[Federal Register Volume 68, Number 228 (Wednesday, November 26, 2003)]
[Notices]
[Pages 66416-66421]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-29320]


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ENVIRONMENTAL PROTECTION AGENCY

[OPP-2003-0364; FRL-7333-8]


Sodium thiosulfate; Notice of Filing a Pesticide Petition to 
Amend 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 amendment 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-2003-0364, must be 
received on or before December 26, 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:  Princess Campbell, Registration 
Division (7505C), Office of Pesticide Programs, Environmental 
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460-
0001; telephone number: (703) 308-8033 ; 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)

[[Page 66417]]

    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-2003-0364. 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 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-2003-0364. 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-2003-0364. 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

[[Page 66418]]

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, DC20460-0001, Attention: Docket ID Number OPP-2003-0364.
    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-2003-0364. 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: November 13, 2003.
Debra Edwards,
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 summary may have been edited by EPA if the terminology used was 
unclear, the summary contained extraneous material, or the summary 
unintentionally made the reader conclude that the findings reflected 
EPA's position and not the position 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.

EDEN Bioscience Corporation

PP OE6177

    EPA has received a pesticide petition (PP OE6177) from EDEN 
Bioscience Corporation, 3830 Monte Villa Parkway, Bothell WA 98021-6942 
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 
amending the current exemption from the requirement of a tolerance for 
the inert ingredient sodium thiosulfate in or on all food crops. 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.
    In the Federal Register of September 6, 2000 (65 FR 54015) (FRL-
6738-4), EPA issued a notice pursuant to section 408 of the Federal 
Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), announcing the 
filing of a tolerance petition (PP OE6177) by EDEN Bioscience. This 
notice included a summary of the petition prepared by the petitioner 
and this summary contained conclusions and arguments to support its 
conclusion that the petition complied with the Food Quality Protection 
Act (FQPA) of 1996. This petition requested that 40 CFR part 180 be 
amended by establishing an exemption from the requirement of a 
tolerance for residues of the inert ingredient sodium thiosulfate in or 
on all food crops. The final rule exempted the inert ingredient sodium 
thiosulfate from requirement of a tolerance when it comprises no more 
than 6% of the formulated product and when used on growing crops or on 
raw agricultural commodities after harvest. EPA published a final rule 
establishing a tolerance exemption in the Federal Register on December 
21, 2001 (66 FR 65850) (FRL-6811-6) amending 40 CFR 180.1001(c). 
Research by EDEN Bioscience Corporation indicates that higher levels of 
sodium thiosulfate are needed in certain situations, such as the use of 
very high water volumes with products containing a low percentage of 
active ingredient. Therefore, EDEN proposes to amend this exemption to 
permit the use of sodium thiosulfate in a pesticide formulated product 
with no numerical limitation when used on growing crops or on raw 
agricultural commodities after harvest.

[[Page 66419]]

A. Residue Chemistry

    1. Plant metabolism. Due to the breakdown of sodium thiosulfate in 
chlorinated water to sodium chloride, water, sulfur, and sulfate prior 
to application to plants, there is no plant metabolism of the parent 
compound. All of the breakdown products are considered to be plant 
nutrients. Sodium thiosulfate pentahydrate (CAS 10102-17-7) is an 
odorless crystalline substance with a molecular weight of 248.18. The 
molecular formula is Na2S23 (Na 
29.08%, O 30.36%, S 40.56%). It has a pKa of 1.6, is soluble in water 
(42%; by weight at 0[deg]C) and insoluble in alcohol. The aqueous 
solution is practically neutral with a pH range of 6.5-8.0. In aqueous 
solution sodium thiosulfate slowly decomposes to its molecular 
constituents. Sodium thiosulfate pentahydrate has a melting point of 
48[deg]C when heated rapidly. It loses all its water at 100[deg]C and 
decomposes at higher temperatures. When sodium thiosulfate is used to 
remove chlorine from an aqueous solution it follows the equations: 
Na2S2O3 + 4Cl2+ 5H2O = 
2NaHSO4 + 8HCl and Na2S2O3 + 2HCl = 
2NaCl + H2O + S + SO2.
    2. Analytical method. Analysis of sodium thiosulfate can be 
accomplished through a variety of methods. Some researchers have 
employed a gas chromatographic (GC) analytical method using a C18 
column and 420-E fluorescence detector for determining elution of 
thiosulfate in plasma and urine. Other researchers have reported using 
a high performance liquid chromatographic (HPLC) method used to 
determine thiosulfate concentrations in plasma and urine. Medical 
researchers have also described the use of a clinical nephelometer to 
determine sulfate and thiosulfate concentrations in plasma and urine.
    3. Magnitude of residues. Due to the breakdown of sodium 
thiosulfate in water to sodium chloride, water, sulfur and sulfate, 
there are no residues of sodium thiosulfate applied to the plants.

