples, 
is 0.01 ppm for each substrate.
    3. Magnitude of residues. A residue program was performed with 
trifloxysulfuron-sodium on a full geography to support use on cotton, 
sugarcane, citrus, and almonds. Adequate residue trials were performed 
to support the proposed use on tomatoes.

B. Toxicological Profile

    1. Acute toxicity. Trifloxysulfuron-sodium has low acute toxicity. 
The oral LD50 in rats is >5,000 millgrams/kilogram (mg/kg) 
for males and females combined. The rat dermal LD50 is 
>2,000 mg/kg and the rat inhalation LC50 is >5.03 
milligrams/liter (mg/L) air. Trifloxysulfuron-sodium is not a skin 
sensitizer in guinea pigs and is considered to have slight dermal or 
eye irritation in rabbits. End-use formulations of Trifloxysulfuron-
sodium have similar low acute toxicity profiles.
    2. Genotoxicity. Trifloxysulfuron-sodium has been tested for its 
potential to induce gene mutation and chromosomal changes in five 
different test systems. Trifloxysulfuron-sodium technical did not 
induce point mutations in bacteria (Ames assay in Salmonella 
typhimurium or Escherichia coli) or in cultured mammalian cells 
(Chinese hamster V79) and was not genotoxic in an in-vitro unscheduled 
DNA synthesis assay in rat hepatocytes. Chromosome aberrations were not 
observed in an in-vitro test using Chinese hamster ovary cells and 
there were no clastogenic or aneugenic effects on mouse bone marrow 
cell in-vivo in a mouse micronucleus test. These studies show that 
trifloxysulfuron-sodium is not genotoxic.

[[Page 13927]]

