United States Office of Prevention, Pesticides EPA 738-R-93-OOS
Environmental Protection And Toxic Substances June 1993
Agency (H-7508W)
&EPA Reregistration
Eligibility Document
(RED)
Silver
Printed on Recycled Paper
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United States
Environmental Protection
Agency
Office of Prevention, Pesticides
And Toxic Substances
(H-7508W)
EPA-xxx-x-xx-xxx
?77month777 1992
R.E.D. FACTS
Pesticide
Reregistration
All pesticides sold or used in the United States must be registered by
EPA, based on scientific studies showing that they can be used without
posing unreasonable risks to people or the environment. Because of
advances in scientific knowledge, the law requires that pesticides which
were first registered years ago be reregistered to ensure that they meet
today's more stringent standards.
In evaluating pesticides for reregistration, EPA obtains and reviews a
complete set of studies from pesticide producers, describing the human
health and environmental effects of each pesticide. The Agency imposes
any regulatory controls that are needed to effectively manage each
pesticide's risks. EPA then reregisters pesticides that can be used without
posing undue hazards to human health or the environment.
When a pesticide is eligible for reregistration, EPA announces this
and explains why in a Reregistration Eligibility Document, or RED. This
feet sheet summarizes the information in the RED for silver.
Use Profile
Silver, a naturally-occurring element, is registered for use in water filters
to inhibit the growth of bacteria within the filter unit of water filter systems
designed to remove objectionable taste, odors, and color from municipally
treated tap water; these bacteriostatic water filters account for over 90% of
its pesticidal use. Silver also is used to control several types of algae in
swimming pool water systems; this algicide use accounts for only about
3% of silver's use as a pesticide.
Silver manufacturing use products are granular formulations, the
bacteriostatic water filters are impregnated with silver, and the swimming
pool algicides are formulated as soluble liquid concentrates.
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Silver also has many other non-pesticidal, industrial uses including use in photo
processing, minor production, dental alloys, coinage, tableware and jewelry
production, solder, electroplating, the manufacture of inks and dyes, the
processing of food and beverages, and the etching of ivory. Silver salts and
nitrate also are used as therapeutic agents in treating warts, burns, and eye
infections.
Regulatory Silver was first registered as a pesticide in the United States in 1954, for
History use m disinfectants, sanitizers and fungicides. Currently, about 80
pesticide products are registered which contain silver as an active
ingredient.
Many regulations pertaining to silver have been promulgated through the
years, particularly by EPA's Office of Water (OW). The most recent of
these was a secondary maximum contaminant level (SMCL) issued in
1991, based on silver's ability to cause argyria, an undesirable cosmetic
condition.
OW classified silver as a Group D carcinogen (one that is not classifiable
as to carcinogenicity in humans) in 1988. EPA established an oral
Reference Dose (RiD), or daily intake limit, of 0.005 mg/kg/day for silver
in 1991.
The Office of Pesticide Programs (OPP) issued a Data Call-In (DCI) for
silver in 1992, requiring additional product chemistry and toxicity data.
The silver RED reflects EPA's reassessment of all data submitted in
response to the DCI.
Human Health
Assessment
Toxicity
Most usually-required toxicity and exposure studies have been waived for
silver since adequate published information is available.
Human Toxicolo
Silver can be absorbed from the lungs and the gastrointestinal tract. When
an excessive amount of silver is absorbed, tissues become impregnated
with silver sulfite, which forms a complex in elastic fibers. Large amounts
of this complex under the skin will give it bluish, grey-blue, or in extreme
cases a black color. This condition is called argyria. Although it is not a
toxic effect, argyria is undesirable and usually permanent.
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Excessive exposure to silver also can cause lung and kidney lesions;
exposure to dusts can cause breathing problems, lung and throat infections
and abdominal pain; and skin contact can cause mild allergic reactions such
as rashes, swelling, and inflammation.
Animal Toxicology
The acute toxicity of silver is relatively low by the oral route (it has been
placed in Tbxicity Category m for this effect). Silver also is of low acute
dermal toxicity (Tbxicity Category m), is not an eye or skin irritant
(Tbxicity Category IV), and is not a skin sensitizer.
Silver is not known to have human carcinogenic potential, and does not
appear to be a mutagen. Although long term ingestion of silver may cause
argyria in humans and animals, this effect is cosmetic only and is not
harmful to health.
Dietary Exposure
Silver is not registered for application to food or feed crops nor for use on
processed commodities. Silver is a natural element and trace amounts are
normally present in the human diet. Minimal dietary exposure may result
from the use of silver in human drinking water systems. EPA does not
anticipate that dietary exposure to these low levels of silver will be
associated with any significant degree of risk.
Occupational and Residential Exposure
Occupational exposure can be expected for individuals handling silver
algaecide solutions or silver-impregnated filter materials. When the soluble
liquid concentrates used for water treatment in swimming pools are applied
through a pool skimmer basket, splashes to the eye or on the skin may
occur. People handling silver-impregnated filters may be exposed to
minute quantities of silver-containing charcoal. Thus, the potential exists
among mixers, loaders and applicators for eye, inhalation and dermal
exposure to concentrated solutions or dusts.
Residential exposure to very low levels of silver may be expected through
consumption of drinking water filtered through bacteriostatic filters, and by
swimming in treated pools.
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Human Risk Assessment
Applicator Exposure
Residential consumption of water filtered through filtering systems
containing silver is not expected to result in build-up of silver in the body
to an argyria-comparable level. The use of silver as a water treatment for
pools is minor, and of little concern from a toxicity perspective. Thus, the
residential uses of silver are not expected to constitute an unreasonable risk
or hazard.
Occupational exposure to silver may occur; however, this exposure
generally would be of such a low level, and silver is of sufficiently low
toxicity, that it is not expected to present unreasonable risks or hazards.
Environmental Environmental Fate
Assessment Because a large data base is available for silver, most environmental fete
testing was waived. However, registrants must clarify the nature of the
concentrate used in swimming pools, due to concern about the potential
formation of water soluble or colloidal species that swimmers may ingest.
Products containing silver are not to be applied in marine/estuarine
environments or oil fields. Discharge of effluent into lakes, streams and
ponds or public water is subject to NPDES license restrictions. Aftbter
treated with silver as a pesticide cannot be discharged into sewage systems
without notifying the sewage plant authority.
Ecological Effects
The available acute toxicity data indicate that silver is highly toxic to fish,
aquatic invertebrates and estuarine organisms. Avian toxicity data were
required in the 1992 Data Call-In and these studies are underway. The
risk to birds will be assessed after the data are submitted and reviewed.
However, exposure to birds should be low from the pesticidal uses of
silver.
Ecological Effects Risk Assessment
Silver exposure from products used for swimming pool and human
drinking water systems will be discharged to municipal water systems, and
treated in municipal water treatment plants and is regulated under NPDES
permits. The Agency does not expect unreasonable adverse effects to the
environment from these uses.
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Additional Data EPA is requiring a new confidential statement of formula (CSF) detailing
Required tte nature of the soluble liquid concentrate. EPA also is requiring product-
specific data and revised labeling for reregistration of pesticide products
containing silver.
Product Labeling The labels of all registered pesticide products containing silver must
Changes Required comply with EPA's current pesticide labeling requirements. EPA has
determined that the current end-use label precautions are still appropriate
and are required for product reregistration. It is the Agency's position that
these precautions must continue to include a statement indicating that:
a. This pesticide [silver] is toxic to fish and aquatic
invertebrates.
b. "Do not discharge effluent containing this product into lakes,
streams, ponds, estuaries, oceans or other waters unless in
accordance with the requirements of a National Pollutant
Discharge Elimination System (NPDES) permit and the
permitting authority has been notified in writing prior to
discharge. Do not discharge effluent containing this product to
sewer systems without previously notifying the local sewage
treatment plant authority. For guidance, contact your State
Water Board or Regional Office of E.P.A."
c. That the drinking water filters are for use on cold water only.
Regulatory The use of currently registered pesticide products containing silver in
Conclusion accordance with approved labeling will not pose unreasonable risks or
adverse effects to humans or the environment. Therefore, all uses of
products containing silver registered as of June 23, 1993 are eligible for
reregistration.
These silver products will be reregistered once the required confirmatory,
product-specific data and revised labeling are received and accepted by
EPA.
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For More EPA is requesting public comments on the Reregistration Eligibility
Information Document (RED) for silver during a 60-day time period, as announced in a
Notice of Availability published in the Federal Register. To obtain a copy
of the RED or to submit written comments, please contact the Pesticide
Docket, Public Response and Program Resources Branch, Field Operations
Division (H-7506C), Office of Pesticide Programs (OPP), US EPA,
TOshington, DC 20460, telephone 703-305-5805.
Following the comment period, the silver RED will be available from
the National Technical Information Service (NTTS), 5285 Port Royal Road,
Springfield, VA 22161, telephone 703-487-4650.
For more information about silver or about EPA's pesticide
reregistration program, please contact the Special Review and
Reregistration Division (H-7508W), OPP, US EPA, \Sfcshington, DC
20460, telephone 703-308-8000. For information about reregistration of
individual products containing silver, please contact Joanne I. Miller,
Product Manager, Registration Division (H-7505C), OPP, US EPA,
Wishington, DC 20460, telephone 703-305-7830.
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REREGISTRATION ELIGIBILITY DOCUMENT
SILVER
LISTD
CASE 4082
ENVnUMMENTAL-ntOrecnON-AGENCY
OOTKXOF-H&IICIUE-IROGRAMS
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SILVER REREGISTRATION ELIGIBILITY TEAM
Office of Pesticide Programs:
Biological and Economic Analysis Division
Rafael Prieto
Martin Lewis
Kay Valente
Norm Cook
Silvia Tennes
Mary Frankenberry
peaJth'EffectS'Division
Nguyen Bich Thoa
San Yvette Williams
Judy Smith
Christina Swartz
Registration-Division
Karen Leavy
Marshall Swindell
Van M. Seabaugh
Special Review and Reregistration Division
Margarita Collantes
Kathryn Davis
Kathleen Depukat
Bruce Sidwell
Biological Analysis Branch
Planning & Evaluation
Ecological Effects Branch
Ecological Effects Branch
Environmental Fate and Groundwater Branch
Science Analysis and Coordination Staff
Chemical Coordination Branch
Toxicology Branch n
Occupational and Residential Exposure Branch
Chemistry Branch Reregistration Support
Antimicrobial Program Branch
Antimicrobial Program Branch
Registration Support Branch
Accelerated Reregistration Branch
Accelerated Reregistration Branch
Accelerated Reregistration Branch
Accelerated Reregistration Branch
Policy and Special Pnoiects Staff
JeanFrane
Food Safety & Regulatory Tracking Section
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SILVER REREGISTRATTON ELIGIBILITY TEAM (cont.)
Office of General Counsel
Phil Ross
Office of Compliance Monitoring
Shruti Sanghavi RFRA Policy & Analysis Branch Policy and
Giants Division
Office of Research and Development
MikeTroyer
Office for Policy, Planning and Evaluation
Ronald N. Dexter Pesticides Policy Branch
Office of Water
Julie Du
11
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a.i.
CAS
CRAVE
DCI
DHHS
EEC
EP
EPA
FDA
FIFRA
FFDCA
HDT
LC
»
LD
'30
GLOSSARY OF TERMS AND ABBREVIATIONS
Active Ingredient
Chemical Abstracts Sendee
Carcinogenic Risk Assessment Verification Endeavor
Confidential Statement of Formula
Data Call-In
U.S. Department of Health and Human Services
RcHmatfld Environmental Concentration (The estimated pesticide concentration
in an environment, such as a terrestrial ecosystem.)
End-Use Product
U.S. Environmental Protection Agency
U.S. Food and Drug Administration
Federal Insecticide, Fungicide, and Rodenticide Act
Federal Food, Drug, and Cosmetic Act
Highest Dose Tested
Intravenous
Median Lethal Concentration (A statistically derived concentration of a substance
that can be expected to cause death in 50% of test animals. It is usually
expressed as the weight of substance per weight or volume of water or feed, e.g.,
mg/1 or ppm.)
Median Lethal Dose (A statistically derived single dose that can be expected to
cause death in 50% of the test animals when administered by the route indicated
(oral, dermal). It is expressed as a weight of substance per unit weight of animal,
e.g., mg/kg.)
Lethal Dose-Low (Lowest Dose at which lethality occurs.)
111
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GLOSSARY OF TERMS AND ABBREVIATIONS (cont.)
LEL Lowest Effect Level
LOEL Lowest Observed Effect Level
IRIS Integrated Risk Information System
MCL Maximum Pnntaminant Level
MP Manufacturing-Use Product
MPI Maximum Permissible Intake
MRID Master Record Identification (number). (EPA's system of recording and tracking
studies submitted.)
N/A Not Applicable
NPDES National Pollutant Discharge Elimination System
NOEL No Observed Effect Level
OW Office of Water
OPP Office of Pesticide Programs
OWRS Office of Water Regulations and Standards
PADI Provisional Acceptable Daily Intake
ppb Parts Per Billion
ppm Parts Per Million
RfD Reference Dose
RS Registration Standard
SMCL Secondary Maximum Contaminant Level (A non-enforceable limit for a
contaminant which may affect the aesthetic qualities of drinking water.)
IV
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GLOSSARY OF TERMS AND ABBREVIATIONS (cent.)
TD Toxic Dose (The dose at which a substance produces a toxic effect.)
1C Toxic Concentration (The dose at which a substance produces a toxic effect.)
TMRC Theoretical Maximum Residue Contribution.
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TABLE OF CONTENTS
SILVER REREGISTRATION ELIGIBILITY TEAM i
GLOSSARY OF TERMS AND ABBREVIATIONS iii
EXECUTIVE SUMMARY ix
I. INTRODUCTION 1
n. CASE OVERVIEW 2
A. Chemical Overview 2
B. Use Profile 2
C. Estimated Usage Of Pesticide 3
D. Regulatory History 4
SCIENCE ASSESSMENT 5
A. Physical Chemistry Assessment 5
1. Product Chemistry 5
2. Residue Chemistry 5
B. Human Health Assessment 6
1. Toxicology Assessment 6
a. Human Toxicology 6
b. Animal Toxicology 7
(1) Acute Toxicity 7
(2) Subchronic Toxicity 8
(3) Chronic toxicity 9
(4) Cardnogenichy 10
(5) Developmental Toxicity 11
(6) Mutagenicity 11
(7) Metabolism 11
(8) Secondary Maximum Contaminant Level
(SMCL) 12
(9) Reference Dose (RfD) 12
2. Exposure Assessment 13
a. Dietary Exposure 13
b. Occupational and Residential 13
3. Risk Assessment 14
a. Dietary 14
b. Occupational and Residential 14
C. Environmental Assessment 15
1. Environmental Fate IS
a. Environmental Chemistry - Fate and Transport IS
b. Environmental Fate Assessment 16
vi
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2. Ecological Effects 16
a. Ecological Effects Data 16
(1) Terrestrial Data 16
(2) Aquatic Data - Freshwater Fish, Freshwater
Invertebrates & Estuarine Organisms 17
b. Ecological Effects Risk Assessment 17
IV. RISK MANAGEMENT AND REREGISTRATION DECISION 18
A. Determination of Eligibility 18
1. Eligibility Decision 18
2. Eligible and Ineligible Uses 18
B. Regulatory Position 19
1. Tolerance Reassessment 19
2. Labeling Rationale 19
V. ACTIONS REQUIRED BY REGISTRANTS 19
A. Manufacturing-Use Products 19
1. Additional Generic Data Requirements 19
2. Labeling Specifications for Manufacturing-Use Products 20
B. End-Use Products 21
1. Additional Product-Specific Data Requirements 21
2. Labeling Specifications for End-Use Products 21
VI. APPENDICES
Appendix A - Use Patterns Subject to Reregistration
Appendix B - Table of the Generic Data Requirements and Studies Used to Make the
Reregistration Decision
Appendix C - Citations Considered to be Part of the Data Base Supporting the
Reregistration of Silver
Appendix D - List of Available Related Documents
Appendix E - Pesticide Reregistration Handbook
Appendix F - Generic Data Call-In
Attachment A - Chemical Status Sheet
Attachment B - Generic DCI Response Forms (Form A) plus Instructions
Attachment C - Requirements Status and Registrants' Response Forms
(Form B) plus Instructions
Attachment D - List of all Registrant(s) sent this DCI
Attachment E - Cost Share/Data Compensation Forms
••
Vll
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Appendix G - Product Specific Data Call-in
Attachment A - Chemical Status Sheet
Attachment B- Product Specific DCI Response Forms (Form A) plus
instructions
Attachment C - Requirements Status and Registrants' Response Forms
(Fonn B) plus Instructions
Attachment D - EPA Grouping of End Use Products for meeting Acute
Toxicology Data Requirements.
Attachment E - EPA Acceptance Criteria
Attachment F - List of all Registrants) sent this DCI
Attachment G - Cost Share/Data Compensation Forms
viii
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EXECUTIVE SUMMARY
The U.S. Environmental Protection Agency (hereafter referred to as "the Agency"), has
conducted a review of the published scientific literature and other relevant information
supporting the reregistration of the pesticide active ingredient silver. The conduct and
submission of commonly required generic toxicology and human exposure studies have been
waived by the Agency due to the availability of adequate published information.
This Reregistration Eligibility Document (RED) addresses the eligibility for reregistration
of products containing silver for currently registered uses. Pesticide products containing silver
are used as an algicide in swimming pool water systems and to inhibit the growth of bacteria
within the filter unit of water filter systems designed to remove objectionable taste, odor and
color from municipally treated tap water. The Agency has determined that the use of silver as
currently registered will not cause unreasonable risk to humans or the environment. The Agency
is requiring a special ecological effects study as confirmatory data and for purposes of labeling
to complete the generic data base.
Accordingly, the Agency has determined that all products containing elemental silver as
the active ingredient are eligible for reregistration and will be reregistered when acceptable
labeling and product specific data are submitted and/or cited. Before reregistering each product,
the Agency is requiring that product specific data be submitted by the registrants within eight
months of the issuance of this document. Additionally, in order to remain in compliance with
FIFRA, it is the Agency's position that revised labeling must be submitted by the registrants
within that same time period. After reviewing these data, including the ecological effects data
and the revised labels, the Agency will determine whether the conditions and requirements of
FIFRA 3(c)(5) have been met for the reregistration of these products.