B. Toxicological Profile

    Sodium thiosulfate has been safely used for over 100 years as a 
therapeutic agent; medical uses of sodium thiosulfate have been well 
documented since 1895. In humans it is employed as an antidote for 
acute cyanide poisoning; as a chemoprotectant against carboplatin and 
cisplatin induced ototoxicity; to prevent cyanide poisoning from 
treatment with sodium nitroprusside, nitrile compounds and laetrile; to 
reduce calcinosis; and is used topically to treat acne and pityriasis 
versicolor (tinea versicolor, a type of ringworm). Recent studies have 
shown that sodium thiosulfate may be effective in reducing some 
chemically induced cancers. In veterinary medicine it is used to treat 
or prevent cyanide poisoning; as a ``general detoxifier'' to treat 
bloat; and when applied dermally to treat ringworm and mange. Sodium 
thiosulfate is also being used experimentally to increase food 
utilization in livestock.
    Sodium thiosulfate is present at 8% in lotion formulations to treat 
acne. Other lotions, containing 25% sodium thiosulfate, are used for 
treating ringworm and may be applied twice daily to affected and 
susceptible skin for at least a week to many months until complete 
control is achieved. Sodium thiosulfate (12%) is also mixed with a 
sterile solution of 0.5% potassium ferricyanide to treat silver nitrate 
burns.
    Sodium thiosulfate is used to treat drinking water where there is 
concern with high levels of chlorine, chloroform or other reactive 
species, especially in drinking water produced by desalination plants. 
It is also used as a dechlorinator in aquariums and aquaculture, and in 
a number of manufacturing processes that require the removal of 
chlorine or other reactive species.
    Sodium thiosulfate is classified in the Code of Federal 
Regulations, U.S. Food and Drug Administration, title 21, part 184, as 
a Direct Food Substance Affirmed As Generally Recognized As Safe (Sec.  
184.1807) and title 21, part 582 as a Substance Generally Recognized As 
Safe, (Sec.  582.6807). According to Sec.  184.1807, sodium thiosulfate 
is used as a formulation aid and a reducing agent. It is used in 
alcoholic beverages and table salt at levels not to exceed good 
manufacturing practice, currently 0.00005% in alcoholic beverages and 
0.1% in table salt. Section 582.6807 authorizes the use of sodium 
thiosulfate as a sequestrant in salt with a tolerance of 0.1%.
    1. Acute toxicity. Sodium thiosulfate exhibits a low order of acute 
toxicity. In an acute oral toxicity study of sodium thiosulfate in the 
rat, an LD50 > 5,000 milligrams/kilograms (mg/kg) was 
established, which places this material in Toxicity Category IV. Sodium 
thiosulfate is not well absorbed through the intestinal tract at high 
doses. Sodium thiosulfate is low in acute toxicity but may cause 
irritation of the gastrointestinal tract and purging if large 
quantities are ingested. Sodium thiosulfate has been used as a topical 
treatment for a variety of ailments for numerous years. Sodium 
thiosulfate is available in various lotion formulations such as 
KomedTM, an acne medication containing 8% sodium thiosulfate 
together with 2% salicylic acid, 25% isopropyl alcohol and other 
ingredients. TinverTM and VersiclearTM, are 
lotions used for tinea versicolor (ringworm). Both lotions contain 25% 
sodium thiosulfate, 1% salicylic acid and 10% isopropyl alcohol. It is 
recommended that the lotions be applied twice daily to affected and 
susceptible skin for at least a week to many months until complete 
control of tinea versicolor is achieved. Sodium thiosulfate (12%) is 
also mixed with a sterile solution of 0.5% potassium ferricyanide to 
treat silver nitrate burns. No adverse effects are expected when sodium 
thiosulfate is used topically. There is little information available on 
inhalation toxicity of sodium thiosulfate, but as with all dust or 
crystalline compounds, breathing product dust or mist may irritate the 
respiratory tract. Product labeling calls for mixers to wear a dust 
mask, thus precluding inhalation of dust when sodium thiosulfate is 
present as part of the product formulation. Eden Bioscence Corporation 
believes that the use of sodium thiosulfate as proposed is not expected 
to pose an inhalation hazard since it is already incorporated into the 
formulation at low to moderate concentrations (1 to 25%), or will be 
added in tablet form. Once the sodium thiosulfate either in tablet form 
or in the formulated end product is mixed with water, it breaks down 
into sodium chloride, water, sulfur and sulfate, which eliminates 
further possibility of inhalation exposure to the parent compound.
    Although intravenous (IV) exposure to sodium thiosulfate is 
irrelevant to concerns with its proposed use, information from IV 
studies and therapeutic uses provides further data on the safety of 
sodium thiosulfate. Sodium thiosulfate is considered to be essentially 
a nontoxic drug, although nausea and vomiting have been described with 
rapid IV administration of antidotal doses to normal adult human 
volunteers. The standard dose of sodium thiosulfate for treatment of 
cyanide poisoning in humans is an IV administration of 50 milliliters 
(mL) of a 250 mg/mL (25%) solution. Patients also have been 
administered 50 mL of a 50% sodium thiosulfate solution without adverse 
effects. Sodium thiosulfate administered IV at 150-200 mg/kg over a 
period of 15 minutes, is part of the therapy to treat suspected cyanide 
toxicity from administration of sodium nitroprusside.
    The lethal dose of sodium thiosulfate when given at intravenous 
doses to rats is greater than 2.5 g/kg. The IV LD50 in