    3. Reproductive and developmental toxicity. Data from developmental 
toxicity studies in the rat and rabbit and a two-generation 
reproduction study in the rat have been considered. In rabbit (0, 50, 
100, 250, 500 mg/kg/day) and rat (0, 30, 300, 1,000 mg/kg/day) 
teratology studies there was no evidence of teratogenicity. Maternal 
toxicity was seen at 500 mg/kg/day and 250 mg/kg/day as evidenced by 
deaths and premature sacrifices. For the control (50, 100, and 250 mg/
kg) groups, pre-implantation losses, number of implantation sites, and 
post-implantation losses were not affected by treatment. The findings 
after fetal post mortem examination and fetal visceral examination 
revealed no treatment related effects. Similarly, there were no 
skeletal malformations in this study and the incidence of anomalies and 
variations were not affected by treatment. In conclusion, the no 
observed adverse effect levels (NOAEL) for maternal toxicity was 100 
mg/kg/day and the NOAEL for fetal toxicity was 250 mg/kg/day. There was 
no indication of embryotoxic, fetotoxic or teratogenic potential for 
trifloxysulfuron-sodium in rabbits.
    In the rat teratology study, 300 and 1,000 mg/kg/day caused 
maternal toxicity consisting of reduced body weight and food 
consumption. Developmental toxicity was secondary to maternal toxicity 
and consisted of slightly reduced fetal body weights and an increase in 
minor skeletal anomalies and variations. The NOAELs for maternal and 
developmental toxicity were both 30 mg/kg/day. Trifloxysulfuron-sodium 
was not embryotoxic, fetotoxic or teratogenic in rats when tested under 
the conditions of this study.
    In a rat multigeneration study, trifloxysulfuron-sodium technical 
was administered in feed at concentrations of 0, 500, 1,000, 8,000 or 
12,000 ppm. The dose in mg/kg/day spans a wide range over the duration 
of the study as animals gain weight and go through gestation and 
lactation. The ranges are 24-70, 48-137, 400-1,133, 608-1,755 for males 
and 32-100, 60-199, 500-1,557, 792-2,374 for females at the 500, 1,000, 
8,000, and 12,000 ppm dietary level, respectively.
    Trifloxysulfuron-sodium had no effect on reproductive parameters. 
Parental body weight gain and food consumption were reduced at 12,000 
ppm in both sexes and at 8,000 ppm in males only. In addition, there 
was an increased relative liver weight and an increased incidence of 
hepatocellular hypertrophy at 12,000 ppm in both sexes of adults and at 
8,000 ppm in adult males only. Offspring body weights were reduced in 
males and females greater than or equal to 8,000 ppm.
    In conclusion, the NOAEL for systemic toxicity in both sexes and 
both generations was 1,000 ppm. The mean dose in mg/kg/day for all 
weekly means for both sexes, both generations, all time points at this 
dietary level was 83.4 mg/kg/day. There were no effects on the 
reproductive parameters and the NOAEL for reproductive toxicity was 
>12,000 ppm. Offspring effects were observed only at dose levels that 
produced parental toxicity. Thus, there is no evidence that developing 
offspring are more sensitive than adults to the effects of 
trifloxysulfuron-sodium, and it is concluded, that trifloxysulfuron-
sodium does not cause developmental or reproductive toxicity.
    4. Subchronic toxicity. Trifloxysulfuron-sodium technical was 
evaluated in a number of subchronic studies. In a 3-month rat feeding 
study the NOAEL was 65.7 mg/kg with hematologic and liver effects 
noted. In a 3-month mouse feeding study, the NOAEL was 67.9 mg/kg. 
Effects seen were adaptive liver effects. In a 3-month feeding study in 
dogs the NOAEL was 19.6 mg/kg and hematopoietic and liver effects were 
seen. In a 28-day dermal (rat) study, the NOAEL was 100 mg/kg. In this 
study only body weight effects were noted, and only occurred at 1,000 
mg/kg.
    5. Chronic toxicity. Trifloxysulfuron-sodium technical was not 
oncogenic in rats or mice. In a 12-month feeding study in dogs fed 
diets containing trifloxysulfuron-sodium that resulted in average 
(sexes combined) daily test substance intakes of 0, 1.67, 6.71, 15.0, 
48.2 or 122 mg/kg/day, all animals survived. In life observations, food 
consumption, eye and neurological examinations, and urine profiles were 
not affected by treatment. Macroscopic and microscopic examinations 
revealed no findings that were considered to be treatment related and 
indicative of systemic toxicity.
    The body weight gain was decreased by 16% in males at 122 mg/kg/
day. The 33% decrease at 48.2 mg/kg/day was mainly due to one male that 
gained significantly less weight than the other animals of this group. 
There was a tendency for a decrease in the erythrocyte count, 
hemoglobin concentration and hematocrit for both sexes at 122 mg/kg/day 
at the end of treatment, and for males throughout the treatment period. 
In female dogs treated with 48.2 and 122 mg/kg/day, the mean absolute 
and relative liver weights were increased, and a tendency for an 
increase in relative liver weight was noted for males at the same dose 
levels.
    The maximum tolerance dose (MTD) was achieved at 122 mg/kg/day 
based on the decrease in the body weight gain in males at 48.2 and 122 
mg/kg/day. Administration of trifloxysulfuron-sodium to dogs for 12 
months caused a tendency for decrease in red blood cell parameters in 
both sexes at 122 mg/kg/day. There was neither histopathological nor 
functional evidence for compound related neurotoxicity. Based on the 
effects at 48.2 and 122 mg/kg/day, the NOAEL was established at 15.0 
mg/kg/day for males and 14.9 mg/kg/day for females.
    In an 18-month oncogenicity study, mice were fed diets containing 
trifloxysulfuron-sodium that resulted in average (sexes combined) daily 
test substance intakes of 0, 5.84, 24.3, 116, and 836 mg/kg/day. 
Treatment had no adverse effect on appearance or behavior. Survival in 
treated animals was comparable to controls. There were no effects on 
organ weights, and there were no macroscopic or microscopic findings 
indicative of treatment-related systemic toxicity. Trifloxysulfuron-
sodium was not carcinogenic in the mouse. Body weight gain in females 
at 836 mg/kg/day was decreased by 21% compared to controls after 3 
months and 16% after 18 months. Food consumption was decreased in this 
group by 8%. The MTD was achieved at 836 mg/kg/day based on a decrease 
in body weight gain of greater than 15% throughout the study. 
Trifloxysulfuron-sodium was not carcinogenic in the mouse. Based on the 
findings at 836 mg/kg/day, the NOAEL for chronic toxicity was 
established at 121 mg/kg/day for males and 112 mg/kg/day for females.
    In a 2-year chronic toxicity and carcinogenicity study, rats were 
fed diets containing trifloxysulfuron-sodium that resulted in average 
(sexes combined) daily test substance intakes of 0, 2.08, 22.0, 91.0 or 
464 mg/kg/day. Clinical signs, survival, eye examinations, blood 
chemistry, urinalysis, and water consumption were not adversely 
affected by treatment. Survival in high dose females was greater than 
80%, than in controls of 60%. There were no treatment-related findings 
at the 12-month interim or terminal necropsy.
    A treatment-related decrease in body weight gain (17% decrease 
compared to controls) was seen in both females and males at 464 mg/kg/
day (10,000 ppm), which was considered to be the maximum tolerated dose 
(MTD). Overall food consumption was decreased by 6% in males or 9% in 
females at 464 mg/kg/day. At the interim and terminal