IX
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I. INTRODUCTION
In 1988, the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) was amended
to accelerate the reregistration of products with active ingredients registered prior to November
1, 1984. The amended Act provides a schedule for the reregistration process to be completed
in nine years. There are five phases to the reregistration process. The first four phases of the
process focus on identification of data requirements to support the reregistration of an active
ingredient and the generation and submission of data to fulfill these requirements. The fifth
phase is a review by the U.S. Environmental Protection Agency (referred to as "the Agency')
of all data submitted to support reregistration.
FIFRA Section 4(g)(2)(A) states that in Phase 5 "the Administrator shall determine
whether pesticides containing such active ingredients are eligible for registration" before calling
in data on products and either reregistering products or taking "other appropriate regulatory
action." Thus, reregistration involves a thorough review of the scientific data base underlying
a pesticide's registration. The purpose of the Agency's review is to reassess the potential hazards
arising from the currently registered uses of the pesticide; to determine the need for additional
data on health and environmental effects; and to determine whether the pesticide meets the "no
unreasonable adverse effects" criterion of FIFRA.
This document presents the Agency's decision regarding the reregistration eligibility of
the registered uses of silver as of June 23, 1993. The document consists of eight sections.
Section I is the Executive Summary. Section n is the introduction. Section m describes silver,
its uses, data requirements and regulatory history. Section IV discusses the physical chemistry,
human health and environmental assessment based on the data available to the Agency. Section
V presents the reregistration decision for silver. Section VI discusses the eligibility decision for
silver. Section Vn discusses the reregistration requirements for silver. Finally, Section VI is the
Appendices which support this Reregistration Eligibility Document. Additional details concerning
the Agency's review of applicable data are available on request.1
reviews of data on the set of registered uses considered for EPA's analysis may be
obtained from the OPP Public Docket, Field Operations Division (H7506C), Office of Pesticide
Programs, EPA, Washington, DC 20460.
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CASE OVERVIEW
A. Chemical Overview
The following active ingredient is covered by this Reregistration Eligibility
Document:
• Common Name: Silver
• Chemical Name: Silver
• CAS Registry Number: 7440-22-4
• OFF Chemical Code: 072501
• Empirical Formula: Ag
B. Use Profile
The following is information on the currently registered uses with an overview
of use sites and application methods. A detailed table of these uses of Silver is in
Appendix A.
For Silver
Type of Pesticide: Bacteriostatic water filter, algicide (swimming pool water
systems)
Use Sites: AQUATIC NON-FOOD RESIDENTIAL:
Swimming Pool Water Systems
INDOOR FOOD:
Human Drinking Water Systems
Target Pests: Black and mustard algae; slime-forming algae (swimming
pool water systems); potable water bacteria (human
drinking water systems)
Formulation Types Registered:
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TYPE: End use, Manufacturing use
FORM: Impregnated material, Granular, Soluble liquid
concentrate (swimming pool water systems)
Method and Rates of Application:
Types of Treatment -
Bacteriostatic filter treatment, Water treatment (swimming
pool water systems)
Equipment - Bacteriostatic filter unit, Bacteriostatic filter media,
Bacteriostatic filter cartridge, Skimmer basket (swimming
pool water systems)
TjmJag - Initial, Subsequent/maintenance, Winterizing, When needed
(human drinking water systems)
Rate of Application -
Human Printing Water Systems:
From 160 up to 17,100 ppm active ingredient by weight
Swimming Pool Water Systems:
0.1 ppm active ingredient by weight
Use Practices Limitations:
Generally for use with cold water only (human drinking
water systems)
C. Estimated Usage Of Pesticide
Industrially, silver is used in photographic processing, mirror production, dental
alloys, coinage, the manufacture of tableware and jewelry, electroplating, the
manufacture of inks and dyes, solder, brazing alloys, and high capacity silver-zinc and
silver-cadmium batteries, the processing of food and beverages, and the etching of ivory.
As therapeutic agents, silver salts are used for their local actions: the nitrate in the
treatment of warts (caustic effect), and the nitrate and insoluble silver compounds (e.g.,
silver sulfadiazine) for prevention of infection associated with extensive burns. Silver
nitrate 1 % opthalmic solution is still used for prophylaxis against ophthalmia neonatorum.
Colloidal silver preparations have been used in the past to treat syphilis, but this use has
been totally supplanted by antibiotics. Silver acetate is used in anti-smoking remedies.
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As a pesticide, silver is registered for use as a microbiocide (algicide) primarily
used with respect to two use groups (sites): Aquatic Non-Food Residential (swimming
pool systems) and Indoor Food (human drinking water systems).
D. Regulatory History
Silver was first registered as a pesticide in the United States in December of 1954
for use in disinfectants, sanitizers, and fungicides. Many regulations and guidelines have
been issued over the following years on silver. In 1980 the Agency's Office of Water
Regulations and Standards (OWRS) established a guideline for silver of 0.05 mg/L for
ambient water quality criteria to protect human health ingesting water and organisms (45
Fed. Rep. 79318, November 28, 1980). These criterion were promulgated for several
states under the National Toxics Rule in December of 1992 (57 Fed. Rep. 60848.
December 22, 1992). In 1985 the Agency's Office of Water (OW) established a
guideline recommending drinking water limits for silver at 0.05 mg/L. In 1987 Agency
OW established a mairimnm contaminant level (MCL) for silver in drinking water of 0.05
mg/L (40 CFR 141) and a proposed drinking water secondary maximum contaminant
level (SMCL) of 0.09 mg/L in 1989. The Agency announced the deletion of the 50 pg/L
MCL for silver on January 30, 1991 (56 Fed. Rep. 3573) and replaced the MCL with
a secondary manmnm contaminant level of 100 /ig/L, based on the fact that silver causes
argyria (a cosmetic effect resulting from the formation of silver complexes in the
subepithelial portions of the skin resulting in a characteristic bluish pigmentation) (56
Fed. Reg. 3526, January 30,1991). A SMCL is non-enforceable but is a limit for a
contaminant which may affect the aesthetic qualitites (e.g., taste and color) of drinking
water. In 1988, the U.S. Food and Drug Administration established a regulation
establishing the permissible levels of silver in bottled water at 0.05 mg/L (21 CFR
103.35).
In 1988 the Agency (OW) classified silver as a Group D carcinogen - not
classifiable as to human carcinogenicity, based on inadequate evidence of carcinogenicity
in animal studies and the lack of carcinogenic evidence in human!;. The classification
was verified by the Agency's Carcinogenic Risk Assessment Verification Endeavor
(CRAVE) work group (09/22/88). An oral RfD was established for silver at 0.005
mg/kg/day. The RfD was verified by the Agency RfD Work Group (07/18/91).
Under Phase 4 of the reregistration program, a comprehensive Data Call-in (DCI)
was issued in September of 1992 for Silver requiring additional product chemistry and
toxicity data.
Currently, there are approximately 80 pesticide products registered for uses of
silver. Approximately 90% of the registered products are for bacteriostatic water filters
that contain silver. A small percentage (7%) of the registered products are media which
contain silver for actual filter housing and 3% of the products are used as algicides.
This Reregistration Eligibility Document reflects a reassessment of all available
technical data.
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SCIENCE ASSESSMENT
A. Physical Chemistry Assessment
1. Product Chemistry
Silver is a naturally occurring element which can be found as the native
metal or combined with other elements in distinct mineral phases. Its
physical chemistry properties are widely reported in the published
scientific literature. The physical and chemical characteristics of silver
are detailed below:
Chemical Name: Silver
Chemical Formula: Ag
Molecular Weight: 107.868
Color. Metallic
Physical State: Solid
Odor None
Melting Point: 960.5° C
Boiling Point: 2000° C
Density: 10.49 g/mL at 15° C
Solubility: Not soluble in water
Vapor Pressure: N/A
Dissociation Constant: N/A
Oct/Water Part. Coeff: N/A
pH: N/A
Stability: Stable to sunlight and metal/metal ions
The Agency has determined through the review of available data that
elemental silver jjeuse is not isolated during the manufacturing process,
nor is it used during the manufacturing process, and that the appropriate
data submitted to support the manufactured products (MP) and end use
products (EP) will satisfy the generic product chemistry data requirements.
2. Residue Chemistry
The nature of the residue in plants and animaly is not applicable, since
treated water is used solely for human consumption, and is not directly applied
to plants or consumed by livestock. Adequate analytical methodology is available
for the determination of silver ions in water; the most common approach is the
use of atomic absorption methods. Storage stability is not an issue for silver ions
in water, since analytical methods determine total silver residues.
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B. Human Health Assessment
1. Toxicology Assessment
The lexicological data base on silver is ad^'atf and will support
reregistration eligibility.
&. Human Toxicology
Silver can be absorbed from the lungs and the gastrointestinal tract.
The major route of excretion is via the gastrointestinal tract. Urinary
excretion has not been reported to occur, even after an intravenous (i.v.)
injection (Goyer, 1991).
The major effect of excessive absorption of silver is local or
generalize impregnation of tissues where the metal remains as silver
sulfite and forms an insoluble complex in elastic fibers. Large amounts
of this complex in the subepithelial portions of the skin will impart a
characteristic bluish pigmentation, a condition called argyria. Although
not a toxic effect, argyria is an undesirable cosmetic condition which is
usually permanent. Argyria has been known to occur during treatment of
syphilis with silver arsphenamine. The local form of argyria is
characterized by gray-blue patches of skin and/or conjunctiva!
pigmentation and the generalized form by widespread pigmentation of the
skin. In severe cases, the skin looks black, with a metallic luster, the
eyes may be so affected that vision may be impaired, and the respiratory
tract may also be affected (Goyer, 1991). In a human study of argyria
associated with the therapeutic use of silver arsphenamine, ten males (23-
64 years old) and two females (23 and 49 years old) who were
administered 31-100 intravenous injections of the silver salt (4-20 g) over
a 2-9.75 year period were shown to develop generalized argyria.
Although one patient showed the condition after only a total dose of 1 g,
the results of the study suggest that argyria may become clinically
apparent when the total accumulated intravenous dose has reached
approximately 8 g (Gaul and Staud, 1935). A LOEL was established at
1 g total intravenous dose, corresponding to an oral dose of 0.014
mg/kg/day, based on the incidence of argyria in one patient. Industrial
argyria is a known occupational condition for workers in primary metal
industries and industries using electrical machinery, equipment, and
supplies (U.S. DHHS # TP-90-24, 1990).
Excessive industrial and/or medicinal exposures to silver have been
associated with arteriosclerosis and lesions of the lungs and kidneys
(Goyer, 1991). Exposure to industrial dusts containing high levels of
silver nitrate and/or silver oxide may cause breathing problems, lung and
throat infections, and abdominal pain. Skin contact with certain silver
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compounds may cause mild allergic reactions such as a rash, swelling, and
inflammation in sensitive people (U.S. DHHS # TP-90-24, 1990).
b. Animal Toxicology
(1) Acute Toxichy
A single oral dose of 420 mg/kg of colloidal silver did not
cause any mortality in rats (Dequidt et al.. 1974). This would
place silver in acute oral toxicity category m. A single application
of silver nitrate (3 drops of a 0.66% solution; 42 ppm silver) into
the right eye of male Wistar rats resulted in silver deposits in the
cornea and conjunctiva. In addition, silver deposits were scattered
in the cells of the outermost part of the anterior cornea!
epithelium, and heavy deposits were found in Bowman's layer,
reticular fibers of the cornea! stroma, Descemet's membrane, and
the posterior cornea! epithelium. These effects were observed 45
days after treatment and were not accompanied by any other
adverse effects (Rungby, 1986). The following lexicological data
were obtained from acute toxicological studies with Sildate, an
end-use product containing 7.5 g powdered Sildate dispersed in
250 ml distill^ water.
ACUTE TOXICITY DATA WITH SILDATE
TEST
OralLDSO
inhalation LC50
in
Dermal LD50
Primary Eye irritation
Primary dermal irritation
Dermal Sensitization
RESULT
LD50 > 5000 mg/kg
N/A
LD50 > 2000 mg/kg
non-irritant
non-irritant
Not a sensitizer
CATEGORY
IV
N/A
m
IV
IV
N/A
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(2) Subchronic Toxicity
The influence of vitamin E and selenium on the toxicity of
silver was investigated in a series of two studies in young rats (21-
day old) of the Holtzman strain. In the first study, silver acetate
was added to the drinking water for 52 days at concentrations of
0, 76, or 751 mg/L. Silver was markedly toxic in rats (10/group)
when their diet contained no vitamin E and only 0.02 ppm
selenium. Growth depression occurred at 76 mg/L and severe
growth depression and death (4/10) at 751 mg/L. Hepatic
glutathione peroxidase activity was undetectable, but there was no
evidence of liver necrosis at necropsy. The toxicity of silver was
reduced when 0.5 ppm selenium was added to the above diet. No
growth depression was observed at 76 mg/L, and survival was
improved at 751 mg/L. Hepatic glutathione activity was,
however, still reduced to 5% of controls at 751 mg/L. In the
second study, silver acetate (751 mg/L; corresponding to 114.2 mg
silver/kg/day) was added to the drinking water for 15 weeks and
the diet contained both vitamin E (100 lU/kg) and selenium (0.5
ppm). The toxicity of silver was further alleviated. Body weight
was only decreased by 15%, but glutathione peroxidase activity
was still decreased in the liver to 5% of control levels. A LOEL
for the 15 week study was suggested at 114.2 mg silver/kg/day
(Wagner, 1975).
In a study in swine, four weanling swine were fed a diet
containing .adequate selenium and vitamin E and 0.5% silver
acetate (3,250 ppm silver, corresponding to 130 mg/kg/day) for 4
weeks. All experienced anorexia, diarrhea, and growth
depression. Three of the four pigs died. Hepatic lesions in all
four pigs were consistent with hepatosis dietetic*. No lesions were
observed when pigs (number unreported) were fed 0.2% silver
acetate (1,300 ppm silver, corresponding to 52 mg/kg/day).
Vitamin E (100 lU/kg diet) but not selenium (1 ppm)
supplementation in the diet (2 pigs/group) prevented development
of lesions and mortality. A NOEL was established at 52
mg/kg/day and a LOEL at 130 mg/kg/day based on the
signs/symptoms of toxicity observed (Van Vleet, 1976).
In a mice study (strain and number unreported), silver
nitrate was added to the drinking water at a concentration
equivalent to 65 mg/kg/day for 12 days to 14 weeks. No toxicity
was observed but silver deposits were observed in the basement
membrane of the kidneys at necropsy. A NOEL was established
8
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at 65 mg/kg/day (Day et al., 1976).
(3) Chronic toxicity
In a rat study, Sprague Dawley rats (number unrepoited)
were given silver nitrate in their drinking water at concentrations
of 6 mM (648 mg/L; equivalent to 65 mg/kg/day assuming a 200
g rat drinks 20 ml water/day) for only 12 weeks or 12 mM (1,296
mg/L; 130 mg/kg/day) for 4, 6, 8, 10, 12, 16, 25, or 60 weeks.
A NOEL was not established (although no toxicity was observed
at 65 mg/kg/day, this dose was administered for only 12 weeks).
The LOEL was established at 130 mg/kg/day, based on clinical
signs of poor grooming and listlessness and histology findings of
silver deposits within the glomerular basement membrane of the
kidneys (Walker, 1971).
The following are three related rat studies, conducted by
the same investigator
In the first study, rats were given silver nitrate in their
drinking water at a concentration equivalent to 63.5 mg/kg/day for
218 days (Olcott, 1948). No toxic effects were observed, but
intense silver pigmentation of many tissues was observed at
necropsy, including the basement membrane of the kidneys'
tubules, the portal vein and other parts of the liver, the choroid
plexus of the brain, the choroid layer of the eyes, and the thyroid
gland. A NOEL was established at 63.5 mg/kg/day (silver
deposition in tissues was apparently not considered an adverse
effect). -.
In the second study, 139 albino rats were given silver
nitrate in their drinking water at a concentration equivalent to 63.5
mg/kg/day for up to 553 days (Olcott, 1947). Examination of
their eyes at various time points showed the color changing from
normal to slightly gray after 218 days (stage 1), to more gray than
pink (stage 2) after 373 days, to dark/translucent (stage 3) after
447 days, and to opaque (stage 4) after 553 days. The total
cumulative amount of silver consumed at these respective stages
were 3.2 g, 5.7 g, 6.8 g, and 9.4 g. Histological observation of
the membrane of Bruch showed a few silver granules after 218
days and complete blackening by silver deposits after 553 days.
The study did not state whether silver deposition in the eye was
accompanied by any vision impairment. A NOEL was nonetheless
identified at 63.5 mg/kg/day.
In the third study, older rats (> 9-months old) were given
-------
silver nitrate in their drinking water at a concentration equivalent
to 63.5 mg/kg/day for an unstated duration (Olcott, 1950). The
treated rats showed an increase in the relative (to body) weight of
the left ventricle (left ventricular hypertrophy rate = 29% in
treated rats and 12% in control rats). The total number of rats
autopsied was 233. Although blood pressure was not measured, it
was postulated that the cardiac effect observed was caused by
hypertension, which was brought about by a thickening of the
basement membrane of the kidney glomeruli caused by deposits of
silver. Neither a NOEL or a LOEL were identified because the
duration of exposure was unspecified.
(4) Carcinogenichy
Although local sarcomas were shown to occur in animaiy
after implantation of foils and discs of silver, these findings were
considered as questionable caxcinogenicity evidence (i.e., they may
only reflect a phenomenon known as solid-state caicinogenesis,
whereby local fibiosaicomas could be induced even by insoluble
solids such as plastics) (Furst 1979, 1981). In a rat
carcinogenicity study designed to avoid solid-state carcinogenesis,
a suspension of silver powder in trioctanion was given once a
month by intramuscular (i.m.) injection to Fischer 344 rats
(50/sex/group). The dose given was 5 mg each for 5 treatments
and 10 mg each for 5 more treatments, for a total of 75 mg of
silver. An inert material was used as the vehicle control, and
cadmium was used as a positive control. No fibrosaicomas (0/50)
appeared at the injection site in silver-treated animals. Injection
site sarcomas were found only in the vehicle-control (1/50) and
cadmium-treated (30/50) rats. The latent period in the vehicle-
control group was 19 months, and the latent period in the
cadmium-treated group was as short as 4 months. The authors
concluded that finely divided silver powder injected i.m. did not
induce cancer (Furst and Schlauder, 1977).
In another carcinogenicity study in rats, colloidal silver
(dose unspecified) injected subcutaneously resulted in tumors in 8
of 26 rats surviving more than 14 months. In 6/8 rats, the tumor
was at the subcutaneous injection site. In 700 untreated rats, the
rate of spontaneous tumor formation was 1 to 3%; no vehicle
control was reported (Schmaehl and Steinhoff, 1960).
