United States
Environmental Protection
Agency
Office of
Pesticides and Toxic Substances
Washington DC 20460
September 1980
Pesticides
Avitirol
Pesticide Registration
Standard
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4-Aminopyridine
Pesticide Registration Standard
Jane Schwemley, Project Manager (SPRD)
Charlotte Blalock, Chemist (HED)
Henry Appleton, Environmental Chemist (HED)
Lionel Richardson, Environmental Chemist (HED)
Roland Gessart, Toxicologist (HED)
R.W. Cook, Residue Chemist (HED)
Bill Jacobs, Product Manager (RD)
Acknowledgements
Jerry Moore, Section Head (SPRD)
Juanita Wills, Section Head (SPRD)
Mary Wyman, Project Manager (SPRD)
September, 1980
Office of Pesticides and Toxic Substances
Environmental Protection Agency
401 !Mf Street, S.W.
Washington, D.C. 204060
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TABLE OF CONTENTS
I. How to Register Under a Registration Standard
Organization of the Standard .... 1
Purpose of the Standard 1
Requirement to Re-register Under the Standard 3
Product Specific Data and Generic Data 3
Data Compensation Requirements Under FIFRA 3(c)(1)(D) 4
Obtaining Data to Fill "Data Gaps", FIFRA 3(c)(2)(B) 5
Amendments to the Standard 5
II. Regulatory Position
Manufacturing-Use 4-Aminopyridine 8
4-Aminopyridine Formulated Products 10
III. Product Chemistry
Introduction ' 17
Topical Discussions
Chemical Identity 17
Manufacturing Process 18
Percentages of Components in Pesticide Products 18
Product Analytical Methods and Data 18
Physical/Chemical Properties 18
Disciplinary Review
Chemistry Profile 20
Generic Data Gaps 20
Required Labeling 21
Bibliography 22
IV. Environmental Fate
Use Profile 23
Topical Discussions
Physico-Chemical Transformation 24
Soil Metabolism 24
Microbial Metabolism 26
Mobility 27
Field Dissipation 29
Accumulation 29
Disciplinary Review
Environmental Fate Profile . 30
Exposure Profile 31
Bibliography 32
V. Ecological Effects
Topical Discussions
Birds 3o
Fish 35
Wild Mammals , 33
Plants 33
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Disciplinary Review
. Ecological Effects Profile 38
Ecological Effects Hazard Assessment 39
Required Labeling 40
Bibliography 42
VI. Toxicology
Topical Discussions
Acute Effects and Neurotoxicity 44
Local Irritation , 46
Sensitization 48
Subchronic Effects and Neurotoxicity 48
Chronic Effects 49
Oncogenicity 49
Reproduction 49
Teratology 49
Mutagenicity 50
Pharmacological Effects 50
Clinical Effects 51
Disciplinary Review
Toxicology Profile 53
Toxicology Hazard Assessment 54
Generic Data Gaps 55
Required Labeling 55
Bibliography 56
VII. Residue Chemistry
Topical Discussions
Metabolism in Plants 59
Metabolism in Animals 60
Analytical Methodology 60
Residue Data 62
Disciplinary Review
Residue Chemistry Profile 64
Tolerance Reassessment 64
Generic Data Gaps 64
Required Labeling '. 65
Bibliography 56
VIII. Regulatory Rationale
Data Gaps ,. 60
Products to be Covered Under this Standard
Manufacturing-Use Products 68
Formulated Products 68
Hazards to Wildlife
Manufacturing-Use Products 69
Formulated Products 53
Hazards to Humans and Domestic Animals Formulated
Formulated Products , 70
Appendix A
Chemical Data Sheets 72
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Appendix B
Summary of Label Ingredient Statements 73
IX. Bibliography
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I. HOW TO REGISTER
UNDER A REGISTRATION STANDARD
Organization of the Standard
Purpose of the Standard
Requirement to Re-register Under the Standard
"Product Specific" Data and "Generic" Data
Data Compensation Requirements under FIFRA 3(c)(1)(D)
Obtaining Data to Fill "Data Gaps"; FIFRA 3(c)(2)(B)
Amendments to the Standard
Organization of the Standard
This first chapter explains the purpose of a Registration Standard and
summarizes the legal principles involved in registering or re-registering under
a Standard. The second chapter sets forth the requirements that must be met to
obtain or retain registration for products covered by this particular
Registration Standard. In the remaining chapters, the Agency reviews the
available data by scientific discipline, discusses the Agency's concerns with
the identified potential hazards, and logically develops the conditions and
requirements that would reduce those hazards to acceptable levels.