[[Page 13928]]

sacrifices, mean carcass weights were lower in males (9% and 13%, 
respectively) and females (17% and 12%, respectively) for the 464 mg/
kg/day group. At terminal sacrifice, the testes to body weight ratio 
was increased by 19% in the 464 mg/kg/day group.
    Microscopical examination revealed a non-dose responsive increase 
in the incidence of kidney tubular atrophy in the two top dose groups 
of female rats, and an increase in Leydig cell hyperplasia in high dose 
males only. Both treatment-related lesions occurred late in age/
treatment, and were not seen in animals sacrificed in the initial year 
of the study. Neither lesion showed an increase in severity (only 
incidence) or a progression of the lesion. Both lesions are commonly 
seen in high incidence in aged control rats; 26% of control females 
showed renal tubular atrophy, and 22% of control males showed Leydig 
cell hyperplasia. The control incidence in 10 studies was less than 
10%, suggesting that the animals in this study were particularly 
susceptible to this lesion. There were no data from other measured 
parameters in this study that suggest kidney or testis as target 
organs, therefore indicating that these lesions are high-dose, long-
term effects.
    In conclusion, the MTD was reached or exceeded at 464 mg/kg/day for 
the 2-year rat feeding study. The NOAEL in males was 82.6 mg/kg/day 
based on the increased incidence of Leydig cell hyperplasia, and 23.7 
mg/kg/day in females based on the increased incidence of kidney tubular 
atrophy. There was no evidence of a carcinogenic effect after 2 years 
of treatment with trifloxysulfuron-sodium in rats.
    6. Animal metabolism. Metabolism in rats proceeded primarily via 
three concurrent metabolic pathways (typical sulfonylurea chemistry: 
Oxidative o-demethylation, hydroxylation of the pyrimidine ring and 
Smiles rearrangement of the sulfonylurea. Hydrolysis of the 
sulfonylurea and oxidative O-demethylation are minor pathways in the 
rat. Parent compound was the major residue in the rat. The metabolite 
pattern in urine and feces extracts of dogs is similar to that of rats. 
Trifloxysulfuron-sodium was the major component detected in extracts of 
urine and feces for dogs, as in the rats. In hens and goats, the 
metabolite profile was very similar to that observed in the rat.
    7. Metabolite toxicology. The metabolism profile for 
trifloxysulfuron-sodium supports the use of an analytical enforcement 
method that accounts for parent trifloxysulfuron-sodium. Other 
metabolites are considered of equal or lesser toxicity than parent 
compound.
    8. Endocrine disruption. Trifloxysulfuron-sodium does not belong to 
a class of chemicals known or suspected of having adverse effects on 
the endocrine system. There is no evidence that trifloxysulfuron-sodium 
has any effect on endocrine function in development or reproduction 
studies. Furthermore, histological investigation of endocrine organs in 
chronic dog, mouse, and rat studies did not indicate that the endocrine 
system is targeted by trifloxysulfuron-sodium.
    9. Neurotoxicity. In an acute range finding neurotoxicity study in 
which rats received a single oral dose of 2,000 or 3,500 mg/kg 
trifloxysulfuron-sodium, there were no effects on clinical signs, body 
weight and food consumption, or parameters in an abbreviated functional 
observational battery (FOB). Therefore, the time to peak effect for FOB 
and motor activity testing was based on a blood kinetic study. In this 
study, trifloxysulfuron-sodium induced peak plasma levels at 1-2 hours 
post-dose, and levels were almost zero at 24 hours.
    In an acute neurotoxicity study in rats, trifloxysulfuron-sodium 
was administered by gavage at 0 or 2,000 mg/kg. Mortality, body weight 
development and food consumption were not affected by treatment. 
Neither clinical signs nor changes in observation and functional test 
conducted as part of the FOB were observed. Reduced horizontal and 
vertical motor activity were observed in males and females only at the 
time of peak effect (1-2 hours post-dosing). There were no persistent 
signs of toxicity and no histopathological evidence of neurotoxicity.
    In a second acute neurotoxicity study in rats, trifloxysulfuron- 
sodium was administered by gavage at 0, 200, 600 and 2,000 mg/kg. 
Mortality, body weight development and food consumption were not 
affected by treatment. There were no effects on clinical signs or on 
parameters in the FOB. During the peak plasma period (1-2 hours post-
dosing), motor activity parameters of the males were comparable to the 
control while females tended to be slightly less active. Based on the 
results of this study, Trifloxysulfuron-sodium was devoid of neurotoxic 
effects. Due to the slightly reduced motor activity in top dose 
females, the NOAEL was established at 600 mg/kg.
    In a 90-day subchronic neurotoxicity study in rats, 
trifloxysulfuron-sodium was not neurotoxic when administered in the 
diet for 13 weeks at concentrations resulting in average daily test 
substance intakes of 0, 112, 472, or 967 mg/kg/day for males or 0, 134, 
553 or 1,128 mg/kg/day for females. There were no treatment-related 
deaths or clinical signs. Effects on body weight development and food 
consumption indicated systemic toxicity in males at doses 472 mg/kg/day 
and in females at 1,128 mg/kg/day. There were no treatment-related 
neurobehavioral or motor activity effects, no macroscopic findings, and 
no microscopic findings in central or peripheral nervous tissue.
    In the absence of any functional or morphological changes in the 
nervous system at any of the dose levels tested, trifloxysulfuron-
sodium is considered devoid of neurotoxic potential when administered 
to rats for 90 days. Based on body weight effects, the NOAEL was 
established at 112 mg/kg/day for male rats and 553 mg/kg/day for female 
rats.