The Agency has classified silver as a Group D carcinogen -
not classifiable as to human carcinogenicity, based on inadequate
carcinogenic evidence in animal studies and the lack of
carcinogenic evidence in humans (IRIS, 9/1/92).
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(5) Developmental Toricity
In a post-natal study in rats, Wistar rat pups from two
litters were given subcutaneous injections of silver lactate
monohydrate: two pups from each litter received daily injections
of 0.10, 0.20, or 0.35 mg during post-natal weeks 1, 2, or 3 to 4,
respectively. The only effect reported was that hippocampal
tissues from the treated pups contained significantly (p < 0.05)
smaller pyramidal cells. The authors speculated that the findings
suggest toxicity and that the hippocampus is a selective site for
silver neurotoxicity (Rungby etal. , 1987).
(6) Mutagenicity
Silver was not mutagenic in several bacterial systems.
Concentrations of silver nitrate from 5 x 10* to 1 x 10*% were
not mutagenic in E. coli in the absence of metabolic activation
(Demerec 3_aL, 1951). The end-point was a reversion to
streptomycin independence. Silver nitrate, at 0.1 /tM, was not
directly mutagenic in E. coli WP2 and did not influence the
mutagenic effect of ultraviolt irradiation on E. coli WP2 (Rossman
and Molina, 1986). Silver chloride, at 0.05 M, was not mutagenic
to B. sqbtijjs. in the absence of metabolic activation (Nishioka,
1975).
(7) Metabolism
Very little absorption occurred in rats administered carrier-
free radioactive silver (<1 fig; 1 /iCi) by stomach tube.
Approximately 99% and 0.18% of the original dose were
eliminated in the feces and urine, respectively, within 4 days after
dosing. Total tissue distribution amounted to 0.835% of the
administered dose (Scott and Hamilton, 1950).
Radiolabeled silver nitrate was administered by oral and
i.v. routes to female RF mice (0.25 pCi, oral; 0.25 to 0.26 pCi,
i.v.), male Sprague-Dawley rats (0.5 pCi via either route), beagle
dogs (0.6 fiCi oral, 0.4 pCi, i.v.), and Macacca mulatta monkeys
(0.6 /iCi via either route). In aU species, cumulative excretion
ranged between 90 and 99% within 2 days of oral ingestion. The
extent of absorption was found to be directly proportional to the
transit time through the gut in these species (Furchner etal.. 1966
and 1968). About 90 to 99% of the silver administered orally as
(silver nitrate) to male Sprague-Dawley rats, female beagle dogs,
and Macacca mulatta monkeys was eliminated in the feces; small
amounts were eliminated in the urine (Furchner etal.. 1968). A
11
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similar elimination pattern was detected in cats after i.v.
administration of silver (Gregus and Klaassen, 1986; Scott and
Hamilton, 1950). Most of the radioactivity found in the feces was
eliminated via the bile (Tichy et al.. 1986; Gregus and Klaassen,
1986; Klaassen, 1979). A marked variation in biliary excretion
was observed in different species administered silver as silver
nitrate in a single i.v. injection at 0.1 mg/kg of silver over a 2-
hour period (Klaassen, 1979). Thirty minutes after treatment,
male Sprague-Dawley cats excreted silver into the bile at a rate of
0.2S pg/min/kg, New Zealand White male rabbits excreted 0.05
/tg/min/kg, and mongrel male dogs excreted 0.005 /ig/min/kg.
The concentration of silver in the plasma was markedly lower in
the dog than in the rat or rabbit, indicating a larger volume of
distribution in the dog. This variation appears to be attributable
to differences in the transfer of silver from liver to bile. The
species with the lowest biliary excretion rate (dog) had the highest
liver concentration of silver (rat = 1.24, rabbit = 2.13 and dog
— 2.9 fig silver/g liver). In all species, the concentration of silver
in the bile was greater than that in plasma with no observable dose
gradient, thereby indicating an active transport process and a
saturl
(8) Secondary Maximum Contaminant Level (SMCL)
The Agency initially regulated silver with a Maximum
Contaminant Level (MCL) of 50 /ig/L drinking water. In 1991,
the Agency replaced the MCL with a Secondary Maximum
Contaminant Level (SMCL) of 100 pg/L, based on the fact that
silver causes argyiia, only a cosmetic effect (FR Notice dated
01/30/91). SMCL are non-enforceable and establish limits for
contaminants which may affect the aesthetic qualities (e.g. taste
and color) of drinking water (DOS, 09/01/92). It is recommended
that systems monitor for these contaminants every three years
(IRIS, 09/01/92).
(9) Reference Dose (RfD)
An oral RfD was established for silver at 0.005 mg/kg/day
(IRIS, 09/01/92). The RfD was based on the Gaul and Staud 2-9
year human i.v. 1935 study, with an oral LOEL of 0.014
mg/kg/day, and an uncertainty factor of 3 to account for minimal
effects in a subpopulation which exhibited an increased propensity
for development of argyiia. A conversion factor was used to
convert i.v. to oral doses (each i.v. dose of 1 g is divided by 0.04,
an assumed oral retention factor). No uncertainty factor for less-
than-chronic to chronic duration was needed since the dose has
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been apportioned over a lifetime of 70 years. The RfD has been
verified (07/18/91) by the Agency (IRIS, 09/01/92).
2. Exposure Assessment
a. Dietary Exposure
Currently, silver is neither registered for application to food or
feed crops nor is it registered for use on processed commodities. The
only current dietary exposure is from the use of silver as a bacteriocide
for use in human drinking water systems. The swimming pool uses of
silver would not be expected to be associated with any significant dietary
exposure; the SMCL of 0.1 mg/L drinking water established by the
Agency's Office of Water is not expected to be exceeded following typical
use of filters containing silver.
b. Occupational and Residential
Occupational exposure can be expected based on the currently
registered uses of this chemical. Silver, formulated as a granular,
impregnated material or soluble liquid concentrate, is used as an algicide
or as part of a bacteriostatic water filter in swimming pool wataer systems
and human drinking watear systems. The potential for
mixer/loader/applicator exposure exists for individuals handling silver
solutions or silver-impregnated filter material^. Based on the application
methods (specified and implied) and the formulation types, the potential
for eye, inhalation^ and dermal exposure to concentrated solutions or dusts
for mixers, loaders and applicators exists.
Filtering media are impregnated with concentrations ranging from
0.026% a.i. to 1.05% a.i. Soluble liquid concentrates are used for
treatment in swimming pools. Typical application rates are 8 fluid ounces
per 10 minute interval with a maximum of 48 fluid ounces being utilized
for winterizing pools. These treatments are applied through the pool
skimmer basket. With ready-to-use solutions, the potential for exposusre
exists for inadvertent splashes to the eye; however, silver is not readily
transported across the skin. Handling of silver-impregnated filters may
frsult in short-term exposure to minute quantities of silver-containing
charcoal. In general, filters containing 1.05 % a.i. or less are replaced one
or two times per year depending upon the use rate and rated filter
capacity.
Silver concentrations in water depend upon pH and chloride
concentration. Maximum silver concentrations in water are expected to
be less than 10 mg/L (10 ppm). Water treatments would result in less
than 0.6 ppm (0.6 mg/L) silver present in pool water (0.8% a.i. used).
13
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Presence of silver in potable water is not uncommon; median
concentrations of silver present in public water supplies of 100 U.S. cities
was reported to average 2.68 /tg/L (2.68 ppb). The Agency's Office of
Water estimates that a concentration of silver in water of 100 pg/L or 0.1
mg/L will not produce darkening of the sMn and other cosmetic effects
associated with argyria.
The overall exposure from silver from human drinking water
systems and swimming pool systems is not expected to result in adverse
effects.
3. Risk Assessment
a. Dietary
Silver is a naturally occurring element and trace amounts are
expected to be present in the human diet. It is not anticipated that tow
levels of exposure to silver such as those normally consumed from water
filtered with filtering systems containing silver would be associated with
any significant degree of risk or result in the build-up of silver in the body
to an argyria compatible level.
The data available on the lexicological effects of silver in humans
and laboratory animals are sufficient for assessing human risks. The acute
toxicity of silver is relatively tow by the oral route (Toxicity Category
HI). The end-product Sildate has low acute oral and dermal toxicity
(Toxicity Categories IV and m), is not inhalable, not a eye or dermal
irritant (Toxicity Category IV), and not a dermal sensitizer. Silver is not
known to have human carcinogenic potential and does not appear to be a
mutagen. Although long term ingestion of silver may be associated with
argyria in humans and animals, this effect is considered cosmetic, not
adverse.
b. Occupational and Residential
The overall human and animal toxicology data on silver indicate
that this pesticide does not meet any Agency toxicity criteria that would
trigger the requirements for occupational or residential exposure data.
Based upon the available use data, the use of the chemical as a water
treatment for pools is of little concern from a toxicity perspective. For
the above reasons, it is not expected that use consistent with the product
label of silver-impregnated filters or the treatment of pool water with
silver-containing compound would constitute an unreasonable risk.
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C. Environmental Assessment
1. Environmental Fate
Because of the available data base on silver chemistry, most standard
environmental fate data requirements were waived. The environmental chemistry
section presented here is based on numerous literature sources that are cited
below.
a. Environmental Chemistry - Fate and Transport
Although silver occurs as native metal, it also occurs as distinct
mineral phases (mostly as sulfide minerals in complex ores) from where
it is mined, processed (primarily by froth flotation) and then refined
(Reese, 1985). The relative abundance of silver in the earth's crust is
about 0.08 ppm ( Greenwood and Earnshaw, 1984).
Silver is the metal with the highest thermal and electrical
conductivity (Cotton and Wilkinson, 1988; Greenwood and Earnshaw,
1984). Although silver is, in general, not prone to ordinary oxidation and
is resistant to corrosion by weak acids, the presence of sulfur-containing
gases in the atmosphere and of sulfide ions in waters can tarnish the
surface of silver (Murr, 1975; Pourbaix, 1974; Shumilova and Zhutaeva,
1978; Zhutaeva and Shumilova, 1985). Strong, concentrated oxidizing
acid solutions can dissolve silver, producing silver(I) species in solution;
in alkaline solutions, silver is generally stable (Pourbaix, 1974). Silver(I)
forms soluble complexes with halide anions and with cyanide (Cotton and
Wilkinson, 1988; Greenwood and Earnshaw, 1984; Irgolic and Martell,
1985). Chloride and bromide ions can react with surface silver oxides to
form complexes that are more soluble than the oxides (Buffle, 1990;
Pourbaix, 1974).
The oxidation states of I, n and m have been identified in silver
compounds, but in aqueous media the only oxidation state is silver(I)
(Cotton and Wilkinson, 1988; Shumilova and Zhutaeva, 1978). The extent
of oxidation (corrosion) of silver metal in aqueous environments is thus
determined by the pH, the redox potential and the temperature of the
media (Morel, 1983; Murr, 1975; Pourbaix, 1974; Stumm, 1992). The
type and concentration of soluble silver(I) that can form in aqueous media
are determined by the nature and concentration of complexing anions
present in the media; formation of insoluble phases (such as silver
sulfides) are also determined by the chemical characteristics of the
aqueous media (Buffle, 1990; Irgolic and Martell, 1985; Morel, 1983;
Stumm, 1992).
SilverOQ can readily react with sulfide ions and organic materials
15
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bearing thiol groups. Silver sulfides are insoluble and in sulfide-rich
natural waters the formation of insoluble sulfides serves to immobilize
silver (Morel, 1983). Thiol groups in aquatic sediments also contribute to
the removal of silver(I) from the aqueous phase (Morel, 1983). However,
in recent years it has been speculated that the transport and re-deposition
of silver in the environment may involve formation of polysulfido silver
species (Morel, 1983; Muller and Krebs, 1984).
The germicidal properties of silver metal and silver compounds
(such as oxides and salts) have long been recognized. The lethal effect of
silver towards bacteria and lower life forms, the so-called "oligodynamic
effect" is high and second to that of copper. The term "oligodynamic
activity" is restricted to solutions in which the metal ion concentration is
many orders of magnitude below what would be lethal to higher order
organisms (Thompson, 1973). Silver-resistant bacteria have been found in
urban and industrial polluted sites (Irgolic and Martell, 198S; Silver,
1983; Silver, fiLaL, 1992). It is believed that the resistance to silver is
determined by genes in plasmids. The lowered affinity of the cells for
silverQQ is related to the tendency of silver(I) to be more effectively
completed with extracellular halides, thiols, or organic compounds
(Silver, 1983; Silver etal.. 1982).
b. Environmental Fate Assessment
Silver from products used for swimming pool and human drinking
water systems is discharged into the municipal wastewater effluent and
treated in municipal water treatment plants. In these sewage treatment
plants, microorganisms convert silver(I) salts to insoluble silver sulfides
and some metallic silver which are removed in the settling step.
Products containing silver are not to be applied in marine/estuarine
environments or oil fields. Discharge of silver-containing effluents into
lakes, streams, 'ponds estuaries, oceans or other waters are subject to
National Pollutant Discharge Elimination System (NPDES) permit
restrictions. In addition, waters treated with silver as a pesticide cannot be
discharged into sewage systems without notifying the sewage plant
authority. (See Sections IV.B.2., V.B.2. on Labeling.)
2. Ecological Effects
a. Ecological Effects Data
(1) Terrestrial Data
There are no avian toxicity data available. In the
reregistration DCI of September 1992, avian studies on one species
16
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of upland gamebiid and/or waterfowl were required using the
formulated product (due to variations in complexes formed by pure
silver as the technical grade active ingredient). Hie risk to birds
will be assessed after the data are submitted and reviewed.
However, exposure to birds is expected to be low from the
pesticidal uses of silver. These studies were required for labeling
statements only.
(2) Aquatic Data - Freshwater Fish, Freshwater
Invertebrates & Estuarine Organisms
The acute LCW for freshwater fish ranges from 3.9 to 280
pg/L (ppb). The average toxicity values were 51.4 ftg/L for
Rainbow trout (Oncorhynchus mykiss1r 36.25 /ig/L for Fathead
minnow (Pimphales promelasi and 44.0 jig/L overall
The acute ECM range for freshwater invertebrates ranges
from 0.25 to 4500 pg/L (ppb). The average toxicity value for
Dapftnia magna was 9.21 /ig/L.
The acute toxicity values for marine/estuarine fish ranged
from 4.7 for Summer flounder (Pfriflljjtfhys dentatus) to 1400 ftg/L
for the Sheepshead minnow (Cyprinodon variegatus^ with an
average of 494.12 /tg/L.
The values for marine/estuarine invertebrates ranged from
5.8 for the Eastern oyster (Crassostrea virpnical to 250 /ig/L for
the Mysid shrimp (Mysidopsis bahia^ with an average of 54.6
These results presented above are sufficient to indicate that
silver is very highly toxic to highly toxic to fish and invertebrates.
No further studies with freshwater fish, freshwater invertebrates,
or estuarine organisms are required for the currently proposed uses
of silver. Neither chronic nor degradate testing is required for the
currently proposed uses of silver.
b. Ecological Effects Risk Assessment
Based on the available acute toxicity data, silver is highly toxic to
fish and aquatic invertebrates. However, silver from products used for
swimming pool anj human drinking water systems is discharged into the
municipal wastewater effluent and treated in municipal water treatment
plants and is, therefore, regulated under NPDES permits. Little exposure
to fish and aquatic invertebrates is expected from these uses. The Agency
does not expect unreasonable adverse effects from these uses.
17
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A risk assessment for birds will be conducted after the required
avian studies are submitted and reviewed. The Agency will use the data
to provide avian labeling statements.
IV. RISK MANAGEMENT AND REREGISTRATION DECISION
A. Determination of Eligibility
Section 4(g)(2)(A) of FIFRA calls for the Agency to determine, after submission
of relevant data concerning an active ingredient, whether products containing the active
ingredient are eligible for reregistration. The Agency has previously identified and
required the submission of the generic (i.e. active ingredient specific) data required to
support reregistration of products containing silver. The Agency has completed its
review of these generic data, and has determined that the data are sufficient to support
reregistration of all products containing silver. Appendix B identifies the generic data
requirements that the Agency considered in its determination of reregistration eligibility
of silver, and lists the submitted studies that the Agency found acceptable for these
requirements.
The data identified in Appendix B are sufficient to allow the Agency to assess the
registered uses of silver and to determine that silver can be used as currently registered
without resulting in unreasonable adverse effects to man and the environment. The
Agency therefore finds that all products containing silver registered as of June 23,1993
as the active ingredients are eligible for reregistration. The reregistration of particular
products is addressed in Section V of this document.
The Agency makes its reregistration eligibility determination based upon the target
data base required for reregistration, the current guidelines for conducting acceptable
studies to generate such data and the data identified in Appendix B. Although the
Agency finds that all uses of silver registered as of June 23, 1993 are eligible for
reregistration, it should be understood that the Agency may take appropriate regulatory
action, and/or require the further submission of additional data to support the registration
of products containing silver, if new information comes to the Agency's attention or if
the data requirements for reregistration (or the guidelines for generating such data)
change.
1. Eligibility Decision
Based on a sufficiently complete database for silver and a determination
that unreasonable adverse effects are unlikely from the uses of the current
products, the Agency concludes that products containing silver for all uses
registered as of June 23, 1993 are eligible for reregistration.
2. Eligible and Ineligible Uses
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The Agency has determined that all uses of products registered as of June
23, 1993 of silver are eligible for reregistration, subject to the label and use
specifications of this document.
B. Regulatory Position
The following is a summary of the regulatory positions and rationales for silver.
Where labeling revisions are needed, specific language is set forth in Section V of this
document.
1. Tolerance Rf
There are no proposed or established U.S. EPA, CODEX (international),
Canadian or Mexican tolerances for silver nor exemptions from the requirements
of a tolerance. Therefore, there are no harmonization issues to be resolved.
The Agency ann^m^d the deletion of the SO pg/L MCL
contaminant level) for silver on January 30, 1991 (56 Fed. Reg. 3S73). Instead,
a SMCL (secondary mamnnnn contaminant level) of 100 ppb (0.1 mg/1) was
established by the Agency (OW) in the same Federal Register notice, based on
the skin cosmetic effect called argyria.
2. Labeling Rationale
In order to remain in compliance with FIFRA, it is the Agency's position
that the labeling of all registered pesticide products containing silver must comply
with the Agency's current pesticide labeling requirements. The Agency has
determined that the current end-use label precautions are still appropriate and are
required for product reregistration. Because the swimming pool water systeam
pesticide uses of silver are regulated by an NPDES permit, it is the Agency's
position that label precautions must continue to include the NPDES permit
required language.