[[Page 66420]]

mice is 1.19 g/kg, while the median lethal dose in dogs is 3 g/kg. The 
lethal dose injected into the flank of rabbits was estimated to be 4 g/
kg. The main toxic effects from IV administration of sodium thiosulfate 
appear to be osmotic, which result from the rapid sodium load together 
with acid-base disturbances. Osmotic and acid-base disturbances have 
not been observed at lower doses or from dermal or oral administration 
of sodium thiosulfate.
    Information from intraperitoneal (IP) studies provide further 
support that sodium thiosulfate has relatively low acute toxicity. 
Sodium thiosulfate protects the auditory system from the major ototoxic 
effects of cisplatin and reduces other overt signs of systemic 
toxicity.
    Hamsters receiving IP injections of sodium thiosulfate at 1,600 mg/
kg every other day until five injections were completed showed no ill 
effects from sodium thiosulfate. When sodium thiosulfate was injected 
in hamsters in combination with cisplatin (a chemotherapeutic agent 
that has been shown to cause ototoxicity), sodium thiosulfate provided 
amelioration over a broad hearing range, as well as providing 
protection from cisplatin induced gastrointestinal necrosis and 
nephrotoxicity. Similarly, in a study where guinea pigs treated with 
cisplatin, cisplatin and sodium thiosulfate, saline or sodium 
thiosulfate only (1,600 mg/kg/day for 8 days), there were no signs of 
toxicity in any of the guinea pigs treated with sodium thiosulfate 
only. There were no effects on body weight (bwt) or auditory brainstem 
response and animals treated with cisplatin and sodium thiosulfate, had 
improved hearing and lost less weight than animals treated with 
cisplatin only.
    Sodium thiosulfate has been shown to be an effective antidote in 
mice exposed to acrylonitrile. Mice were given IP injections of sodium 
thiosulfate at 400 mg/kg from 10 to 30 minutes prior to acrylonitrile 
administration at the LD50 dose level of 60 mg/kg. All mice 
appeared normal after prophylactic treatment with sodium thiosulfate 
and showed no ill effects from subsequent acrylonitrile exposure. 
Animals treated with sodium thiosulfate only, showed no evidence of 
toxicity.
    Aquated cisplatin has a higher uptake by tumors than that of 
cisplatin, but aquated cisplatin is also more nephrotoxic. Subcutaneous 
injection of sodium thiosulfate (1,000 mg/kg) five minutes before IP 
administration of aquated cisplatin to B6D2F1 mice resulted in reduced 
aquated cisplatin-induced nephrotoxicity.
    2. Genotoxicity. Sodium thiosulfate is not genotoxic and is 
regularly used in cell culture mediums as a source of sulfur. Sodium 
thiosulfate does not cause cell death or reduce the rate of growth in a 
wide variety of bacteria. Sodium thiosulfate is non-mutagenic to 
Salmonella typhimurium and can reduce the mutagenic effects induced by 
other chemicals. Sodium thiosulfate does not increase the rate of 
sister chromatid exchanges (SCEs) or chromosomal aberrations in human 
lymphocytes. Sodium thiosulfate has been shown to reduce the number of 
SCEs in human lymphocytes and Chinese hamster (CH) lung cells when 
administered simultaneously with known SCE inducers. When sodium 
thiosulfate at concentrations up to 5 X 10\2\ M was added to untreated 
human cells, there was no effect at all on the cells. In vitro studies 
with sodium thiosulfate and LX-1 small-cell lung carcinoma cells found 
that sodium thiosulfate concentrations of 10 mg/kg and above were toxic 
to LX-1 cells, presumably due to high osmolarity. However, lower 
concentrations of sodium thiosulfate had no effect on cell growth. 
Sodium thiosulfate has also been shown to inhibit cisplatin-induced 
mutagenesis in somatic tissue of Drosophila.
    3. Reproductive and developmental toxicity. Sodium thiosulfate is 