C. Aggregate Exposure

    1. Dietary exposure. Dietary exposure from trifloxysulfuron-sodium 
potentially exists through both food commodities and drinking water. 
Each exposure pathway is addressed below.
    i. Food. Chronic dietary exposure to trifloxysulfuron-sodium was 
estimated based on proposed tolerance-based residue values and the 
assumption that 100% of all planted acres were treated. The assessment 
included cotton, processed cotton fractions, sugarcane and associated 
processed commodities, citrus, almonds and tomatoes. Chronic exposure 
for all populations was compared to a reference dose (RfD) of 0.15 
milligrams/kilogram/body weight/day (mg/kg/bwt/day) based on a no 
observed adverse effect level (NOAEL) of 14.9 mg/kg/bwt/day from a 1-
year study in dogs and a 100X uncertainty factor. The analysis was 
conducted using the dietary exposure evaluation model 
(DEEMTM) and the USDA's 1994-96 Continuing Survey of Food 
Intake by Individuals (CSFII). Secondary residues in animal commodities 
were not considered in this evaluation since calculations showed that 
transfer from livestock and poultry was minimal and would result in 
residue levels significantly below current analytical method 
capabilities. Chronic exposure to trifloxysulfuron-sodium was found to 
be essentially zero with less than 0.1% of the RfD utilized for all 
populations. These exposure calculations are conservative in that 100% 
of the crop was assumed as treated and tolerance-based residue levels 
were entered into the dietary model.
    Acute dietary assessments were conducted for trifloxysulfuron-
sodium using proposed tolerance-based residue values and the assumption 
that 100% of all planted acres were treated. The assessment included 
cotton, processed cotton fractions, sugarcane and