Based on the submitted data, it is the Agency's position that a label
statement indicating that silver is "toxic to fish and aquatic invertebrates" must
be included on all registered products containing silver in order to remain in
compliance with FIFRA.
V. ACTIONS REQUIRED BY REGISTRANTS
This section specifies the data requirements and responses necessary for the reregistration
of both manufacturing-use and end-use products.
A. Manufacturing-Use Products
1. Additional Generic Data Requirements
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The generic data base supporting the leregistration of silver for the above
eligible uses has been reviewed and determined to be substantially complete. No
additional data are required on these products at this time.
2. Labeling Specifications for Manufacturing-Use Products
In order to remain in compliance with FIFRA, it is the Agency's position
that the following statement must be included on all products whose use requires
an NPDES permit:
"Do not discharge effluent containing this product into lakes, streams,
ponds, estuaries, oceans or other waters unless in accordance with the
requirements of a National Pollutant Discharge Elimination System
(NPDES) permit and the permittting authority has been notified in writing
prior to discharge. Do not discharge effluent containing this product to
sewer systems without previously notifying the local sewage treatment
plant authority. For guidance contact your State Water Board or Regional
Office of the EPA."
This statement must appear in the Environmental Hazards section of the
label and be in addition to any other required statements.
Registrants should make the changes specified above and submit revised
labels to the Agency via notification in accordance with PR Notice 88-6 or refer
to 40 CFR § 152.46(a)(l). In order to be in compliance with FIFRA, all
products distributed or sold by registrants and distributors (supplemental
registrants) after July 1. 1995 must bear labeling which is consistent with this
notice. All products distributed or sold by persons other than registrants or
supplemental registrants after July 1.1997 must bear labeling which is consistent
with these notices. After these dates, the Agency may either issue a Notice of
Intent to Cancel a product or bring enforcement action against products bearing
false or misleading claims covered by this notice.
In order to remain in compliance with FIFRA, the following label
statement must appear in the Environmental Hazards section of the label on all
manufacturing-use products.
"This pesticide is toxic to fish and aquatic invertebrates."
In order to remain in compliance with FIFRA, the following label
statement must appear on the label on all manufacturing-use products intended for
use for human drinking water systems:
"Use with cold water only."
In order to remain in compliance with FIFRA, the labels and labeling of
20
-------
all products must comply with EPA's current regulations and requirements as
specified in 40 CFR §156.10. All label amendments must be submitted to the
Agency within 8 months from issuance of the product specific data call-in. Please
follow the instructions in the Pesticide Registration Handbook with respect to
labels and labeling.
The Agency has determined that the current label precautions are still
applicable and are required for product reiegistxation if the product is to remain
in compliance with FIFRA.
B. End-Use Products
1. Additional Product-Specific Data Requirements
Section 4(g)(2)(B) of FIFRA calls for the Agency to obtain any needed
product-specific data regarding the pesticide after a determination of eligibility has
been made. The product specific data requirements are listed in Appendix G, the
Product Specific Data Call-In Notice.
The registrants must clarify the nature of the "soluble liquid/concentrate"
used in swimming pools, due to concerns over the potential formation of water
soluble or colloidal species that may be ingested by swimmers. A new
Confidential Statement of Formula (CSF) must be submitted Hailing the nature
of the "soluble liquid/concentrate".
Ecological effects studies on one species of upland gamebird and/or water
fowl as required in the September 1992 DCI are due to the Agency shortly. Both
tests are being conducted using the formulated product (due to variations in
complexes formed by pure silver as the technical grade active ingredient). The
risk to birds will be assessed after the data are submitted and reviewed.
However, exposure to birds from the pesticide uses of silver is expected to be
low. These data were required for labeling statements only.
Registrants must review previous data submissions to ensure that they meet
current EPA acceptance criteria (Appendix G; Attachment E) and if not, commit
to conduct new studies. If a registrant believes that previously submitted data
meet current testing standards, then study MRID numbers should be cited
according to the instructions in the Requirement Status and Registrants Response
Form provided for each product.
2. Labeling Specifications for End-Use Products
In order to remain in compliance with FIFRA, it is the Agency's position
that the following statement must be included on all products whose use requires
an NPDES permit:
21
-------
"Do not discharge effluent containing this product into lakes, streams,
ponds, estuaries, oceans or other waters unless in accordance with the
requirements of a National Pollutant Discharge Elimination System
(NPDES) permit and the permittting authority has been notified in writing
prior to discharge. Do not discharge effluent containing this product to
sewer systems without previously notifying the local sewage treatment
plant authority. For guidance contact your State Water Board or Regional
Office of the EPA."
This statement must appear in the Environmental Hazards section of the
label 9nd be in addition to any other required statfmfnts
Registrants should make the changes specified above and submit revised
labels to the Agency via notification in accordance with PR Notice 88-6 or refer
to 40 CFR § 152.46(a)(l). In order to be in compliance with FIFRA, all
products distributed or sold by registrants and distributors (supplemental
registrants) after July 1. 1995 must bear labeling which is consistent with this
notice. All products distributed or sold by persons other than registrants or
supplemental registrants after July 1.1997 must bear labeling which is consistent
with these notices. After these dates, the Agency may either issue a Notice of
Intent to Cancel a product or bring enforcement action against products bearing
false or misleading claims covered by thfc notice.
In order to remain in compliance with FIFRA, the following label
statement must appear in the Environmental Hazards section of the label on all
end-use products intend^ for use in swimming pool water systems:
"This pesticide is toxic to fish and aquatic invertebrates."
In order to remain in compliance with FIFRA, the following label
statement must appear in the directions for use section of the label on all end-use
products intended for use for human drinking water systems:
"Use with cold water only."
1. "This product inhibits the growth of bacteria in the filter to
prolong the life of the filter."
2. "This product is designed to remove objectional tastes, odors, and
color from municipally treated tap water."
22
-------
In order to remain in compliance with FIFRA, the labels and labeling of
all products must comply with EPA's current regulations and requirements as
specified in 40 CFR §156.10. All label amendments must be submitted to the
Agency within 8 months from issuance of the product specific data call-in. Please
follow the instructions in the Pesticide Reregistration Handbook with respect to
labels and labeling.
The Agency has determined that the current label precautions are still
applicable and are required for product reregistration if the product is to remain
in compliance with FIFRA.
23
-------
VI. APPENDICES
24
-------
JulyS. 1993
•M*
mai
im-4
MMM
tan
MMM
•in-1
MMM
48B6-2
10324-18
4BSS-2
10324-18
APPENDIX A - Case 4082. [Silver, and Compounds] Chemical 072501 [Sliver]
Apploatbn Applntton Appfcotfen Surfm
Type Ttnho Equbmnt Typ*
Pomi
MbwniaTii
AppfcMion
Rite
tamaJLI
a\Aab^«*^M
HfaJOTPmi
Apportion
Rate
(ppm..l.|
Max.f
Appt.
Mn.ff
Appi.»
MoLRot*
U8E8 ELOQIBLE FOR RE RE G 1 STRATI ON
MMn> WntWW
BatwMnAppi.
OMn.Rat*
(D.y.1
nMtrtOnQ
Ertiy
Mwvd
GHgnpMo
I ft^^bt^^KA
unmioiw
ABowtd
Dhilhwid
Un LMlatkm
FOOD/FEED USES
Site: Human DrMdnQ Watar System* (UM Group: INDOOR FOOD)
baotariottatio fitter treatment, when
needed, bacterloetatio filter unit. NA
baotariottatio filter treatment, when
needed, baoterlottatio filter oartridga,
NA
baotariottatio filter treatment, when
needed, baeterloetatio filter media. NA
watar purifier filter, NA
Impr
Impr
Impr
Impr
160W
160W
260 W
260 W
17,100 W
17,100 W
2.000 W
260 W
NON-FOOD/NON-fEED USES
NS
NS
NS
NS
NS
NS
NS
NS
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
She! Swlmmlna Peel Watar SyatMiw (Uee Group: AQUATIC NON-FOOD RESIDENTIAU
water treatment. Initial, aklmmer baeket,
NA
water treatment,
eubaequantAnaintenanee, •klmmer
baeket NA
sen.
sen.
0.1 W
0.1 W
0.1 W
0.1 W
NS
NS
NS
NS
NA
NA
NA
NA
NA
NA
NA
NA
ObMMeW^B* •^^Iwk fVk OMHft
rivvmn oa>aTii> uo not
fliMnMQi) •ffluwit oontMnbiQ
«M§pHdoU(Meww«a*
MJtnoflty. Do nov fltoonaVQv
•ffhwil Cdita»iJnj thb
preduot Into WOM, wtntntt,
pOfftOBf ••tUHIDCf OOMMW* Of
j.j- »• »
mimmoni>
PraohmeUn. Do not
thb pMlMdi hie Mwiga
oyotonw wltnotii notnyfeiy vno
•uthotlty. Do not dbohoFpjo
offluont oontoWnfl tHo
pvoouot btto fewBO, otroonM^
ponoo* ootUaVteO( oo0omf of
puUo water (NPOES hanM
^•^ »-4>B«|__l
ivsnnmvmij.
25
-------
_*
4858-2
10324-18
APPENDIX A - Case 4082, [Silver, and Compounds] Chemical 072501 [Stiver)
Apptallon AppftMUon Apotmttai Bufee*
Typ» Ttahg Equtommt Typ*
Fonn
Apportion
Rat*
(pome.L)
USES ELIGIBLE FOR REREGI8 TR ATI ON
water treetmeirt. winterizing, ekimmer
basket NA
sen.
0.1 W
Apportion
KM*
Enby
m,,,, _, •
•rmnni
QwgnDhb
IMMhm.
AlbVMd
MiilaxiJ
NA
NA
NA
NA
UMlMMbni
PnelMneMn. Do not
•yttonv wHlHNat notify ng tho
•^IMaMH^ •^•^a^BA^* ^e^^al
••9VTBBSJ nenmvin |Mani
•fflwnleontaMhglhli
pubh tratar (NPDCS IOMM
Abbreviations uaed
Header:
FOfffVK
Rote:
In general:
ppm aJ. • parts per minion of active ingredient: Max. I Appt. - maximum number of applleattora
Max. f Appe. 0 Max. Rate • maximum number of appHcattona at maximum rate
Mn. Interval Between Appe. 9 Max. Rete (Day*) - minimum interval between epplloatlone at maximum rate (In daye)
SC/L • Soluble Conoentrate/UqukI; Impr - Impregnated Material
W - oeloulated by weight
NOL - not on the label; NA - not applicable; NS - not specified
26
-------
APPENDIX B
Table of The Generic Data Requirements and
Studies Used to Make the Reregistration Decision
27
-------
GUIDE TO APPENDIX B
Appendix B contains listings of data requirements which support the reregistration for the
silver covered by this Reregistration Eligibility document. It contains generic data requirements
that apply to silver in all products, including data requirements for which a "typical formulation"
is the test substance.
The data table is organized in the following format:
1. Data Requirement (Column 1). The data requirements are listed in the order in which
they appear in 40 CFR Part 158. the reference numbers accompanying each test refer to the test
protocols set in the Pesticide assessment Guidelines, which are available from the National
Technical Information Service, 5285 Port Royal Road, Springfield, VA 22161 (703) 487-4650.
2. Use Pattern (Column 2). This column indicates the use patterns for which the data
requirements apply. The following letter designations are used for the given use patterns:
A Terrestrial food
B Terrestrial feed
C Terrestrial non-food
D Aquatic food
E Aquatic non-food outdoor
F Aquatic non-food industrial
G Aquatic non-food residential
H Greenhouse food
I Greenhouse non-food
J Forestry
K Residential
L Indoor food
M Indoor non-food
N Indoor medical.
O Indoor residential
3. Bibliographic citation (Column 3). If the Agency has acceptable data in its files, this
column lists the identifying number of each study. This normally is the Master Record
Identification (MRTO) number, but may be a "GS" number if no MRID number has been
assigned. Refer to the Bibliography appendix for a complete citation of the study.
28
-------
SILVER
GUIDELINE GUIDELINE NAME
§158.120 Product Chemistry
USE BIBLIOGRAPHIC
SITES CITATION
61-1
61-2(a)
61-2(b)
62-1
62-2
62-3
63-2
63-3
63-4
63-5
63-6
63-7
63-8
63-10
63-12
63-13
Chemical Identity
Beginning Materials and Manufacturing Process
Formulation of Impurities
Preliminary Analysis
Certification of Limits
Analytical Methods
Color
Physical State
Odor
Melting Point
Boiling Point
Density
Solubility
Dissociation Constant
PH
Storage Stability
All
All
All
All
All
All
All
All
All
All
All
All
All
All
All
All
WAIVED
WAIVED
WAIVED
WAIVED
WAIVED
WAIVED
WAIVED
WAIVED
WAIVED
WAIVED
WAIVED
WAIVED
WAIVED
WAIVED
WAIVED
WAIVED
29
-------
SILVER
GUIDELINE GUIDELINE NAME
§158.130 Environmental Fate
USB BIBLIOGRAPHIC
SITES CITATION
All environmental fate data requirements have been waived.
§158.135 Toxicology
81-1
81-2
81-3
81-4
81-5
81-6
§158.145
71-l(a)
71-2(a)
71-2(b)
72-l(a)
72-l(c)
72-2(a)
Acute Oral Toxicity - Rat
Acute Dermal Toxicity - Rabbit
Acute Inhalation Toxicity - Rat
Primary Eye Irritation - Rabbit
Primary Dermal Irritation
Dermal Sensitization - Guinea Pig
Ecological Effects
Acute Avian Oral Toxicity - Quail/Duck
Avian Dietary Toxicity - Quail/Duck
Acute Avian Dietary - Duck
Freshwater Fish Toxicity - Bluegill
Fish Toxicity - Rainbow Trout
Freshwater Invertebrate Toxicity
All
All
All
All
All
All
All
All
All
All
All
All
WAIVED
WAIVED
WAIVED
WAIVED
WAIVED
WAIVED
REQUIRED
REQUIRED
WAIVED
WAIVED
426S0501
42650501
30
-------
APPENDIX C
SILVER BIBLIOGRAPHY
Citations Considered to be Fart of the Data Base
Supporting the Reregistration of Silver
31
-------
GUIDE TO APPENDIX. C
1. CONTENTS OF BIBLIOGRAPHY. This bibliography contains citations of all studies
considered relevant by EPA in arriving at the positions and conclusions stated elsewhere
in the Reregistiation Eligibility Document. Primary sources for studies in this
bibliography have been the body of data submitted to EPA and its predecessor agencies
in support of past regulatory decisions. Selections from other sources including the
published literature, in those instances where they have been considered, are included.
2. UNITS OF ENTRY. The unit of entry in this bibliography is called a "study". In the
case of published materials, this corresponds closely to an article. In the case of
unpublished materials submitted to the Agency, the Agency has sought to identify
documents at a level parallel to the published article from within the typically larger
volumes in which they were submitted. The resulting "studies" generally have a distinct
title (or at least a single subject), can stand alone for purposes of review and can be
described with a conventional bibliographic citation. The Agency has also attempted to
unite basic documents and commentaries upon them, treating them as a single study.
3. IDENTIFICATION OF ENTRIES. The entries in this bibliography are sorted
numerically by Master Record Identifier, or "MRID number*. This number is unique
to the citation, and should be used whenever a specific reference is required. It is not
related to the six-digit "Accession Number" which has been used to identify volumes of
submitted studies (see paragraph 4(d)(4) below for further explanation). In a few cases,
entries added to the bibliography late in the review may be preceded by a nine character
temporary identifier. These entries are listed after all MRID entries. This temporary
identifying number is also to be used whenever specific reference is needed.
4. FORM OF ENTRY. In addition to the Master Record Identifier (MRID), each entry
consists of a citation containing standard elements followed, in the case of material
submitted to EPA, by a description of the earliest known submission. Bibliographic
conventions used reflect the standard of the American National Standards Institute
(ANSI), expanded to provide for certain special needs.
i
a. Author. Whenever the author could confidently be identified, the Agency has chosen
to show a personal author. When no individual was identified, the Agency has shown
an identifiable laboratory or testing facility as the author. When no author or laboratory
could be identified, the Agency has shown the first submitter as the author.
b. Document date. The date of the study is taken directly from the document.
When the date is followed by a question mark, the bibliographer has deduced the
date from the evidence contained in the document. When the date appears as
(19??), the Agency was unable to determine or estimate the date of the document.
32
-------
c. Tide. In some cases, it has been necessary for the Agency bibliographers to
create or enhance a document title. Any such editorial insertions are contained
between square brackets.
d. Trailing parentheses. For studies submitted to the Agency in the past, the trailing
parentheses include (in addition to any self-explanatory text) the following
elements describing the earliest known submission:
(1) Submission date. The date of the earliest known submission appears
immediately following the word "received."
(2) Administrative number. The next element immediately following the
word "under* is the registration number, experimental use permit number,
petition number, or other administrative number associated with the
earliest known submission.
(3) Submitter. The third element is the submitter. When authorship is
defaulted to the submitter, this element is omitted.
(4) Volume Identification (Accession Numbers). The final element in the
trailing parentheses identifies the EPA accession number of the volume in
which the original submission of the study appears. The six-digit
accession number follows the symbol "CDL," which stands for "Company
Data Library." This accession number is in turn followed by an
alphabetic suffix which shows the relative position of the study within the
volume.
33
-------
1ERENCES
Buffle, J. Complexation Reactions in Aquatic Chemistry: An Analytical Approach, 1990, Ellis
Horwood, New Yoik.
Cotton, F. A. and Wilkinson, G. Advanced Inorganic Chemistry. Fifth Edition, 1988, John
Wiley and Sons, New York.
Day, W. A., Hunt, J. S. and McGiven, A. R. 1976. Silver deposition in mouse glomexuli.
- 8:201-204.
Demerec, M., Beitani, G. and Flint, J. 1951. A survey of chemicals for mutagenic action on
E. coli. Am. Nat. 85:119-136.
Dequidt, J., Vasseur, P. and Gromez-Potentier. 1974. Etude toricologique experimentale de
quelques derives argentiques. I. Localization et elimination. Bull. Soc. Pha^m, lf\]]$t 1:23-35.
Furchner, J. E., Drake, G. A. and Richmond, C. R. 1966. Retention of silver-110 by mice. UC
at Los Alamos: U.S. Atomic Energy Commission, Science Laboratories, 186-190.