Purpose or the Standard
Section 3 of the Federal Insecticide, Fungicide, and Rodenticide Act
(FIFRA) provides that "no person in any State may distribute, sell, offer for
sale, hold for sale, ship, deliver for shipment, or receive (and having so
received) deliver or offer to deliver, to any person any pesticide which is not
registered with the Administrator [of EPA]." To approve the registration of a
pesticide, the Administrator must find, pursuant to Section 3(c)(5) that:
"(A) its composition is such as to warrant the proposed claims for it;
(B) its labeling and other material required to be submitted comply with
the requirements of this Act;
(C) it will perform its intended function without unreasonable adverse
effects on the environment; and
(D) when used in accordance with widespread and commonly recognized
practice it will not generally cause unreasonable adverse effects on
the environment."
In making these findings, the Agency reviews a wide range of data which
registrants are required to submit, and assesses the risks and benefits
associated with the use of the proposed pesticide. But the established
approach to making these findings has been found to be defective on two counts:
First, EPA and its predecessor agency, the United States Department of
Agriculture (USDA), routinely reviewed registration applications on a 'product
by product' basis, evaluating each product-specific application somewhat
independently. In the review of products containing similar components, there
was little opportunity for a retrospective review of the full range of
pertinent data available in Agency files and in the public literature. Thus
the 'product by product' approach was often inefficient and sometimes resulted
in inconsistent or incomplete regulatory judgments.
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Second, over the years, as a result of inevitable and continuing advances
in scientific knowledge, methodology, and policy, the data base for many
pesticides came to be considered inadequate by current scientific and
regulatory standards. Given the long history of pesticide regulation in
several agencies, it is even likely that materials may have been lost from the
data files. When EPA issued new requirements for registration in 1975 (40 CFR
162) and proposed new guidelines for hazard testing in 1978 (43 FR 29686, July
10, 1973 and 43 FR 37336, August 2, 1973), many products that had already been
registered for years were being sold and used without the sane assurances of
human and environmental safety as was being required for new products. Because
of this inconsistency, Congress directed EPA to re-register all previously
registered products, so as to bring their registrations and their data bases
into compliance with current requirements [See FIFRA Section 3(g)L
Facing the enormous job of re-reviewing and calling-in new data for the
approximately 35,000 current registrations, and realizing the inefficiencies of
the 'product by product1 approach, the Agency decided that a new, more
effective method of review was needed.
A new review procedure has been developed. Under it, EPA publishes
docunents called Registration Standards, each of which discusses a particular
pesticide active ingredient. Each Registration Standard summarizes all the
data available to the Agency on a particular active ingredient and its current
uses, and sets forth the Agency's comprehensive position on the conditions and
requirements for registration of all existing and future products which contain
that active ingredient. These conditions and requirements, all of which must
be met to obtain or retain full registration or re-registration under Section
3(c)(5) of FIFRA, include the submission of needed scientific data which the
Agency does not now have, compliance with standards of toxicity, conposition,
labeling, and packaging, and satisfaction of the data compensation provisions
of FIFRA Section 3(c)(1)(D).
The Standard will also serve as a tool for product classification. As part
of the registration of a pesticide product, EPA may classify each product for
"general use" or "restricted use" [FIFRA Section 3(d)]. A pesticide is
classified for "restricted use" when some special regulatory restriction is
needed to ensure against unreasonable adverse effects to man or the
environment. Many such risks of unreasonable adverse effects can be lessened
if expressly-designed label precautions are strictly followed. Thus the
special regulatory restriction for a "restricted use" pesticide is usually a
requirement that it be applied only by, or under the supervision of, an
applicator who has been certified by the State or Federal government as being
competent to use pesticides safely, responsibly, and in accordance with label
directions. A restricted-use pesticide can have other regulatory restrictions
[40 CFR 162.11(c)(5)] instead of, or in addition to, the certified applicator
requirement. These other regulatory restrictions may include such actions as
seasonal or regional limitations on use, or a requirement for the monitoring of
residue levels after use. A pesticide classified for "general use," or not
classified at all, is available for use by any individual who is in compliance
with State or local regulations. The Registration Standard review compares
information about potential adverse effects of specific uses of the pesticide
with risk criteria listed in 40 CFR 162.11(c), and thereby determines whether a
product needs to be classified for "restricted use." If the Standard does
classify a pesticide for "restricted use," this determination is stated in the
second chapter,
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Requirement £o Re-register Under the Standard
FIFRA Section 3(g), as amended in 1978, directs EPA to re-register all
currently registered products as expeditiously as possible. Congress also
agreed that re-registration should be accomplished by the use of Registration
Standards.