[[Page 13929]]

associated processed commodities, citrus, almonds and tomatoes. Acute 
exposure to the female population (13-50 years old) was compared to a 
RfD of 0.30 mg/kg/bwt/day based on a NOAEL of 30 mg/kg/bwt/day from a 
rat teratology study and a 100X uncertainty factor. Acute exposure to 
the general population and all other population subgroups (including 
infants and children) was compared to a RfD of 6.0 mg/kg/bwt/day based 
on a NOAEL of 600 mg/kg/bwt/day from an acute neurotoxicity study in 
rats and a 100X uncertainty factor. The analyses were conducted using 
the Dietary Exposure Evaluation Model (DEEMTM) from Novigen 
Sciences and the USDA's 1994-96 CSFII. Secondary residues in animal 
commodities were not considered in this evaluation since calculations 
showed that transfer from livestock and poultry was minimal and would 
result in residue levels significantly below current analytical method 
capabilities. The acute exposures are presented at the 
99.9th percentile of exposure although the Agency accepts 
the 95th percentile when conservative Tier I estimates are 
made (tolerance-based residues and 100% crop treated assumptions). Even 
at the 99.9th percentile, exposure and subsequent risk was 
found to be 0.2% of the acute reference dose (aRfD) for the female 
population (13-19 years not pregnant or nursing) and essentially zero 
with less than 0.1% of the aRfD utilized for all other populations. 
These exposure calculations are conservative in that 100% of the crop 
was assumed as treated, and tolerance-based residue levels were entered 
into the dietary model.
    ii. Drinking water. For chronic exposure in water, the estimated 
maximum concentrations of trifloxysulfuron-sodium in surface water at 
day 56/3 was 0.35 parts per billion (ppb) generic expected 
environmental concentration (GENEEC) (sugarcane) and 0.051 ppb in 
ground water (SCI-GROW) (turf). The chronic drinking water levels of 
concern (DWLOC) values were calculated and compared to these estimated 
water concentrations. From the chronic dietary exposure analysis, an 
exposure estimate of 0.000015 mg/kg/day was determined for the U.S. 
population and less than or equal to 0.000037 mg/kg/day for all 
subgroups. Using this information, chronic drinking water levels of 
concern (DWLOCchronic) were calculated for trifloxysulfuron-
sodium. The trifloxysulfuron-sodium estimated ground water (0.051 ppb) 
and surface water (0.35 ppb) concentrations do not exceed the 
calculated chronic DWLOC values ([mu]g/L): 1,500 to 5,250). Therefore, 
trifloxysulfuron-sodium exposures would not exceed the exposure 
allowable by the chronic risk cup.
    The estimated maximum proposed rates for the ``worst case'' 
estimation of the proposed use concentrations of trifloxysulfuron-
sodium in surface water at Peak Day-0 was 2.56 ppb GENEEC (sugarcane) 
and 0.051 ppb in ground water (SCI-GROW) (turf). The acute DWLOC values 
were calculated and compared to these estimated water concentrations.
    From the acute dietary exposure analysis, the lowest margin of 
exposure (MOE) from the use of trifloxysulfuron-sodium was at the 
95th percentile for the U.S. population and all population 
subgroups. This indicates a food exposure of less than or equal to 
0.00016 mg/kg/day for all populations. Based on the EPA's ``Interim 
Guidance for Conducting Drinking Water Exposure and Risk Assessments'' 
document (draft 12/2/97), acute drinking water levels of concern 
(DWLOCacute) were calculated for trifloxysulfuron-sodium. 
The lowest acceptable MOE for any pesticide is 100. This value was used 
in the DWLOC calculations. Based on this analysis, trifloxysulfuron-
sodium estimated surface water (2.56 ppb) and ground water (0.051 ppb) 
concentrations, for sugarcane, do not exceed the calculated acute DWLOC 
values ([mu]g/L: 8997 to 209,965). Therefore, trifloxysulfuron-sodium 
exposures would not exceed the exposure allowable by the risk cup.
    2. Non-dietary exposure. The acute MOE for children ingesting 
pesticide-treated turf exceeds 190 million. The risk estimate does not 
exceed the level of concern (MOE = 100), indicating there are no oral 
exposure concerns for children ingesting trifloxysulfuron-sodium-
treated turf.

D. Cumulative Effects

    The potential for cumulative effects of trifloxysulfuron-sodium and 
other substances that have a common mechanism of toxicity has also been 
considered. Trifloxysulfuron-sodium is a member of the class of 
herbicides designated as sulfonylureas. There is no reliable 
information to indicate that toxic effects produced by 
trifloxysulfuron-sodium would be cumulative with those of any other 
chemical including another pesticide. Therefore, Syngenta believes it 
is appropriate to consider only the potential risks of 
trifloxysulfuron-sodium in an aggregate risk assessment.