Furchner, J. E., Richmond, C. R. and Drake, G. A. 1968. Comparative metabolism of
radiomiclides in mammals. IV. Retention of silver-110 in the mouse, rat, monkey, and dog.
Health Physics. 15:505-514.
Furst, A. 1979. Problems in metal carcinogenesis. Trace metals in heart and disease. Raven
Press, N.Y. pps 83-92.
Furst, A. 1981. Bioassays of metals for carcinogenesis: Whole animals. Environ. Health
Perspect. 40:83-92.
Furst, A. and Schlauder, M. C. 1977. Inactivity of two noble metals as carcinogens. J. Environ.
Pathol. Toxicol. 1:51-57.
Gaul, L. E. and Staud, A. H. 1935. Clinical Spectroscopy. Seventy cases of generalized
argyrosis following organic and colloidal silver medication, including a biospectrometric analysis
often cases. J. Am. Med. Assoc. 104:1387-1390.
Goyer, R. A. 1991. Toxic effects of metals. Casserett and DoulTs Toxicology. Eds. M. Amdtir,
J. Doull, and C. Klaassen. Pergamon Press. 623-680.
Gregus, G. and Klaassen, C. D. 1986. Disposition of metals in rats: a comparative study of
fecal, urinary, and biliary excretion and tissue distribution of eighteen metals. Toxicol. Appl.
Pharmacol. 85:24-38.
34
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Greenwood, N. N. and Eamshaw, A. Chemistry of the Elements. 1984, Pergamon Press Ltd.,
Oxford, UK.
Harvey, S. C. 1975. Heavy metals. The Pharmacological Basis of Therapeutics. Eds. L. S.
Goodman and A. Oilman. McMillan Publishing Company. 924-945.
Integrated Risk Information System (IRIS) on silver. 09/01/92.
Irgolic, K. J. and Maitell, A. E. Environmental Inorganic Chemistry.
1985, VCH Publishers, Inc.
Klaassen, C. D. 1979. Biliary excretion of silver in the rat, rabbit, and dog. Toxicol. Appl.
Pharmacol. 50:49-55.
Morel, F. M. M. Principles of Aquatic Chemistry. 1983, John Wiley and Sons, New York.
Muller, A. and Krebs, B. Studies in Inorganic Chemistry. Vol.5: Sulfur. Its Significance for
Chemistry, for the Geo- Bio- and Cosmosphere and Technology, 1984, Elsevier Publishers,
Amsterdam.
Murr, L. E. Interfactal Phenomena in Metals and Alloys. 1975, Addison Wesley Publishing
Company, Reading, MA.
Nishioka, H. 1975. Mutagenic activity of metal compounds in bacteria. Mutat. Res. 31:185-189.
Olcott, C. T. 1947. Experimental argyrosis. m. Pigmentation of the eyes of rats following
ingestion of silver during long periods of time. Am. J. Path. 23:783-789.
Olcott, C. T. 1948. Experimental argyrosis. IV. Morphological changes in the experimental
animal. Am. J. Path. 24:813-833.
Olcott, C. T. 1950. Experimental argyrosis. V. Hypertrophy of the left ventricle of the heart
in rats ingesting silver salts. Arch. Path. 49:138-149.
Pourbaix, M. Atlas of Electrochemical Equilibria in Aqueous Solutions. 1974, Translated by J.
A. Franklin, National Association of Corrosion Engineers, Houston, TX.
Reese, R. J. "Silver", Minerals Pacts and Problems,. U.S. Department of the Interior, Bureau
of Mines; Bulletin 675, 1985 Edition; U.S. Printing Office, Washington, D.C.
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Rossman, T. G. and Molina, M. 1986. The genetic toxicology of metal compounds: H.
Enhancement of ultraviolet light-induced mutagenesis in Escherichia coli WP2. Environ.
Mutagen. 8:263-271.
Rungby, J. 1986. The silver nitrate prophylaxis of crede causes silver deposition in the cornea
of experimental animals. Exp. Eve Res. 42:93-94.
Rungby, J., Slomianka, L., Dansker, G., Anderson, A. H. and West, M. J. 1987. A
quantitative evaluation of the neurotoxic effect of silver on the volumes of the components of
the developing rat hippocampus. Toxicol. 43:261-268.
Schmaehl, D. and Steinhoff, D. 1960. Versuke zur krebseizeugung mit kolloidalen silber-und
goldlo ungen an ratten. Z. Krebsforsch. 63:586-591 (in German).
Scott, K. G. and Hamilton, I. G. 1950. The metabolism of silver in the rat with radio-silver
used as an indicator. U. California. Publ. Pharmacol. 2:241-262.
Shumilova, N. A. and Zhutaeva, G. V. "Silver", in Encyclopedia of Electrochemistry of the
A. J. Bard, Editor, Vol m, 1978, Marcel Dekker, Inc., New York.
"Silver Compounds" in Kirk-Othmer Encyclopedia of Chemical Technology. 3rd. Edition, 1983,
John Wiley and Sons, New York.
Silver, S. "Bacterial Transformation of Resistance to Heavy Metals" in Changing Metal Cycles
and Human Health. J. O. Nriagu, Editor, 1974, Dahlem Konferenze, Berlin 1983; Published by
Springer-Verlag, Berlin.
Silver, S., Perry, R. D., Tynecka, S. and Kinscher, T. G. "Mechanisms of Bacterial Resistances
to the Toxic Heavy Metals Antimony, Arsenic, Cadmium, Mercury and Silver", Drug
Resistance in Bacteria. S. Mitsubishi, Editor; 1982, Japan Scientific Societies Press, Tokyo.
Stumm, W. Chemistry of the Solid-Water Interface: Processes at the Mineral-Water and
Particle-Water Interface in Natural Systems. 1992, John Wiley and Sons, New York.
Thompson, N. R. "Silver", Comprehensive Inorganic Chemistry. J. C. Bailar, Editor, 1973,
Pergamon Press, UK.
U.S. DHHS. PHS. Agency for Toxic Substances and Diseases Registry. Dec. 1990. Toxicology
Profile for Silver. Publ. No. TP-90-24.
U. S. Environmental Protection Agency, 1980. Ambient Water Quality Criteria for Silver -
1980. Office of Water Regulations and Standards, Criteria and Standards Division, Washington,
DC.
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U. S. Environmental Protection Agency. "AQUIRE" database. Environmental Research
Laboratory, Duluth, MN.
U.S. Environmental Protection Agency. Office of Water. April 1992. Silver. Drinking Water
Health Advisory.
Van Vleet, J. F. 1976. Induction of lesions of selenium-vitamin E deficiency in pies fed silver
Am. J. Vet. Res. 37:1425-1420.
Wagner, P. A., Hoekstro, W. and Ganther, H. E. 1975. Alleviation of silver toxicity by selenite
in the rat in relation to tissue gluthathione peroxidase. Proc. Soc. Ero. Biol. Med.
148:1106-1110. — -.
Walker, F. 1971. Experimental Argyria: A model for basement membrane studies. Brit. J. Em.
PHIL 52:589-593.
Zhutaeva, G. V. and Sbumilova, N. A. "Silver", in Standard Potentials in Aqueous Solutinn.
A. J. Bard, R. Parsons, and I. Jordan, Editors. Prepared under the auspices of IUPAC, Physical
and Analytical Chemistry Divisions, Commissions on Electrochemistry and Electroanalytical
Chemistry, 1985, Marcel Dekker, New York.
37
-------
SILVER BIBLIOGRAPHY
MRTO CITATION
41021701 Tyreman, D. (1989) Eurocarb Bacteriostatic Water Filter Media-Pro-
duct Identity and Composition: Project ID EPA 1. Unpublished
study prepared by EuTOcarb Products Ltd. 8 p.
41298401 Tyreman, D. (1989) Eurocarb Bacteriostatic Water Filter
Media-Analysis and Certification of Product Ingredients:
Lab Project No. EPA 2. Unpublished study prepared by Eurocarb
Products Ltd. 4 p.
41298402 Tyreman, D. (1989) Eurocarb Bacteriostatic Water Filter
Media-Physical and Chemical Characteristics: Lab Project
Number EPA 3. Unpublished study prepared by Eurocarb
Products Ltd. 3 p.
41S46701 Sarathy, A. (1990) Product Chemistry Data: Silver Impregnated
Carbon. Unpublished study prepared by Active Carbon India Ltd.
lip.
41546801 Sarathy, A. (1990) Product Chemistry Data: Silver Impregnated
Carbon. Unpublished study prepared by Active Carbon India Ltd.
lip.
41546901 Sarathy, A. (1990) Product Chemistry Data: Silver Impregnated
Carbon. Unpublished study prepared by Active Carbon India Ltd.
lip.
41547001 Sarathy, A. (1990) Product Chemistry Data: Silver Impregnated
Carbon. Unpublished study prepared by Active Carbon India Ltd.
lip.
41816301 Mason, M. (1991) Silver Product Chemistry. Unpublished study pre-
prepared by Mason Chemical Co. 8 p.
41867501 Rhodes, K. (1991) Product Chemistry: Silver. Unpublished study
prepared by The Rhodes Corp. 4 p.
41867502 Rhodes, K. (1991) Chemical Test-Silver Release: Lab Project No:
S52/37/4A: 4106: S52/37/4B. Unpublished study prepared by
38
-------
Froehling & Robertson, Inc. 6 p.
41877801 Moiy, I. (1991) Product Chemistry for Metallic Silver. Unpublished
study prepared by National Safety Associates, Inc. 16 p.
42069401 Cerven, D. (1991) Single Dose Oral Toxicity in Rats/LD SO in Rats:
Lab Project Number. MB 91-620 A. Unpublished study prepared by
MB Research Laboratories, Inc. 10 p.
42069402 Cerven, D. (1991) Acute Dermal Toxicity in Rabbits/LD SO in Rabbits
: Lab Project Number MB 91-620 B. Unpublished study prepared
by MB Research Laboratories, Inc. 13 p.
42069403 Cerven, D. (1991) Primary Dermal Irritation in Albino Rabbits: Lab
Project Number MB 91-620 C. Unpublished study prepared by MB
Research Laboratories, Inc. 10 p.
42069404 Cerven, D. (1991) Primary Eye Irritation/Corrosion in Rabbits: Lab
Project Number MB 91-620 D. Unpublished study prepared by MB
Research Laboratories, Inc. 11 p.
42069405 Cerven, D. (1991) Guinea Pig Sensitization (Buehler): Lab Project
Number MB 91-620 F. Unpublished study prepared by MB Research
Laboratories, Inc. 11 p.
42069406 Sibinovic, K. (1991) The Effectiveness of 3 Lots of Sildate "Silver
n Oxide] When Used as a Disinfectant (Water) for Swimming
Pools: Lab Proj. No.: J10-1991-DWSP-01. Unpublished study
prepared by Shaldra, Inc. 7 p.
42069407 Sibinovic, K. (1991) Sildate: Swimming Pool Sanitizer and Germicide
: Lab Project Number J10-PC-1991. Unpublished study prepared
by Shaldra, Inc. 5 p.
4237S401 Chauvin, R. (1991) Silver Emission of Finished Units: Lab
Project Number GE-9107230-6. Unpublished study prepared by
Coffey Laboratories, Inc. 7 p.
4237SS01 Chauvin, R. (1991) Silver Emission of Finished Units: Lab
Project Number GE-9107230-6. Unpublished study prepared by
Coffey Laboratories, Inc. 7 p.
39
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42383501 Ramirez, R. (1992) Study of Three Bacteriostatic Water
Treatment Units up to 95% of Life, Following EPA Protocol to
Determine Silver Release in the Effluent: Lab Project Number
B-191. Unpublished study prepared by Quantum Laboratories,
Corp. IS p.
42410601 Chauvin, R. (1991) Silver Emission of Finished Units: Lab
Project Number GE9107230-6: MG910701D-1. Unpublished
study prepared by Coffey Laboratories, Inc. 8 p.
42627701 Mason, M. (1992) Product Chemistry: Silver. Unpublished study
prepared by Mason Chemical Co. 7 p.
42650501 Mason Chemical Co. (1993) Rainbow Trout, Invertebrate
Toxicity: Silver Case 4082: Lab Project Number 440/5-80-071.
Unpublished study. 43 p.
40
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APPENDIX E
Pesticide Reregistration Handbook,
PR Notice 91-2 and PR Notice 86-5
41
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PR Notice 91-2
42
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON. D.C. 20460
OFFICE OF
PREVENTION. PESTICIDES
AND TOXIC SUBSTANCES
PR NOTICE 91-2
NOTICE TO MANUFACTURERS, PRODUCERS, FORMULATORS,
AND REGISTRANTS OF PESTICIDES
ATTENTION: Persons Responsible for Federal Registration of
Pesticide Products.
SUBJECT: Accuracy of Stated Percentages for Ingredients
Statement
I. PURPOSE:
The purpose of this notice is to clarify the Office of
Pesticide Program's policy with respect to the statement of
percentages in a pesticide's label's ingredient statement.
Specifically, the amount (percent by weight) of ingredient(s)
specified in the ingredient statement on the label must be stated
as the nominal concentration of such ingredient(s), as that term
is defined in 40 CFR 158.153(i). Accordingly, the Agency has
established the nominal concentration as the only acceptable
label claim for the amount of active ingredient in the product.
II. BACKGROUND
For some time the Agency has accepted two different methods
of identifying on the label what percentage is claimed for the
ingredient(s) contained in a pesticide. Some applicants claimed a
percentage which represented a level between the upper and the
lower certified limits. This was referred to as the nominal
concentration. Other applicants claimed the lower limit as the
percentage of the ingredient(s) that would be expected to be
present in their product at the end of the product's shelf-life.
Unfortunately, this led to a great deal of confusion among the
regulated industry, the regulators, and the consumers as to
exactly how much of a given ingredient was in a given product.
The Agency has established the nominal concentration as the only
acceptable label claim for the amount of active ingredient in the
product.
Current regulations require that the percentage listed in
the active ingredient statement be as precise as possible
reflecting good manufacturing practices 40 CFR 156.10(g)(5). The
certified limits required for each active ingredient are intended
to encompass any such "good manufacturing practice" variations 40
CFR 158.175(C)(3).
43
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The upper and lower certified limits, which must be proposed in
connection with a product's registration, represent the amounts
of an ingredient that may legally be present 40 CFR 158.175. The
lower certified limit is used as the enforceable lower limit for
the product composition according to FIFRA section 12(a)(1)(C),
while the nominal concentration appearing on the label would be
the routinely achieved concentration used for calculation of
dosages and dilutions.
The nominal concentration would in fact state the greatest
degree of accuracy that is warranted with respect to actual
product composition because the nominal concentration would be
the amount of active ingredient typically found in the product.
It is important for registrants to note that certified
limits for active ingredients are not considered to be trade
secret information under FIFRA section 10 (b). In this respect the
certified limits will be routinely provided by EPA to States for
enforcement purposes, since the nominal concentration appearing
on the label may not represent the enforceable composition for
purposes of section 12(a)(1)(C).
III. REQUIREMENTS
As described below under Unit V. • COMPLIANCE SCHEDULE,11 all
currently registered products as well as all applications for new
registration must comply with this Notice by specifying the
nominal concentration expressed as a percentage by weight as the
label claim in the ingredient (s) statement and equivalence
statements if applicable (e.g., elemental arsenic, metallic zinc,
salt of an acid) . In addition, the requirement for performing
sample analyses of five or more representative samples must be
fulfilled. Copies of the raw analytical data must be submitted
with the nominal ingredient label claim. Further information
about the analysis requirement may be found in the 40 CFR
158.170. All products are required to provide certified limits
for each active, inert ingredient, impurities of toxicological
significance (i.e., upper limit (s) only) and on a case by case
basis as specified by EPA. These limits are to be set based on
representative sampling and chemical analysis (i.e., quality
control) of the product.
The format of the ingredient statement must conform to 40
CFR 156-Labeling Requirements For Pesticides and Devices.
After July 1, 1997, all pesticide ingredient Statements must
be changed to nominal concentration.
44
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IV. PRODUCTS THAT REQUIRE EFFICACY DATA
All pesticides are required to be efficacious. Therefore,
the certified lower limits may not be lower then the minimum
level to achieve efficacy. This is extremely important for
products which are intended to control pests which threaten the
public health, e.g., certain antimicrobial and rodenticide
products. Refer to 40 CFR 153.640.
In those cases where efficacy limits have been established,
the Agency will not accept certified lower limits which are below
that level for the shelf life of the product.
V. COMPLIANCE SCHEDULE
As described earlier, the purpose of this Notice is to make
the registration process more uniform and more manageable for
both the agency and the regulated community. It is the Agency's
intention to implement the requirements of this notice as
smoothly as possible so as not to disrupt or delay the Agency's
high priority programs, i.e., reregistration, new chemical, or
fast track (FIFRA section 3(c)(3)(B). Therefore,
applicants/registrants are expected to comply with the
requirements of this Notice as follows:
(1) Beginning July 1, 1991, all new product registrations
submitted to the Agency are to comply with the
requirements of this Notice.
(2) Registrants having products subject to reregistration
under FIFRA section 4(a) are to comply with the
requirements of this Notice when specific products are
called in by the Agency under Phase V of the
Reregistration Program.
(3) All other products/applications that are not subject to
(1) and (2) above will have until July 1, 1997, to
comply with this Notice. Such applications should note
•Conversion to Nominal Concentrations on the
application form. These types Or amendments will not be
handled as "Fast Track" applications but will be
handled as routine requests.
VI. FOR FURTHER INFORMATION
Contact Tyrone Aiken for information or questions concerning
this notice on (703) 557-5024
- - *- C -
ABM fi. tindaay, Director
Registration Division (H-7505
45
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PESTICIDE REGISTRATION HANDBOOK
PR Notice 86-5
46
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
July 29. 1986
OFFICE OF
PR NOTICE 86-5 PREVENTION. PESTICIDES
AND TOXIC SUBSTANCES
NOTICE TO PRODUCERS, PORMULATORS, DISTRIBUTORS
AND REGISTRANTS
Attention: Persons responsible for Federal registration of
pesticides.
Subject: Standard format for data submitted under the
Federal Insecticide, Fungicide, and Rodenticide
Act (FIFRA) and certain provisions of the Federal
Food, Drug, and Cosmetic Act (FFDCA).
I. Purpose
To require data to be submitted to the Environmental
Protection Agency (EPA) in a standard format. This Notice also
provides additional guidance about, and illustrations of, the
required formats.