not considered to be a reproductive or developmental toxicant due to 
its rapid breakdown in the body to normal constituents, (i.e. 
thiosulfate is a normal constituent of blood and is utilized by 
mitochondrial enzyme rhodanase, a.k.a. thiosulfate sulfurtransferase, 
as a sulfur donor). In addition, remaining thiosulfate is rapidly 
hydrolyzed by water into sodium chloride, water, sulfur and sulfate, 
which are all compounds readily used by living organisms. Teratology 
studies conducted in two species established that the administration of 
550 mg/kg sodium thiosulfate for 13 days in the mouse and of 580 mg/kg 
sodium thiosulfate for 10 days in the rabbit had no effect on nidation 
or on maternal or fetal survival in either species. Use of sodium 
nitroprusside for the treatment of hypertensive emergencies in 
pregnancy has been hampered by concern for the possibility of cyanide 
poisoning in both the mother and fetus. Coinfusion of sodium 
thiosulfate with nitroprusside in gravid ewes prevented fetal and 
maternal cyanide toxicity. Physicians are currently treating some 
pregnant women with IV administration of sodium thiosulfate and sodium 
nitroprusside.
    4. Subchronic toxicity. No studies that fall into the usual 
subchronic category were found. However, data from chronic and acute 
studies provide adequate information as to the non-toxicity of sodium 
thiosulfate. It should be noted that VersiclearTM Lotion 
containing 25% sodium thiosulfate and 1% salicylic acid in propylene 
glycol is recommended for subchronic treatment of tinea versicolor in 
humans. In a series of studies of various therapeutics for cyanide 
poisoning in sheep, up to 660 mg/kg of sodium thiosulfate was 
administered in distilled water via stomach tube directly to the rumen 
of ewes that had been treated with lethal doses of sodium cyanide (7.6 
mg/kg). All ewes treated with 660 mg/kg sodium thiosulfate survived. 
Ewes receiving 66.7 mg/kg sodium thiosulfate still exhibited severe 
signs of cyanide poisoning and subsequently died. Based on this study, 
it is recommended that cyanide toxicity in ruminants should be treated 
with high doses of sodium thiosulfate (500 mg/kg or more) and repeated 
as needed, since sodium thiosulfate is rapidly cleared from the body 
and sustained release of free cyanide from the rumen is possible.
    An evaluation of 41 potential chemopreventive agents using the 
inhibition of carcinogen-induced aberrant crypt foci (ACF) in the rat 
colon as the measure of efficacy found that sodium thiosulfate was one 
of 18 agents that significantly reduced the incidence of ACF.
    5. Chronic toxicity. Long term treatment of patients with a variety 
of illnesses has shown that ingestion of low levels of sodium 
thiosulfate is a non-toxic and safe therapeutic agent. A patient with 
renal tubular acidosis I was treated for 9 years with sodium 
thiosulfate, 15-20 mmol daily (orally), to control nephrocalcinosis. 
During this time period, there were no treatment-related adverse 
effects, nephrocalcinosis did not worsen, and renal function improved. 
Thirty-four patients received daily oral doses of sodium thiosulfate 
(10 mmol twice daily with meals) for 3 to 4 years in the treatment of 
recurrent calcium urinary lithiasis. Sodium thiosulfate was well 
tolerated by all patients for over 4 years with no apparent toxic or 
side effects. It was also found that the patients only absorbed 20-25% 
of the oral dose, excreting four to five mmol as urinary thiosulfate. 
Higher oral dose levels of sodium thiosulfate resulted in watery stools 
in some patients so higher oral dose levels were not used in this 
clinical trial.
    Three patients undergoing maintenance hemodialysis for more than 4 
years developed calcified masses.