E. Safety Determination

    1. U.S. population. In assessing the potential for additional 
sensitivity of infants and children to residues of trifloxysulfuron-
sodium, data from developmental toxicity studies in the rat and rabbit 
and a two-generation reproduction study in the rat have been 
considered.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of trifloxysulfuron-
sodium, data from developmental toxicity studies in the rat and rabbit 
and a two-generation reproduction study in the rat have been 
considered. In rabbit (0, 50, 100, 250, 500 mg/kg/day) and rat (0, 30, 
300, 1,000 mg/kg/day) teratology studies there was no evidence of 
teratogenicity. Delayed fetal development was apparent only at 
maternally toxic doses of trifloxysulfuron-sodium technical in rats. In 
rabbits, 500 mg/kg/day was clearly toxic to does and at 250 mg/kg/
day,lesser toxicity was seen. For the control (50, 100, and 250 mg/kg) 
groups, pre-implantation losses, number of implantation sites, and 
post-implantation losses were not affected by treatment. The findings 
after fetal post mortem examination and fetal visceral examination 
revealed no treatment related effects. Similarly, there were no 
skeletal malformations in this study and the incidence of anomalies and 
variations were not affected by treatment. The no observed adverse 
effect levels (NOAEL) for maternal toxicity was 100 mg/kg/day and the 
NOAEL for fetal toxicity was 250 mg/kg/day. There was no indication of 
embryotoxic, fetotoxic, or teratogenic potential for trifloxysulfuron-
sodium in rabbits.
    In the rat teratology study developmental toxicity was secondary to 
maternal toxicity and consisted of slightly reduced fetal body weights 
and an increase in minor skeletal anomalies and variations. The NOAELs 
for maternal and developmental toxicity were both 30 mg/kg/day. 
Trifloxysulfuron-sodium was not embryotoxic, fetotoxic, or teratogenic 
in rats when tested under the conditions of this study.
    In a rat multigeneration study, trifloxysulfuron-sodium had no 
effect on reproductive parameters. The NOAEL for systemic toxicity in 
both sexes and both generations was 1,000 ppm. The mean dose in mg/kg/
day for all weekly means for both sexes, both generations, all time 
points at this dietary level was 83.4 mg/kg/day. There were no effects 
on the reproductive parameters and the NOAEL for

[[Page 13930]]

reproductive toxicity was > 12,000 ppm. Offspring effects were not 
observed at dose levels that did not produce parental toxicity. There 
is no evidence that developing offspring are more sensitive than adults 
to the effects of trifloxysulfuron-sodium.
    FFDCA section 408 provides that EPA may apply an additional safety 
factor for infants and children in the case of threshold effects to 
account for prenatal and postnatal toxicity and the completeness of the 
data base. Based on the current toxicological requirements, the data 
base for trifloxysulfuron-sodium relative to prenatal and postnatal 
effects for children is complete. Further, for trifloxysulfuron-sodium, 
the developmental studies showed no increased sensitivity in fetuses as 
compared to maternal animals following in-utero exposures in rats and 
rabbits, and no increased sensitivity in pups as compared to the adults 
in the multi-generation reproductive toxicity study. Therefore, it is 
concluded that an additional uncertainty factor is not warranted to 
protect the health of infants and children and that a RfD of 0.15 mg/
kg/day is appropriate for assessing aggregate risk to infants and 
children of trifloxysulfuron-sodium.
    Assuming tolerance level residues and 100% of crops treated, less 
than 0.1% of the trifloxysulfuron-sodium chronic RfD is utilized in the 
population subgroup all infants (>1 year old). Therefore, based on the 
completeness and reliability of the toxicity data base, Syngenta 
concludes that there is reasonable certainty that no harm will result 
to infants and children from aggregate exposure to trifloxysulfuron-
sodium residues.

F. International Tolerances

    There are no Codex MRLs established for residues of 
trifloxysulfuron-sodium on cottonseed, cotton byproducts, citrus, 
almonds, sugarcane or tomatoes.

[FR Doc. 03-6822 Filed 3-20-03; 8:45 am]
BILLING CODE 6560-50-S