II. Applicability
This PR Notice applies to all data that are submitted to EPA
to satisfy data requirements for granting or maintaining
pesticide registrations, experimental use permits, tolerances,
and related approvals under certain provisions of FIFRA and
FFDCA. These data are defined in FIFRA §10(d)(1). This Notice
does not apply to commercial, financial, or production
information, which are, and must continue to be, submitted
differently under separate cover.
III. Effective Date
This notice is effective on November 1, 1986. Data formatted
according to this notice may be submitted prior to the effective
date. As of the effective date, submitted data packages that do
not conform to these requirements may be returned to the
submitter for necessary revision.
IV. Background
On September 26, 1984, EPA published proposed regulations in
the Federal Register (49 FR 37956) which include Requirements for
Data Submission (40 CFR §158.32), and Procedures for Claims of
Confidentiality of Data (40 CFR §158.33). These regulations
47
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specify the format for data submitted to EPA under Section 3 of
FIFRA and Sections 408 and 409 of FFDCA, and procedures which
must be followed to make and substantiate claims of confiden-
tiality. No entitlements to data confidentiality are changed,
either by the proposed regulation or by this notice.
OPP is making these requirements mandatory through this
Notice to gain resource-saving benefits from their use before the
entire proposed regulation becomes final. Adequate lead time is
being provided for submitters to comply with the new
requirements.
V. Relationship Of this Notice to Other OPP Policy and Guidanr*
While this Notice contains requirements for organizing and
formatting submittals of supporting data, it does not address the
substance of test reports themselves. "Data reporting" guidance
is now under development in OPP, and will specify how the study
objectives, protocol, observations, findings, and conclusions are
organized and presented within the study report. The data
reporting guidance will be compatible with submittal format
requirements described in this Notice.
OPP has also promulgated a policy (PR Notice 86-4 dated
April 15, 1986) that provides for early screening of certain
applications for registration under FIFRA S3. The objective of
the screen is to avoid the additional costs and prolonged delays
associated with handling significantly incomplete application
packages. As of the effective date of this Notice, the screen
will include in its criteria for acceptance of application
packages the data formatting requirements described herein.
OPP has also established a public docket which imposes
deadlines for inserting into the docket documents submitted in
connection with Special Reviews and Registration Standards (see
40 CFR §154.15 and §155.32). To meet these deadlines, OPP is
requiring an additional copy of any flata submitted to the docket.
Please refer to Page 10 for more information about this
requirement.
For several years, OPP has required that each application
for registration or other action include a list of all applicable
data requirements and an indication of how each is satisfied--the
statement of the method of support for the application.
Typically, many requirements are satisfied by reference to data
previously submitted--either by the applicant or by another
party. That requirement is not altered by this notice, which
applies only to data submitted with an application.
VI. Format Requirements
A more detailed discussion of these format requirements
follows the index on the next page, and samples of some of the
requirements are attached. Except for the language of the two
alternative forms of the Statement of Data Confidentiality Claims
(shown in Attachment 3) which cannot be altered, these samples
are illustrative. As long as the required information is
included and clearly identifiable, the form of the samples may be
altered to reflect the submitter's preference.
48
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- INDEX-
Text Example
Page Page
A. Organization of the Submittal Package 3 17
B. Transmittal Document 4 n
C. Individual Studies 4
C. 1 Special Considerations for Identifying Studies . . 5
D. Organization of each Study Volume 6 17
D. 1 Study Title Page 7 12
D. 2 Statement of Data Confidentiality Claims
(based on PIPRA §10(d)(l)) 8 13
D. 3 Confidential Attachment 8 15
D. 4 Supplemental Statement of Data Confidentiality
Claims (other than those based on FIFRA §10(d)(1)) 8 14
D. 5 Good Laboratory Practice Compliance Statement . . 9 16
E. Reference to Previously Submitted Data 9
F. Physical Format Requirements & Number of Copies .... 9
6. Special Requirements for Submitting Data to the Docket 10
**************
A. Organization of Submittal Package
A •submittal package" consists of all studies submitted at
the same time for review in support of a single regulatory
action, along with a transmittal document and other related
administrative material (e.g. the method of support statement,
EPA Forms 8570-1, 8570-4, 8570-20, etc.) as appropriate.
Data submitters must organize each submittal package as
described in this Notice. The transmittal and any other admin-
istrative material must be grouped together in the first physical
volume. Each study included in the submittal package must then
be bound separately.
Submitters sometimes provide additional materials that are
intended to clarify, emphasize, or otherwise comment to help
Product Managers and reviewers better understand the submittal.
- If such materials relate to one study, they should be
included as an appendix to that study.
- If such materials relate to more than one study (as for
example a summary of all studies in a discipline) or to the
submittal in general, they must be included in the submittal
package as a separate study (with title page and statement
of confidentiality claims).
49
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B- Transmittal Document
The first item in each submit tal package must be a trans-
mittal document. This document identifies the submitter or all
joint submitters; the regulatory action in support of which the
package is being submitted--i.e., a registration application,
petition, experimental use permit (EUP), §3(c)(2)(B) data
call-in, §6(a)(2) submittal, or a special review; the transmittal
date; and a list of all individual studies included in the
package in the order of their appearance, showing (usually by
Guideline reference number) the data requirement(s) addressed by
each one. The EPA-assigned number for the regulatory action
(e.g. the registration, EUP, or tolerance petition number) should
be included in the transmittal document as well, if it is known
to the submitter. See Attachment 1 for an example of an
acceptable transmittal document.
The list of included studies in the transmittal of a data
submittal package supporting a registration application should be
subdivided by discipline, reflecting the order in which data
requirements appear in 40 CFR 158.
The list of included studies in the transmittal of a data
submittal package supporting a petition for tolerance or an
application for an EUP should be subdivided into sections A, B,
C, of the petition or application, as defined in 40 CFR 180.7
and 158.125, (petitions) or Pesticide Assessment Guidelines,
Subdivision I (EUPs) as appropriate.
When a submittal package supports a tolerance petition and
an application for a registration or an EUP, list the petition
studies first, then the balance of the studies. Within these two
groups of studies follow the instructions above.
C. Individual Studies
A study is the report of a single scientific investigation,
including all supporting analyses required for logical complete-
ness. A study should be identifiable and distinguishable by a
conventional bibliographic citation including author, date, and
title. Studies generally correspond in scope to a single Guide-
line requirement for supporting data, with some exceptions dis-
cussed in section C.I. Each study included in a submittal
package must be bound as a separate entity. (See comments on
binding studies on page 9.)
Each study must be consecutively paginated, beginning from
the title page as page 1. The total number of pages in the com-
plete study must be shown on the study title page. In addition
(to ensure that inadvertently separated pages can be reassociated
with the proper study during handling or review) use either of
the following:
- Include the total number of pages in the complete study on
each page (i.e., 1 of 250, 2 of 250, ...250 of 250).
- Include a company name or mark and study number on each
page of the study, e g , Company Name-1986-23. Never reuse
a study number for marking the pages of subsequent studies.
50
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When a single study is extremely long, binding it in mul-
tiple volumes is permissible so long as the entire study is pag-
inated in a single series, and each volume is plainly identified
by the study title and its position in the multi-volume sequence.
C.I Special Considerations for Identifying Studies
Some studies raise special problems in study identification,
because they address Guidelines of broader than normal scope or
for other reasons.
a. Safety Studies. Several Guidelines require testing for
safety in more than one species. In these cases each species
tested should be reported as a separate study, and bound
separately.
Extensive supplemental reports of pathology reviews, feed
analyses, historical control data, and the like are often assoc-
iated with safety studies. Whenever possible these should be
submitted with primary reports of the study, and bound with the
primary study as appendices. When such supplemental reports are
submitted independently of the primary report, take care to fully
identify the primary report to which they pertain.
Batteries of acute toxicity tests, performed on the same end
use product and covered by a single title page, may be bound
together and reported as a single study.
b. Product Chemistry Studies. All product chemistry data
within a submittal package submitted in support of an end-use
product produced from registered manufacturing-use products
should be bound as a single study under a single title page.
Product chemistry data submitted in support of a technical
product, other manufacturing-use product, an experimental use
permit, an import tolerance petition, or an end-use product
produced from unregistered .source ingredients, should be bound as
a single study for each Guideline series (61, 62, and 63) for
conventional pesticides, or for the equivalent subject range for
biorational pesticides. The first of the three studies in a
complete product chemistry submittal for a biochemical pesticide
would cover Guidelines 151-10, 151-11, and 151-12; the second
would cover Guidelines 151-13, 151-15, and 151-16; the third
would cover Guideline 151-17. The first study for a microbial
pesticide would cover Guidelines 151-20, 151-21, and 151-22; the
second would cover Guidelines 151-23 and 151-25; the third would
cover Guideline 151-26.
Note particularly that product chemistry studies are likely
to contain Confidential Business Information as defined in FIFRA
§10(d)(1)(A), (B), or (C), and if so must be handled as described
in section D.3. of this notice.
51
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c. Reaidue Chemistry Stud-j^a. Guidelines 171-4, 153-3,
and 153-4 are extremely broad in scope; studies addressing
residue chemistry requirements must thus be defined at a level
below that of the Guideline code. The general principle,
however, of limiting a study to the report of a single inves-
tigation still applies fully. Data should be treated as a single
study and bound separately for each analytical method, each
report of the nature of the residue in a single crop or animal
species, and for each report of the magnitude of residues
resulting from treatment of a single crop or from processing a
single crop. When more than one commodity is derived from a
single crop (such as beet tops and beet roots) residue data on
all such commodities should be reported as a single study. When
multiple field trials are associated with a single crop, all such
trials should be reported as a single study.
D. Organization of Each Study Volume
Each complete study must include all applicable elements in
the list below, in the order indicated. (Also see Page 17.)
Several of these elements are further explained in the following
paragraphs. Entries in the column headed •example* cite the
page number of this notice where the element is illustrated.
Element When Required
Study Title Page Always Page 12
Statement of Data One of the two alternative Page 13
Confidentiality forms of this statement
Claims is always required
Certification of Good If study reports laboratory Page 16
Laboratory Practice work subject to GLP require-
ments
Flagging statements For certain toxicology studies (When
flagging requirements are finalized.)
Body of Study Always - with an English language
translation if required.
Study Appendices At submitter's option
Cover Sheet to Confi- if CBI is claimed under FIFRA
dential Attachment §10(d)(1)(A), (B), or (C)
CBI Attachment if CBI is claimed under FIFRA
§10 (d) (1) (A), (B), or (C) Page 15
Supplemental Statement Only if confidentiality is Page 14
of Data Confidentiality claimed on a basis other than
Claims FIFRA §10 (d) (1) (A), (B), or (C)
52
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D.I. Title Page
A title page is always required for each submitted study,
published or unpublished. The title page must always be freely
releasable to requestors; DO NOT INCLUDE CBZ ON THE TITLE PAGE.
An example of an acceptable title page is on page 12 of this
notice. The following information must appear on the title page:
a. Study title. The study title should be as descriptive as
possible It must clearly identify the substance(s) tested and
correspond to the name of the data requirement as it appears in
the Guidelines.
b. Data requirement addressed, include on the title page the
Guideline number(s) of the specific requirement(s) addressed by
the study.
c. Authorfa). Cite only individuals with primary intellectual
responsibility for the content of the study. Identify them
plainly as authors, to distinguish them from the performing
laboratory, study sponsor, or other names that may also appear on
the title page.
d. Study Date. The title page must include a single date for
the study. If parts of the study were performed at different
times, use only the date of the latest element in the study.
e. Performing Laboratory Identification. If the study reports
work done by one or more laboratories, include on the title page
the name and address of the performing laboratory or
laboratories, and the laboratory's internal project number(s) for
the work. Clearly distinguish the laboratory's project
identifier from any other reference numbers provided by the study
sponsor or submitter.
f. Supplemental Submissions. if the study is a commentary on
or supplement to another previously submitted study, or if it
responds to EPA questions raised with respect to an earlier
study, include on the title page elements a. through d. for the
previously submitted study, along with the EPA Master Record
Identifier (MRID) or Accession number of the earlier study if you
know these numbers. (Supplements submitted in the same submittal
package as the primary study should be appended to and bound with
the primary study. Do not include supplements to more than one
study under a single title page).
g. Facts of Publication, if the study is a reprint of a pub-
lished document, identity on the title page all relevant facts of
publication, such as the journal title, volume, issue, inclusive
page numbers, and publication date.
53
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D.2. Statements of Data Confidentiality Claims Under PIFRA
§10(d)(1).
Each submitted study must be accompanied by one of the two
alternative forms of the statement of Data Confidentiality Claims
specified in the proposed regulation in §158.33 (b) and (c) (See
Attachment 3) . These statements apply only to claims of data
confidentiality based on FIFRA §10(d)(1)(A), (B), or (C). Use
the appropriate alternative form of the statement either to
assert a claim of §10(d)(l) data confidentiality (§158.33 (b)) or
to waive such a claim (§158.33 (c)). In either case, the
statement must be signed and dated, and must include the typed
name and title of the official who signs it. Do not make CBI
claims with respect to analytical methods associated with pet-
itions for tolerances or emergency exemptions (see NOTE Pg 13).
D.3. Confidential Attachment
If the claim is made that a study includes confidential
business information as defined by the criteria of FIFRA
§10 (D) (1) (A). (B), or (C) (as described in D.2. above) all such
information must be excised from the body of the study and
confined to a separate study-specific Confidential Attachment.
Bach passage of CBI so isolated must be identified by a reference
number cited within the body of the study at the point from which
the passage was excised (See Attachment 5).
The Confidential Attachment to a study must be identified by
a cover sheet fully identifying the parent study, and must be
clearly marked "Confidential Attachment." An appropriately
annotated photocopy of the parent study title page may be used as
this cover sheet. Paginate the Confidential Attachment
separately from the body of the study, beginning with page 1 of X
on the title page. Each passage confined to the Confidential
Attachment must be associated with a specific cross reference to
the page(s) in the main body of the study on which it is cited,
and with a reference to the applicable passage (s) of FIFRA
§10(d)(1) on which the confidentiality claim is based.
D.4. Supplemental Statement of Data Confidentiality Claims (See
Attachment 4)
If you wish to make a claim of confidentiality for any
portion of a submitted study other than described by FIFRA §10 (d)
(l) (A) , (B), or (C), the following provisions apply:
- The specific information to which the claim applies must
be clearly marked in the body of the study as subject to a
claim of confidentiality.
- A Supplemental Statement of Data Confidentiality Claims
must be submitted, identifying each passage claimed confi-
dential and describing in detail the basis for the claim.
A list of the points to address in such a statement is
included in Attachment 4 on Pg 14.
- The Supplemental Statement of Data Confidentiality Claims
must be signed and dated and must include the typed name and
title of the official who signed it.
54
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D.5. Good Laboratory Practice Compliance Statement
This statement is required if the study contains laboratory
work subject to GLP requirements specified in 40 CFR 160. Sam-
ples of these statements are shown in Attachment 6.
E. Reference to Previously Submitted Data
DO NOT RESUBMIT A STUDY THAT EAS PREVIOUSLY BEEN SUBMITTED
FOR ANOTHER PURPOSE unless EPA specifically requests it. A copy
of the title page plus the MRID number (if known) is sufficient
to allow us to retrieve the study immediately for review. This
prevents duplicate entries in the Agency files, and saves you
the cost of sending more copies of the study. References to pre-
viously submitted studies should not be included in the transmit-
tal document, but should be incorporated into the statement of
the method of support for the application.
F. Physical Format Requirements
All elements in the data submittal package must be on
uniform 8 1/2 by 11 inch white paper, printed on one side only in
black ink, with high contrast and good resolution. Bindings for
individual studies must be secure, but easily removable to permit
disassembly for microfilming. Check with EPA for special
instructions before submitting data in any medium other than
paper, such as film or magnetic media.
Please be particularly attentive to the following points:
• Do not include frayed or torn pages.
• Do not include carbon copies, or copies in other than
black ink.
• Make sure that photocopies are clear, complete, and
fully readable.
• Do not include oversize computer printouts or fold-out
pages.
• Do not bind any documents with glue or binding tapes.
• Make sure that all pages of each study, including any
attachments or appendices, are present and in correct
sequence.
Number of Copies Required - All submittal packages except
those associated with a Registration Standard or Special Review
(See Part G below) must be provided In thraa complete, identical
copies. (The proposed regulations specified two copies; three
are now being required to expedite and reduce the cost of
processing data into the OPP Pesticide Document Management System
and getting it into review.)
55
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Special Requirements for Submitting n^fl to the Docket
Data submittal packages associated with a Registration Stan-
dard or Special Review must be provided in four copies, from one
of which all material claimed as CBI has been excised. This
fourth copy will become part of the public docket for the RS or
SR case. If no claims of confidentiality are made for the study,
the fourth copy should be identical to the other three. When
portions of a study submitted in support of an RS or SR are
claimed as CBI, the first three copies will include the CBI
material as provided in section D of this notice. The following
special preparation is required for the fourth copy.
• Remove the "Supplemental Statement of Data
Confidentiality Claims".
• Remove the "Confidential Attachment".
• Excise from the body of the study any information you
claim as confidential, even if it does not fall within
the scope of FIPRA §10 (d) (1) (A) , (B) , or (C) . Do not
close up or paraphrase text remaining after this
excision.
• Mark the fourth copy plainly on both its cover and its
title page with the phrase "Public Docket Material -
contains no information claimed as confidential".
V. For Further Information
For further information contact John Car ley, Chief,
Information Services Branch, Program Management and Support
Division, (703) 305-5240.
W. Akinun
Acting 9*rtetor.
Division
Attachment 1. Sample Transmittal Document
Attachment 2. Sample Title Page for a Newly Submitted Study
Attachment 3. Statements of Data Confidentiality Claims
Attachment 4. Supplemental Statement of Data Confidentiality
Claims
Attachment 5. Samples of Confidential Attachments
Attachment 6. Sample Good Laboratory Practice Statements
Attachment 7. Format Diagrams for Submittal Packages and Studies
56
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ATTACHMENT 1
ELEMENTS TO BE INCLUDED IN THE TRANSMITTAL DOCUMENT*
1. Name and address of submitter (or all joint submitters**)
+Smith Chemical Corporation Jones Chemical Company
1234 West Smith Street -and- 5678 Wilson Blvd
Cincinnati, OH 98765 Covington, KY 56789
+Smith Chemical Corp will act as sole agent for all submitters.
2. Regulatory action in support of which this package is
gubmjfcted
Use the EPA identification number (e.g. 359-EUP-67) if you know
it. Otherwise describe the type of request (e.g. experimental
use permit, data call-in - of xx-xx-xx date).