[[Page 66421]]

To reduce the symptoms, each patient was given 20 mmol of sodium 
thiosulfate IV at the end of each hemodialysis for the next 6 to 12 
months. A considerable regression of calcified masses with concurrent 
clinical improvement was observed in two of the patients while the 
third patient showed a softening in the mass but no regression in size 
due to encapsulation prior to starting sodium thiosulfate treatment. 
For all patients, there were no new calcified masses observed during 
sodium thiosulfate treatment, sodium thiosulfate was well tolerated, 
and no apparent side effects were observed.
    6. Animal metabolism. Thiosulfate is a normal constituent of 
mammalian urine. In humans, urinary thiosulfate excretion averages 
approximately 30 mole per 24 hours, which is less than 1% of the total 
urinary sulfur load. Sodium thiosulfate is not well absorbed when 
administered orally as it is broken down in the acidic gastric juices 
to form sulfite and sulphur. Research has shown that 20-25% of a 
chronic low level dose is excreted in the urine as urinary thiosulfate.
    When sodium thiosulfate is given intravenously, it is distributed 
throughout the extracellular fluid and renal excretion occurs by 
glomerular filtration and secretion. The serum half-life of thiosulfate 
in humans (after bolus injections) is around 15 to 20 minutes. When 
sodium thiosulfate is administered during sodium nitroprusside therapy, 
the plasma half life of thiosulfate is reported to be as short as 15 
minutes to as long as 3 hours. Depending on the dosage, around 10 to 
50% of exogenous thiosulfate is eliminated unchanged via the kidneys. 
Endogenous levels of plasma and urinary thiosulfate concentrations, 
determined from healthy volunteers are 1.13 +/- 0.11 milligrams/
deciliter (mg/dL) and 0.28 +/- 0.02 mg/dL, respectively. Clearance of 
endogenous thiosulfate in normal males was 0.26 +/- 0.04 mL/min, with 
net excretion accounting for only 0.17% of the filtered load. The 
majority of endogenous thiosulfate is actively reabsorbed and 
endogenous levels are regulated by the kidney through secretion into 
and reabsorption out of tubules.
    Sodium thiosulfate is known to be a strong diuretic. Following IV 
administration of sodium thiosulfate, peak thiosulfate concentrations 
were obtained 5 minutes after injection. The half-life of the 
distribution phase was 23 minutes while that of the elimination phase 
was 182 minutes. Urine concentration, clearance and rate of thiosulfate 
excretion increased markedly after injection. Total excretion was 42.6 
+/- 3.5% of the injected dose at 180 minute. Total excretion increased 
to only 47.4 +/- 2.4% at 18 hours after injection. Sodium thiosulfate 
kinetics were also studied in patients undergoing cancer treatment. 
Sodium thiosulfate was eliminated from the plasma by first-order 
kinetics. On the average approximately 28% of the dose was recovered 
unchanged in the urine. In these patients, 95% of the total recoverable 
thiosulfate was excreted within 4 hours after termination of infusion. 
When sodium thiosulfate is coadministered with cisplatin (a 
chemotherapeutic agent that often causes nephrotoxicity), inactive 
mobile metabolites of cisplatin are formed by a direct reaction between 
cisplatin and sodium thiosulfate in the systemic circulation, which 
results in a reduction in the amount of cisplatin in the kidney. The 
strong diuretic action of sodium thiosulfate also increases elimination 
of both compounds, thus minimizing the time the remaining cisplatin is 
in the kidneys.
    Sodium thiosulfate has been used to estimate extracellular water in 
cattle and was found to reach equilibrium with extracellular water in 5 
to 10 minutes after infusion. Sodium thiosulfate was cleared from 
venous blood in a two part fashion: First, it was cleared from the 
plasma into the interstitial fluid, then secondly through renal 
clearance from the extracellular water. A first-order clearance of the 
sodium thiosulfate was demonstrated 15 to 20 minutes after infusion. 
When combined with urea, sodium thiosulfate gave reasonable estimates 
of empty body water, extracellular water, intracellular water and lean 
body mass. No adverse effects were noted in any of the steers.
    7. Metabolite toxicology. None of the metabolites of sodium 
thiosulfate are considered to be of toxicological significance. 
Thiosulfate is a normal body constituent as are the other breakdown 
products from the reaction of sodium thiosulfate in chlorinated water: 
Sodium chloride, water, sulfur and sulfate.
    8. Endocrine disruption. Sodium thiosulfate does not affect the 
endocrine system, except as a detoxifying agent of compounds that have 
been shown to adversely affect the endocrine system (i.e. chlorine and 
other reactant species).

