[Federal Register Volume 65, Number 173 (Wednesday, September 6, 2000)]
[Notices]
[Pages 54015-54019]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-22390]



[[Page 54015]]

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ENVIRONMENTAL PROTECTION AGENCY

[PF-969; FRL-6738-4]


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 control number PF-969, must be 
received on or before October 6, 2000.

ADDRESSES: Comments may be submitted by mail, electronically, or in 
person. Please follow the detailed instructions for each method as 
provided in Unit I.C. of the SUPPLEMENTARY INFORMATION. To ensure 
proper receipt by EPA, it is imperative that you identify docket 
control number PF-969 in the subject line on the first page of your 
response.

FOR FURTHER INFORMATION CONTACT: By mail: Indira Gairola, Registration 
Division (7505C), Office of Pesticide Programs, Environmental 
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460; 
telephone number: (703) 308-6379; e-mail address: 
[email protected].

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this Action Apply to Me?

    You may be affected by this action if you are an agricultural 
producer, food manufacturer or pesticide manufacturer. Potentially 
affected categories and entities may include, but are not limited to:

 
------------------------------------------------------------------------
                                                          Examples of
           Categories                 NAICS codes         potentially
                                                      affected  entities
------------------------------------------------------------------------
Industry                          111                 Crop production
                                  112                 Animal production
                                  311                 Food manufacturing
                                  32532               Pesticide
                                                       manufacturing
------------------------------------------------------------------------

    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 the table could also be 
affected. The North American Industrial Classification System (NAICS) 
codes have been provided to assist you and others in determining 
whether or not this action might apply to certain entities. If you have 
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 Additional Information, Including Copies of this 
Document and Other Related Documents?

    1. Electronically. You may obtain electronic copies of this 
document, and certain other related documents that might be available 
electronically, from the EPA Internet Home Page at http://www.epa.gov/. 
To access this document, on the Home Page select ``Laws and 
Regulations,'' ``Regulations and Proposed Rules,'' and then look up the 
entry for this document under the ``Federal Register--Environmental 
Documents.'' You can also go directly to the Federal Register listings 
at http://www.epa.gov/fedrgstr/.
    2. In person. The Agency has established an official record for 
this action under docket control number PF-969. The official record 
consists of the documents specifically referenced in this action, any 
public comments received during an applicable comment period, and other 
information related to this action, including any information claimed 
as confidential business information (CBI). This official record 
includes the documents that are physically located in the docket, as 
well as the documents that are referenced in those documents. The 
public version of the official record does not include any information 
claimed as CBI. The public version of the official record, which 
includes printed, paper versions of any electronic comments submitted 
during an applicable comment period, is available for inspection in the 
Public Information and Records Integrity Branch (PIRIB), Rm. 119, 
Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA, from 8:30 
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The 
PIRIB telephone number is (703) 305-5805.

C. How and to Whom Do I Submit Comments?

    You may submit comments through the mail, in person, or 
electronically. To ensure proper receipt by EPA, it is imperative that 
you identify docket control number PF-969 in the subject line on the 
first page of your response.
    1. By mail. Submit your comments to: Public Information and Records 
Integrity Branch (PIRIB), Information Resources and Services Division 
(7502C), Office of Pesticide Programs (OPP), Environmental Protection 
Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460.
    2. In person or by courier. Deliver your comments to: Public 
Information and Records Integrity Branch (PIRIB), Information Resources 
and Services Division (7502C), Office of Pesticide Programs (OPP), 
Environmental Protection Agency, Rm. 119, Crystal Mall #2, 1921 
Jefferson Davis Highway, Arlington, VA. The PIRIB is open from 8:30 
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The 
PIRIB telephone number is (703) 305-5805.
    3. Electronically. You may submit your comments electronically by 
e-mail to: [email protected], or you can submit a computer disk as 
described above. Do not submit any information electronically that you 
consider to be CBI. Avoid the use of special characters and any form of 
encryption. Electronic submissions will be accepted in Wordperfect 6.1/
8.0 or ASCII file format. All comments in electronic form must be 
identified by docket control number PF-969. Electronic comments may 
also be filed online at many Federal Depository Libraries.