3. Tranamittal date
4. List of; submitted studies
Vol 1. Administrative materials - forms, previous corres-
pondence with Project Managers, and so forth.
Vol 2. Title of first study in the submittal (Guideline
No.)
Vol n Title of nth study in the submittal (Guideline
No.)
* Applicants commonly provide this information in a tran-
smittal letter. This remains an acceptable practice so
long as all four elements are included.
* Indicate which of the joint submitters is empowered to
act on behalf of all joint submitters in any matter
concerning data compensation or subsequent use or
release of the data.
Company Official:.
Name Signature
Company Name:_
Company Contact:
Name Phone
57
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ATTACHMENT 2
SAMPLE STUDY TITLE PAGE FOR A NEWLY SUBMITTED STUDY
Study
(Chemical name) - Magnitude of Residue on Corn
Data Requirement
Guideline 171-4
Author
John C. Davis
Study Completed On
January 5, 1979
Performing Laboratory
ABC Agricultural Laboratories
940 West Bay Drive
Wilmington, CA 39897
Laboratory Pro^eet ID
ABC 47-79
Page 1 of X
(X is the total number of pages in the study)
58
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ATTACHMENT 3
STATEMENTS OF DATA CONFIDENTIALITY CLAIMS
1. No claim of confidentiality under FIFRA §10(d)(1)(A),(B), or
(C) .
STATEMENT OF NO DATA CONFIDENTIALITY CLAIMS
No claim of confidentiality is made for any information
contained in this study on the basis of its falling within
the scope of FIFRA 6§10(d)(1)(A), (B), or (C).
Company
Company Agent: Typed Name Date:.
Title Signature
2. Claim of confidentiality under FIFRA §10(d)(1) (A), (B), or
(C).
STATEMENT OF DATA CONFIDENTIALITY CLAIMS
Information claimed confidential on the basis of its falling
within the scope of FIFRA §10(d)(1)(A), (B), or (C) has been
removed to a confidential appendix, and is cited by
cross-reference number in the body of the study.
Company:
Company Agent: Typed Name Date:.
Title Signature
NOTE: Applicants for permanent or temporary tolerances should
note that it is OPP policy that no permanent tolerance, temporary
tolerance, or request for an emergency exemption incorporating an
analytical method, can be approved unless the applicant waives
all claims of confidentiality for the analytical method. These
analytical methods are published in the FDA Pesticide Analytical
Methods Manual, and therefore cannot be claimed as confidential.
OPP implements this policy by returning submitted analytical
methods, for which confidentiality claims have been made, to the
submitter, to obtain the confidentiality waiver before they can
be processed.
59
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ATTACHMENT 4
SUPPLEMENTAL STATEMENT OF DATA CONFIDENTIALITY CLAIMS
For any portion of a submitted study that is not described
by FIFRA §10 (d) (1) (A), (B), or (C), but for which you claim
confidential treatment on another basis, the following informa-
tion must be included within a Supplemental Statement of Data
Confidentiality Claims:
• Identify specifically by page and line number(s) each
portion of the study for which you claim
confidentiality.
• Cite the reasons why the cited passage qualifies for
confidential treatment.
• Indicate the length of time--until a specific date or
event, or permanently-- for which the information should
be treated as confidential.
• Identify the measures taken to guard against undesired
disclosure of this information.
• Describe the extent to which the information has been
disclosed, and what precautions have been taken in con-
nection with those disclosures.
• Enclose copies of any pertinent determinations of
confidentiality made by EPA, other Federal agencies, of
courts concerning this information.
• If you assert that disclosure of this information would
be likely to result in substantial harmful effects to
you, describe those harmful effects and explain why
they should be viewed as substantial.
• If you assert that the information in voluntarily sub-
mitted, indicate whether you believe disclosure of this
information might tend to lessen the availability to
EPA of similar information in the future, and if so,
how.
60
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ATTACHMENT 5
EXAMPLES OF SEVERAL CONFIDENTIAL ATTACHMENTS
Example i. (Confidential word or phrase that has been deleted
from the study)
CROSS REFERENCE NUMBER i This cross reference number is used in the study
in place of the following words or phrase at the
indicated volume and page references.
DELETED WORDS OR PHRASE: gt->.y-i.».o raiy^i
PAGE LIKE REASON FOR THE DELETION PIPRA REFERENCE
6 14 Identity of Inert Ingredient 210(d)(1)(C)
12 25 • •
100 19 • »
Example 2. (Confidential paragraph (s) that have been deleted from the study)
CROSS REFERENCE NUMBER £ This cross reference number is used in the study
in place of the following paragraph(s) at the
indicated volume and page references.
DELETED PARAGRAPH(S):
( )
( Reproduce the deleted paragraph(s) here )
( )
PAGE LINES REASON FOR THE DELETION FIFRA REFERENCE
20. 2-17 Description of the quality control process §10(d)(1)(C)
Example 3. (Confidential S&3&S. that have been deleted from the study)
CROSS REFERENCE NUMBER 2 This cross reference number noted on a place-
holder page is used in place of the following
whole pages at the indicated volume and page
references.
DELETED PAGE(S)! are attached immediately behind this page.
PAGE LINES REASON FOR THE DELETION FIFRA REFERENCE
20. 2-17 Description of the product manufacturing process §10(d)(1) (A)
61
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ATTACHMENT 6.
SAMPLE GOOD LABORATORY PRACTICE STATEMENTS
Example!.
This study meets the requirements for 40 CFR Part 160
Submitter —•
Sponsor
Study Director
Example 2.
This study does not meet the requirements of 40 CFR Part 160, and differs
in the following ways:
1..
2..
3.
Submitter,
Sponsor
Study Director
Example 3,
The submitter of this study was neither the sponsor of this study nor
conducted it, and does not know whether it has been conducted in
accordance with 40 CFR Part 160.
Submitter
62
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ATTACHMENT 7.
FORMAT OP THE SUBNITTAL PACKAGE
LEGEND
Transmittal Doeuneat.
Related Adainistrative Materials
te.g., Method of Support Statement, etc.)
I Other materials about the submlttal
—— (e.g.. aunaariee of groups of studies
to aid in their review).
Studies, submitted as unique
physical entitle*, according
to the format beLow.
FORKAT Of SUBMITTED STUDIES
Study title page.
Statement of Confidentiality Claias.
CLP and flagging* atateoenta - aa appropriate.
Body of the atudy, with Engliah
language tranalation if required.
Appendleee to the atudy.
Title fago cf the Confidential
Attaehaent.
,. confidential Attachment,
Supplemental Stateoant
-— of Confidentiality Claim*,
* Whan flagging requirement*
are finalised.
Ooeunentt which »uat be ajbaltted aa
appropriate to Mat established requirements.
I Documents subaifeted at submitter'a option.
63
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APPENDIX F
Generic Data Call-In
64
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For Case 4082, Silver, no Generic Data Call-In will be issued.
65
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APPENDIX G
Product Specific Data Call-in
66
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ATTACHMENT A
CHEMICAL STATUS SHEET
67
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SILVER: DATA CALL-IN CHEMICAL STATUS SHEET
INTRODUCTION
You have been sent this Product Specific Data Call-In Notice because you have
product(s) containing silver.
This Product Specific Data Call-in Chemical Status Sheet, contains an ntun*** of HO*.
required by this notice, and point of contact for inquiries pertaining to the reregistration of
silver. This attachment is to be used in conjunction with (1) the Product Specific Data Call-In
Notice, (2) the Product Specific Data Call-in Response Form (Attachment B), (3) the
Requirements Status and Registrant's Form (Attachment Q, (4) EPA's Grouping of End-Use
Products for Meeting Acute Toxicology Data Requirements (Attachment D), (5) the EPA
Acceptance Criteria (Attachment E), (6) a list of registrants receiving this Dd (Attachment F)
and (7) the Cost Share and Data Compensation Forms in replying to this Silver Product Specific
Data Call-In (Attachment G). Instructions and guidance accompany each form.
DATA REQUIRED BY THIS NfYTTrfl
The additional data requirements needed to complete the database for silver are contained
m the Requirements Status and Registrant's Response., Attachment C. The Agency has
concluded that additional data on silver are needed for specific products. These data are required
to be submitted to the Agency within the timeframe listed. These data are needed to fully
complete the reregistration of all eligible silver products.
INQUIRIES AND RESPONSES TO THIS NOTTPB
If you have any questions regarding the generic database of silver, please contact
Kathleen Depukat at (703) 308-8587.
If you have any questions regarding the product specific data requirements and
procedures established by this Notice, please contact Joanne I. Miller at (703) 305-7830.
All responses to this Notice for the Product Specific data requirements should be
submitted to:
Joanne I. Miller, Product Manager Team 23
Herbicide/Fungicide Branch
Registration Division (H7505C)
Office of Pesticide Programs
U.S. Environmental Protection Agency
Washington, D.C. 20460
RE: SILVER
68
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ATTACHMENT B
PRODUCT SPECIFIC DATA CALL-IN RESPONSE FORMS (Form A) PLUS
INSTRUCTIONS
69
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PRODUCT SPECIFIC DATA CALL-IN RESPONSE FORMS (Form A) PLUS
INSTRUCTIONS
Item 1-4. Already completed by EPA.
Item 5. If you wish to voluntarily caned your product, answer "yes." If you choose
this option, you will not have to provide the data required by the Data Call-In
Notice and you will not have to complete any other forms. Further sale and
distribution of your product after the effective date of cancellation must be in
accordance with the Existing Stocks provision of the Data Call-In Notice
(Section IV-C).
Item 6. Not applicable since this form calls in product specific data only. However, if
your product is identical to another product and you qualify for a data
exemption, you must respond with "yes" to Item 7a (MUP) or 7B (EUP) on
this form, provide the EPA registration numbers of your source(s); you
would not complete the •Requirements Status and Registrant's Response"
form. Examples of such products include repackaged products and Special
Local Needs (Section 24c) products which are identical to federally registered
products.
Item 7a. For each manufacturing use product (MUP) for which you wish to maintain
registration, you must agree to satisfy the data requirements by responding
"yes."
Item 7b. For each end use product (EUP) for which you wish to maintain registration,
you must agree to satisfy the data requirements by responding "yes." If you
are requesting a data waiver, answer myes* here; in addition, on the
"Requirements Status and Registrant's Response" form under Item 9, you must
respond with Option 7 (Waiver Request) for each study for which you are
requesting a waiver. See Item 6 with regard to identical products and data
exemptions.
Items 8-11. Self-explanatory.
NOTE: You may provide additional information that does not fit on this form
in a signed letter that accompanies this form. For example, you may
wish to report that your product has already been transferred to another
company or that you have already voluntarily cancelled this product.
For these cases, please supply all relevant details so that EPA can
ensure that its records are correct.
70
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ATTACHMENT C
PRODUCT SPECIFIC REQUIREMENT STATUS AND
REGISTRANT'S RESPONSE
FORMS (Form B) PLUS INSTRUCTIONS
71
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INSTRUCTIONS FOR COMPLETING THE "REQUIREMENTS STATUS AND
REGISTRANT'S RESPONSE" FORM FOR PRODUCT SPECIFIC DATA
Item 1-3. Completed by EPA. Note the unique identifier number assigned by EPA in Item 3.
This number must be used in the transmittal document for any data submissions in response
to this Data Call-In Notice.
Item 4.The guideline reference numbers of studies required to support the product's continued
registration are identified. These guidelines, in addition to the requirements specified in the
Notice, govern the conduct of the required studies. Note that series 61 and 62 in product
chemistry are now listed under 40 CFR 158.155 through 158.180, Subpart C.
Item S.The study title associated with the guideline reference number is identified.
Item 6.The use pattem(s) of the pesticide associated with the product specific requirements is
(are) identified. For most product specific data requirements, all use patterns are covered by the
data requirements. In the case of efficacy data, the required studies only pertain to products
which have the use sites and/or pests indicated
Item T.The substance to be tested is identified by EPA. For product specific data, the product
as formulated for sale and distribution is the test substance, except in rare cases.
Item S.The due date for submission of each study is identified. It is normally based on 8 months
after issuance of the Reregistration Eligibility Document unless EPA determines that a longer
time period is necessary.
Item 9. Enter only one of the following response Codes for each data requirement to
show how you intend to comply with the data requirements listed in this
table. Fuller descriptions of each option are contained in the Data Call-In Notice.
1. I will generate and submit data by the specified due date (Developing Data). By
indicating that I have chosen this option, I certify that I will comply with all the
requirements pertaining to the conditions for submittal of this study as outlined
in the Data Call-In Notice.
2. I have entered into an agreement with one or more registrants to develop data
jointly (Cost Sharing). I am submitting a Copy of this agreement. I understand
that this option is available only for acute toxicity or certain efficacy data and
only if EPA indicates in an attachment to this Notice fhat my product is similar
enough to another product to qualify for this option. I certify that another party
in the agreement is committing to submit or provide the required data: if the
required study is not submitted on time, my product may be subject to
suspension.
72
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3. I have made offers to share in the cost to develop data (Offers to Cost Share).
I understand that this option is available only for acute toxicity or certain efficacy
data and only if EPA indicates in an attachment to this Data Call-In Notice that
my product is similar enough to another product to qualify for this option. I am
submitting evidence that I have made an offer to another registrant (who has
an obligation to submit data) to share in the cost of that data. I am also submitting
a completed •Certification of Offer to Cost Share in the Development Data"
form. I am including a copy of my offer and proof of the other registrant's
receipt of that offer. I am identifying the patty which is committing to submit or
provide the required data: if the required study is not submitted on time, my
product may be subject to suspension. I understand that other terms under Option
3 in the Data Call-in Notice (Section m-C.l.) apply as well.
4. By the specified due date, I will submit an existing study that has not been
submitted previously to the Agency by anyone (Submitting an
I certify that this study will meet all the requirements for submhtal of existing
data outlined in Option 4 in the Data Call-In Notice (Section m-C.l.) and will
meet the attached acceptance criteria (for acute toxicity and product chemistry
data). I will attach the needed supporting information along with this response.
I also certify that I have determined that this study will fill the data requirement
for which I have indicated this choice.
5. By the specified due date, I will submit or cite data to upgrade a study classified
by the Agency as partially acceptable and upgradable (upgrading a Study). I
will submit evidence of the Agency's review indicating that the study may be
upgraded and what information is required to do so. I will provide the MRTD or
Accession number of the study at the due date. I understand that the conditions
for this option outlined Option 5 in the Data Call-In Notice (Section m-C.l.)
apply.
6. By the specified due date, I will cite an existing study that the Agency has
classified as acceptable or an existing study that has been submitted but not
reviewed by the Agency (Citing an Existing Study). If I am citing another
registrant's study, I understand that this option is available only for acute toxicity
or certain efficacy data and only if the cited study was conducted on my product,
an identical product or a product which EPA has "grouped" with one or more
other products for purposes of depending on the same data. I may also choose this
option if I am citing my own data. In either case, I will provide the MRID or
Accession Number(s) for the cited data on a "Product Specific Data Report"
form or in a similar format. If I cite another registrant's data, I will submit a
completed "Certification with Respect To Data Compensation Requirements"
form.
73
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7. I request a waiver for this study because it is inappropriate for my product
(waiver Request). I am attaching a complete justification for this request,
including technical reasons, data and references to relevant EPA regulations,
guidelines or policies. [Note: any supplemental data must be submitted in the
format required by P.R. Notice 86-5]. I understand that this is my only
opportunity to state the reasons or provide information in support of my request.
If the Agency approves my waiver request, I will not be required to supply the
data pursuant to Section 3(c)(2)(B) of FTFRA. If the Agency denies my waiver
request, I must choose a method of meeting the data requirements of this Notice
by the due date stated by this Notice. In this case, I must, within 30 days of my
receipt of the Agency's written decision, submit a revised "Requirements Status
and Registrant's Response" Form indicating the option chosen. I also understand
that the deadline for submission of data as specified by the original data call-in
notice will not change.
Items 10-13 Self-explanatory.
NOTE: You may provide additional information that does not fit on this form in a
signed letter that accompanies this form. For example, you may wish to report
that your product has already been transferred to another company or that you
have already voluntarily cancelled this product. For these cases, please supply all
relevant details so that EPA can ensure that its records are correct.
74
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ATTACHMENT D
EPA GROUPING OF END-USE PRODUCTS FOR MEETING
DATA REQUREMENTS FOR REREGISTRATION
75
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EPA'S DECISION TO BATCH END-USE PRODUCTS CONTAINING SILVER FOR
PURPOSES OF MEETING ACUTE TOXICITY DATA REQUIREMENTS FOR
REREGISTRATTON
In an effort to reduce the time, resources and number of animals needed to fulfill the
acute toxicity data requirements for reregistration of end-use products containing the active
ingredient silver, the Agency has batched products which can be considered similar for
purposes of acute toxicity. Factors considered in the sorting process include each product's
active and inert ingredients (identity, percent composition and biological activity), type of
formulation (e.g., emulsifiable concentrate, aerosol, wettable powder, granular, etc.), and
labeling (e.g., signal word, use classification, precautionary labeling, etc.). Note that the
Agency is not describing batched products as "substantially similar" since some products
within a batch may not be considered chemically similar or have identical use patterns.
Batching has been accomplished using the readily available information described above.
Frequently acute toxicity data on individual end-use products has been found to be
incomplete. Notwithstanding the batching process, the Agency reserves the right to require,
at any time, acute toxicity data for an individual end-use product should the need arise.
Registrants of end-use products within a batch may choose to cooperatively gener- ate,
submit or cite a single battery of six acute lexicological studies to represent all the products
within that batch. It is the registrants' option to participate in the process with all other
registrants, only some of the other registrants, or only their own products within a batch, or
to generate all the required acute lexicological studies for each of their own products. If a
registrant chooses to generate the data for a batch, he/she must use one of the products
within the batch as the test material. If a registrant chooses to rely upon previously
submitted acute toxicity data, he/she may do so provided that the data base is complete and
valid by today's standards (see acceptance criteria attached), the formulation tested is
considered by EPA to be similar for acute toxicity, and the formulation has not been
significantly altered since submission and acceptance of the acute toxicity data. Regardless
of whether new data is generated or existing data is cited, the registrants are must clearly
identify the material tested by its EPA registration number.