C. Aggregate Exposure

    1. Dietary exposure. The proposed use of sodium thiosulfate to 
remove chlorine and other reactive species from tank water ensures that 
there is no dietary exposure to sodium thiosulfate. Due to the 
breakdown of sodium thiosulfate in water to sodium chloride, water, 
sulfur and sulfate, there are no residues of sodium thiosulfate applied 
to the plants and thus there are no residues in food.
    i. Food. The proposed use will not result in any dietary exposure 
beyond what is currently present in salt and alcohol.
    ii. Drinking water. There is no exposure to sodium thiosulfate 
through drinking water. Any sodium thiosulfate that gets into water is 
quickly broken down to the following non-toxic compounds: Sodium 
chloride, water, sulfur and sulfate.
    2. Non-dietary exposure. The only anticipated human exposure to 
non-dietary sources of sodium thiosulfate would be through medical 
treatment, occupational exposure, or aquaculture (hobbyists).

D. Cumulative Effects

    Studies have shown that excess sodium thiosulfate beyond endogenous 
levels of thiosulfate is rapidly cleared from the body and there are no 
cumulative effects. It should also be noted that with the exception of 
possible occupational exposure of the mixer/loader/applicator, the 
proposed uses of sodium thiosulfate will not result in exposure to any 
other persons or any non-target organisms.

E. Safety Determination

    1. U.S. population. EDEN Bioscience Corporation believes that the 
use of sodium thiosulfate as an adjuvant added to tank mixes does not 
pose a safety concern for the U.S. population due to the non-toxic 
nature of the compound and the absence of exposure.
    2. Infants and children. Infants and children will not be exposed 
to sodium thiosulfate from its use as an adjuvant in conjunction with 
formulated products.

F. International Tolerances

    There are no known international tolerances for sodium thiosulfate.

[FR Doc. 03-29320 Filed 11-25-03; 8:45 am]
BILLING CODE 6560-50-S