D. How Should I Handle CBI That I Want to Submit to the Agency?

    Do not submit any information electronically that you consider to 
be CBI. You may claim information that you submit to EPA in response to 
this document as CBI by marking any part or all of that information as 
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 version of the 
official record. Information not marked confidential will be included 
in the public version of the official record without prior notice. If 
you have any questions about CBI or the procedures for claiming CBI, 
please consult the person identified 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.

[[Page 54016]]

    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 
control 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 Comestic Act (FFDCA), 21 U.S.C. 346a. 
EPA has determined that this petition contains data or information 
regarding the elements set forth in 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: August 23, 2000.
  Peter Caulkins, Acting
Director, Registration Division, Office of Pesticide Programs.

Summary of Petition

    The petitioner summary of the pesticide petition is printed below 
as required by section 408(d)(3) of the FFDCA. The summary of the 
petition was prepared by the petitioner and represents the view of the 
petitioner. EPA is publishing the petition summary verbatim without 
editing it in any way. 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, 11816 North Creek Parkway N., Bothell WA 98011-
8205] proposing, pursuant to section 408(d) of the (FFDCA), 21 U.S.C. 
346a(d), to amend 40 CFR part 180 to establish an exemption from the 
requirement of a tolerance for the inert ingredient sodium thiosulfate 
when used as a dechlorinator in pesticide formulations for protein 
based products when applied to growing crops or to raw agricultural 
commodities after harvest. 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. 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 Na2S2O3 (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\O\ 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\O\ C when heated rapidly. It loses all its water at 100\O\ 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 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 is considered to have low toxicity and 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 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 
(Section 184.1807) and title 21, part 582 as a Substance Generally 
Recognized As Safe, (Section 582.6807). According to section 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 percent 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%.

[[Page 54017]]

    1. Acute toxicity. 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. Doses of 8 g/kg in rats are 
reported to be non-toxic upon ingestion.
    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 Komed\TM\, an acne medication 
containing 8% sodium thiosulfate together with 2% salicylic acid, 25% 
isopropyl alcohol and other ingredients. Tinver\TM\ and Versiclear\TM\, 
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. 
However, sodium thiosulfate will be compressed into tablets for ease of 
use, thus eliminating the hazard of dust inhalation. 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.
    The use of sodium thiosulfate as an adjuvant is not expected to 
pose an inhalation hazard since it will be in tablet form or is already 
incorporated into the formulation at low concentrations (one to six%). 
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 from the parent compound.
    Although intravenous (IV) exposure to sodium thiosulfate is 
irrelevant to concerns with its use as an adjuvant, 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 mL of a 250 milligrams/mL (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 milligrams/kilograms (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 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 eight 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. Genotoxicty. 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.
    Use of sodium nitroprusside for the treatment of hypertensive 
emergencies in pregnancy has been hampered by

[[Page 54018]]

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 provides adequate information as to the non-toxicity of sodium 
thiosulfate. However, it should be noted that Versiclear\TM\. 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 who 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 illness have shown that ingestion of low levels of sodium 
thiosulfate is a non-toxic and safe therapeutic agent. A patient with 
renal tubular acidosis 1 was treated for nine 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 p=meals) for three to four years in the 
treatment of recurrent calcium urinary lithiasis. Sodium thiosulfate 
was well tolerated by all patients for over four 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 was not used in this 
clinical trial.
    Three patients undergoing maintenance hemodialysis for more than 
four years developed calcified masses. To reduce the symptoms, each 
patient was given 20 mmol of sodium thiosulfate IV at the end of each 
hemodialysis for the next six 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 30mole 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 three 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/dL (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 five 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 min. 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 four 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 
five to ten 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 effect the 
endocrine system, except as a detoxifying agent of compounds that have 
been shown to

[[Page 54019]]

adversely effect the endocrine system (i.e. chlorine and other reactant 
species).

C. Aggregate Exposure

    1. Dietary exposure. The proposed use of sodium thiosulfate as an 
adjuvant (1 tablet to 100 gallons of water or up to 14 oz. of end 
product containing 1-6% sodium thiosulfate to 100 gallons of water) 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 person or any non-target organism.

E. Safety Determination

    1. U.S. population. 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. 00-22390 Filed 9-5-00; 8:45 am]
BILLING CODE 6560-50-S