In deciding how to meet the product specific data requirements, registrants must follow
the directions given in the Data Call-In Notice and its attachments appended to the RED. The
DCI Notice contains two response forms which are to be completed and submitted to the
Agency within 90 days of receipt. The first form, "Data Call-In Response," asks whether
the registrant will meet the data requirements for each product. The second form,
"Requirements Status and Registrant's Response," lists the product specific data required for
each product, including the standard six acute toxicity tests. A registrant who wishes to
participate in a batch must decide whether he/she will provide the data or depend on someone
else to do so. If a registrant supplies the data to support a batch of products, he/she must
select one of the following options: Developing Data (Option 1), Submitting an Existing
Study (Option 4), Upgrading an Existing Study (Option 5) or Citing an Existing Study
76
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(Option 6). If a registrant depends on another's data, he/she must choose among: Cost
Sharing (Option 2), Offers to Cost Share (Option 3) or Citing an Existing Study (Option 6).
If a registrant does not want to participate in a batch, the choices are Options 1, 4, 5 or 6.
However, a registrant should know that choosing not to participate in a batch does not
preclude other registrants in the batch from citing his/her studies and offering to cost share
(Option 3) those studies.
77
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End-Use Products Containing Silver
78
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The following table (Table I) lists 5 batches containing 62 products containing silver.
Table I.
Botch No.
1
EPA
Registration
Number
35900-3
35900-6
35900-7
35900-13
35900-16
35900-18
35920-1 1
35966-2
36430-1
37589-2
37589-4
37589-5
39104-1
39446-3
39446-4
39446-5
39446-6
39446-7
40184-1
40184-8
44751-1
44751-2
44751-3
44751-4
44751-5
% Silver
0.07
0.50
0.20
0.47
0.026
0.35
0.20
0.20
1.05
0.20
1.05
0.75
1.05
1.05
1.05
1.05
1.05
1.05
1.05
1.05
0.105
0.087
0.10
0.08
0.624
Formulation Type
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
79
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Batch No.
1 (con't.)
I EPA
Registration
Number
44751-7
44751-9
44751-10
44751-11
44919-2
44919-5
44919-6
46379-5
51160-1
51160-2
51160-3
54159-1
54646-2
55228-1
57700-1
58295-1
58295-2
58295-3
59243-2
61388-1
61944-1
62275-1
63949-1
63949-2
64906-1
64906-2
64938-1
65172-1
% Silver
0.624
0.624
0.624
0.624
0.026
0.026
0.026
1.05
1.05
1.05
1.05
1.05
0.026
1.05
0.10
0.026
1.05
0.50
0.20
0.20
0.026
0.07
1.05
0.50
0.026
0.026
0.20
0.20
Formulation Type
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials |
80
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Batch No.
2
3
4
5
EPA
Registration
Number
54625-1
54625-2
2623-4
2623-5
4855-2
10324-18
35900-2
35900-9
35900-12
% Silver
0.016
0.016
1.71
0.171
0.8
0.8
1.05
0.07
0.07
Formulation Type
Impregnated Materials
Impregnated Materials
Impregnated Materials
Impregnated Materials
Ready To Use Solutions
Ready To Use Solutions
Impregnated Materials
Impregnated Materials
Impregnated Materials
One product (Table II) was considered not to be similar for purposes of acute
toxicity or the Agency lacked sufficient information for decision making and not
placed in any batch. The registrant is responsible for meeting the acute toxicity
data requirements for the product.
Table II.
EPA Registration Number
l^SS
37589-6
% Silver
0.80
Formulation Type
Impregnated Materials
81
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ATTACHMENT E
EPA ACCEPTANCE CRITERIA
82
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SUBDIVISION D
Guideline Study Title
Series 61 Product Identity and Composition
Series 62 Analysis and Certification of Product Ingredients
Series 63 Physical and Chemical Characteristics
83
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61 Product Identity and Composition
ACCEPTANCE CRITERIA
Does your study meet the following acceptance criteria?
1- Name of technical material tested (include product name and trade name, if appropriate).
2. Name, nominal concentration, and certified limits (upper and lower) for each active ingredient and each
intentionally-added inert ingredient.
3. Name and upper certified limit for each impurity or each group of impurities present at >_ 0.1 % by
weight and for certain lexicologically significant impurities (e.g., dioxins, nitrosamines) present at
<0.1%.
4. Purpose of each active ingredient and each intentionally-added inert.
5. Chemical name from Chemical Abstracts index of Nomenclature and Chemical Abstracts Service (CAS)
Registry Number for each active ingredient and, if available, for each intentionally-added inert.
6. Molecular, structural, and empirical formulas, molecular weight or weight range, and any company
assigned experimental or internal code numbers for each active ingredient.
7. Description of each beginning material in the manufacturing process.
EPA Registration Number if registered; for other beginning materials, the following:
Name and address of manufacturer or supplier.
Brand name, trade name or commercial designation.
Technical specifications or data sheets by which manufacturer or supplier describes composition,
properties or toxicity.
8. Description of manufacturing process.
Statement of whether batch or continuous process.
Relative amounts of beginning materials and order in which they are added.
Description of equipment.
Description of physical conditions (temperature, pressure, humidity) controlled in each step and
the parameters that are maintained.
Statement of whether process involves intended chemical reactions.
Flow chart with chemical equations for each intended chemical reaction.
Duration of each step of process.
Description of purification procedures.
Description of measures taken to assure quality of final product.
9. Discussion of formation of impurities based on established chemical theory addressing (1) each impurity
which may be present at >_ 0.1% or was found at >_ 0.1% by product analyses and (2) certain
toxicologically significant impurities (see #3).
84
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62 Analysis and Certification of Product Ingredients
ACCEPTANCE CRITERIA
The following criteria apply to the technical grade of the active ingredient being reregistered. Use a table to present
the information in items 6, 7, and 8.
Does your study meet the following acceptance criteria?
1 • Five or a*0*6 representative samples (batches in case of batch process) analyzed for each active ingredient
and all impurities present at > 0.1%.
2- Degree of accountability or closure .>. eg 98 %.
3. Analyses conducted for certain trace toxic impurities at lower than 0.1 % (examples, nitrosamines in the
case of products containing dinitroanilines or containing secondary or tertiary amines/alkanolamines plus
nitrites; polyhalogenated dibenzodioxins and dibenzonirans). [Note that in the case of nitrosamines both
fresh and stored samples must be analyzed.].
4- Complete and detailed description of each step in analytical method used to analyze above samples.
5- Statement of precision and accuracy of analytical method used to analyze above samples.
6- Identities and quantities (including mean and standard deviation) provided for each analyzed ingredient.
7- Upper and lower certified limits proposed for each active ingredient and intentionally added inert along
with explanation of how the limits were determined.
8. Upper certified limit proposed for each impurity present at >. 0.1 % and for certain lexicologically
significant impurities at < 0.1% along with explanation of how limit determined.
9. Analytical methods to verify certified limits of each active ingredient and impurities Qatter not required
if exempt from requirement of tolerance or if generally recognized as safe by FDA) are fully described
10. Analytical methods (as discussed in #9) to verify certified limits validated as to their precision and
accuracy.
85
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63 Physical and Chemical Characteristics
ACCEPTANCE CRITERIA
The following criteria apply to the technical grade of the active ingredient being reregistered.
Does your study meet the following acceptance criteria?
63-2 Color
Verbal description of coloration (or lack of it)
Any intentional coloration also reported in terms of Munsell color system
63-3 Physical State
Verbal description of physical state provided using terms such as "solid, granular, volatile liquid"
Based on visual inspection at about 20-25° C
63-4 Odor
Verbal description of odor (or lack of it) using terms such as * garlic-like, characteristic of aromatic
compounds"
Observed at room temperature
63-5 Melting Point
Reported in °C
Any observed decomposition reported
63-6 Boiling Point
Reported in °C
Pressure under which B.P. measured reported
Any observed decomposition reported
63-7 Density, Bulk Density, Specific Gravity
Measured at about 20-25° C
Density of technical grade active ingredient reported in g/ml or the specific gravity of liquids reported
with reference to water at 20° C. [Note: Bulk density of registered products may be reported in Ibs/ft3
or Ibs/gallon.]
63-8 Solubility
Determined in distilled water and representative polar and non-polar solvents, including those used in
formulations and analytical methods for the pesticide
Measured at about 20-25° C
Reported in g/100 ml (other units like ppm acceptable if sparingly soluble)
63-9 Vapor Pressure
Measured at 25° C (or calculated by extrapolation from measurements made at higher temperature if
pressure too low to measure at 25° C)
Experimental procedure described
Reported in mm Hg (torr) or other conventional units
86
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63 Physical and Chemical Characteristics
ACCEPTANCE CRITERIA (cont.)
63-10 Dissociation Constant
Experimental method described
Temperature of measurement specified (preferably about
20-25°Q
63-11 Octanol/water Partition Coefficient
Measured at about 20-25° C
Experimentally determined and description of procedure provided (preferred method-45 Fed Register
77350)
Data supporting reported value provided
63-12 pH
Measured at about 20-25° C
Measured following dilution or dispersion in distilled water
63-13 Stability
Sensitivity to metal ions and metal determined
Stability at normal and elevated temperatures
Sensitivity to sunlight determined
87
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SUBDIVISION F
Guideline Study Title
81-1 Acute Oral Toxicity in the Rat
81-2 Acute Dermal Toxicity in the Rat, Rabbit or Guinea Pig
81-3 Acute Inhalation Toxicity in the Rat
81-4 Primary Eye Irritation in the Rabbit
81-5 Primary Dermal Irritation Study
81-6 Dermal Sensitization in the Guinea Pig
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81-1 Acute Oral Toxicity in the Rat
ACCEPTANCE CRITERIA
Does your study meet the following acceptance criteria?
1- Identify material tested (technical, end-use product, etc).
2. At least 5 young adult rats/sex/group.
3. Dosing, single oral may be administered over 24 hrs.
4.* Vehicle control if other than water.
5. Doses tested, sufficient to determine a toxicity category or a limit dose (5000 mg/kg).
6. Individual observations at least once a day.
7- Observation period to last at least 14 days, or until all test animals appear normal whichever is longer.
8. Individual daily observations.
9. Individual body weights.
10. Gross necropsy on all animals.
Criteria marked with an * are supplemental and may not be required for every study.
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81-2 Acute Dermal Toxicity in the Rat, Rabbit or Guinea Fig
ACCEPTANCE CRITERIA
Does your study meet the following acceptance criteria?
1. Identify material tested (technical, end-use product, etc).
2. At least 5 animals/sex/group.
3.* Rats 200-300 gm, rabbits 2.0-3.0 kg or guinea pigs 350-450 gm.
4. Dosing, single dermal.
5. Dosing duration at least 24 hours.
6.* Vehicle control, only if toxicity of vehicle is unknown.
7. Doses tested, sufficient to determine a toxicity category or a limit dose (2000 mg/kg).
8. Application site clipped or shaved at least 24 hours before dosing.
9. Application site at least 10% of body surface area.
10. Application site covered with a porous nonirritating cover to retain test material and to prevent
ingesuon.
11. Individual observations at least once a day.
12. Observation period to last at least 14 days.
13. Individual body weights.
14. Gross necropsy on all animals.
Criteria marked with an * are supplemental and may not be required for every study.
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81-3 Acute Inhalation Toricity in the Rat
ACCEPTANCE CRITERIA
Does your study meet the following acceptance criteria?
1. Identify material tested (technical, end-use product, etc).
2. Product is a gas, a solid which may produce a significant vapor hazard based on toxicity and expected use
or contains particles of inhalable size for man (aerodynamic diameter IS pm or less).
3. At least 5 young adult rats/sex/group.
4. Dosing, at least 4 hours by inhalation.
S. Chamber air flow dynamic, at least 10 air changes/hour, at least 19% oxygen content.
6. Chamber temperature, 22° C (±2*), relative humidity 40-60%.
7. Monitor rate of air flow.
8. Monitor actual concentrations of test material in breathing zone.
9. Monitor aerodynamic particle size for aerosols.
10. Doses tested, sufficient to determine a toxicity category or a limit dose (5 mg/L actual concentration of
respirable substance).
11. Individual observations at least once a day.
12. Observation period to last at least 14 days.
13. Individual body weights.
14. Gross necropsy on all animals.
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81-4 Primary Eye Irritation in the Rabbit
ACCEPTANCE CRITERIA
Does your study meet the following acceptance criteria?
1. Identify material tested (technical, end-use product, etc).
2. Study not required if material is corrosive, causes severe
dermal irritation or has a pH of <2 or _>.! 1.5.
3. 6 adult rabbits.
4. Dosing, instillation into the conjunctival sac of one eye
per animal.
5. Dose, 0.1 ml if a liquid; 0.1 ml or not more than 100 mg if a solid, paste or paniculate substance.
6. Solid or granular test material ground to a fine dust.
7. Eyes not washed for at least 24 hours.
8. Eyes examined and graded for irritation before dosing and
at 1, 24, 48 and 72 hr, then daily until eyes are normal
or 21 days (whichever is shorter).
9.* Individual daily observations.
Criteria marked with an * are supplemental and may not be required for every study.
92
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81-5 Primary Dermal Irritation Study
ACCEPTANCE CRITERIA
Does your study meet the following acceptance criteria?
1- Identify material tested (technical, end-use product, etc).
2. Study not required if material is corrosive or has a pH of <2 or _>.!!.5.
3. 6 adult animals.
4. Dosing, single dermal.
5. Dosing duration 4 hours.
6. Application site shaved or clipped at least 24 hours prior to dosing.
7. Application site approximately 6 cm2.
8. Application site covered with a gauze patch held in place with nonirritating tape.
9. Material removed, washed with water, without trauma to application site.
10. Application site examined and graded for irritation at 1, 24, 48 and 72 hr, then daily until normal or 14
days (whichever is shorter).
11.* Individual daily observations.
Criteria marked with an * are supplemental and may not be required for every study.
93
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81-6 Dermal Sensitization in the Guinea Fig
ACCEPTANCE CRITERIA
Does your study meet the following acceptance criteria?
1- _ Identify material tested (technical, end-use product, etc).
2. _ Study not required if material is corrosive or has a
.
3. _ One of the following methods is utilized:
_ Freund's complete adjuvant test
_____ Guinea pig maximization test
_ Split adjuvant technique
_ Buehlertest
_ Open epicutaneous test
_ Mauer optimization test
_ Footpad technique in guinea pig.
4. _ Complete description of test.
5.* _ Reference for test.
6. _ Test followed essentially as described in reference document.
1- _ Positive control included (may provide historical data conducted within the last 6 months).
Criteria marked with an * are supplemental and may not be required for every study.
94
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ATTACHMENT F
LIST OF ALL REGISTRANTS SENT THIS DATA CALL-IN NOTICE
95
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ATTACHMENT G
COST SHARE AND DATA COMPENSATION FORMS
96
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r/EPA
United States Environmental Protection Agency
Washington, DC 20460
CERTIFICATION OF OFFER TO COST
SHARE IN THE DEVELOPMENT OF DATA
Form Approved
OMB No. 2070-0106
Approval Expires 12-31-92
Public reporting burden for this collection of information is estimated to average 15 minutes per response, including
time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and
completing and reviewing the collection of information. Send comments regarding the burden estimate or any other
aspect of this collection of information, including suggestions for reducing this burden, to Chief, Information Policy
Branch, PM-223, U.S. Environmental Protection Agency, 401 M St., S.W., Washington, DC 20460; and to the Office
of Management and Budget, Paperwork Reduction Project (2070-0106), Washington, DC 20503.
Please fill In blanks below.
Company Name
Company Number
Chemical Name
EPA Chemical Number
I Certify that:
My company is willing to develop and submit the data required by EPA under the authority of the Federal
Insecticide, Fungicide and Rodenticide Act (FIFRA), if necessary. However, my company would prefer to
enter into an agreement with one or more registrants to develop jointly or share in the cost of developing
data.
My firm has offered in writing to enter into such an agreement. That offer was irrevocable and included an
offer to be bound by arbitration decision under section 3(c)(2)(B)(iii) of FIFRA if final agreement on all
terms could not be reached otherwise. This offer was made to the following firm(s) on the following
date(s):
Name of Firm(s)
Date of Offer
Certification'
I certify that I am duly authorized to represent the company named above, and that the statements that I have made on
this form and all attachments therein are true, accurate, and complete. I acknowledge that any knowingly false or
misleading statement may be punishable by fine or imprisonment or both under applicable law.
Signature
Name and
of Company's Authorized Repreaentaltve
Date
Title (Please Type or Print)
EPA Form 8570-32
-------
c/EPA
United States Environmental Protection Agency
Washington, DC 20460
CERTIFICATION WITH RESPECT TO
DATA COMPENSATION REQUIREMENTS
OMB No, 2070-0107
2070-0087
Approval Expire* 3-31-»C
PubDc reporting burden for this collection of information is estimated to average 15 minutes per response, including
time tor reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and
completing and reviewing the collection of information. Send comments regarding the burden estimate or any other
^^L ^J^ lec?n of lnformation. Including suggestions for reducing this burden, to Chief, Information Policy
Branch, PM-223, U.S Environmental Protection Agency, 401 M St., S.W., Washington. DC 20460; and to the Office
of Management and Budget. Paperwork Reduction Project (2070-0106), Washington, DC 20503.
Please fill In blanks below.
Company
BPA Hog
Number
• HO*
I Certify that
1. For each study tiled in support of registration or registration under the Federal Insecticide. Fungicide and
Rodentfcide Act (FIFRA) that is an exclusive use study. I am the original data submitter, or I have obtained the
written permission of the original data submitter to cite that study.
2. That tor each study ctted in support of registration or ^registration under FIFRA that is NOT an exclusive use
study. I am the original data submitter, or I have obtained the written permission of the original data submitter, or I
have notified in writing the company(ies) that submitted data I have tiled and have offered to: (a) Pay
compensation for those data in accordance with sections 3(c)d)(D) and 3(c)(2)(D) of FIFRA: and (b) Commence
negotiation to determine which data are subject to the compensation requirement of FIFRA and the amount of
compensation due, tf any. The companies I have notified are: (check one)
11 The companies who have submitted the studies listed on the back of this form or attached
sheets, or indicated on the attached •Requirements Status and Registrants' Response Form.'
3. That I have previously complied with section 3(c)(!)(D) of FIFRA for the studies I have tiled in support of
registration or ^registration under FIFRA.
Signature
Dat*
GENERAL OFFER TO PAY: I hereby offer and agree to pay compensation to other persons, with regard to the
registration or reregistration of my products, to the extent required by FIFRA sections 3(C)(1)(D) and 3(c)(2)(D).
Signature
Nam* and TIU* (Pteaa* Typ* or Print)
Oat*
,
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