Each registrant of a currently registered product to which this Standard
applies, and who wishes to continue to sell or distribute his product in
commerce, must apply for re-regisration. His application must contain proposed
labeling that complies with this Standard.
EPA will issue a notice of intent to cancel the registration of any
currently registered product to which this Standard applies if the registrant
fails to comply with the procedures for re-registration set forth in the
Guidance Package which accompanies this Standard.
"Product Specific" Data and "Generic" Data
In the course of developing this Standard, EPA has determined the types of
data needed for evaluation of the properties and effects of products to which
the Standard applies, in the disciplinary areas of Product Chemistry,
Environmental Fate, Toxicology, Residue Chemistry, and Ecological Effects.
These determinations are based primarily on the data Guidelines proposed in
1978 (43 FR 29686, July 10, 1978, and 43 FR 37336, August 2, 1978), as applied
to the use patterns of the products to which this Standard applies. Where it
appeared that data from a normally applicable Guidelines requirement was
actually unnecessary to evaluate these products, the Standard indicates that
the requirement has been waived. On the other hand, in some cases studies not
required by the Guidelines may be needed because of the particular composition,
or use pattern of products the Standard covers; if so, the Standard explains
the Agency's reasoning. Data guidelines have not yet been proposed for the
Residue Chemistry discipline, but the requirements for such data have been in
effect for some time and are, the Agency believes, relatively familiar to
registrants. Data which we have found are needed to evaluate the
registrability of some products covered by the Standard may not be needed for
the evaluation of other products, depending upon the composition, formulation
type, and intended uses of the product in question. The Standard states which
data requirements apply to which product categories. (See the second chapter.)
The various kinds of data normally required for registration of a pesticide
product can be divided into two basic groups:
(A) data that is "product specific," i.e., data that relates only to
the properties or effects of a product with a particular composition
(or a group of products with closely similar composition); and
(B) "generic" data that pertains to the properties or effects of a
particular ingredient, and thus is relevant to an evaluation of the
risks and benefits of all products containing that ingredient (or all
such products having a certain use pattern), regardless of any such
product's unique composition.
The Agency requires certain "product specific" data for each product to
characterize the product's particular composition and physical/chemical
properties (Product Chemistry), and to characterize the product's acute
toxicity (which is a function of its total composition). The applicant for
registration or re-registration of any product, whether it is a manufacturing-
use or end-use product, and without regard to its intended use pattern, must
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submit or cite enough of this kind of data to allow EPA to evaluate the
product. For such purposes, "product specific" data on any product other than
the applicant's is irrelevant, unless the other product is closely similar in
'composition to the applicant's. (Where it has been found practicable to group
similar products for purposes of evaluating, with a single set of tests, all
products in the group, the Standard so indicates.) "Product, specific" data on
the efficacy of particular end-use products is also required where the exact
formulation may affect efficacy and where failure of efficacy could cause
public health problems.
.All other data needed to evaluate pesticide products concerns the
properties or effects of a particular ingredient of products (normally a
pesticidally active ingredient, but in some cases a pesticidally inactive, or
"inert," ingredient). Some data in this "generic" category are required to
evaluate the properties and effects of all products containing that ingredient
[e.g., the acute LD-50 of the active ingredient in its technical or purer
grade; see proposed 40 CFR I63.8l-1(a), 43 FR 37355].
Other "generic" .data are required to evaluate all products which both
contain a particular ingredient and are intended for certain uses (see, e.g.,
proposed 40 .CFR 163.82-1, 43 FR 37363, which requires subchronic oral testing
of the active ingredient with respect to certain use patterns only). Where a
particular data requirement is use-pattern dependent, it will apply to each
end-use product which is to be labeled for that use pattern (except where such
end-use product is formulated from a registered manufacturing-use product
permitting such formulations) and to each manufacturing-use product with
labeling that allows it to be used to make end-use products with that use
pattern. Thus, for example, a subchronic oral dosing study is needed to
evaluate the safety of any manufacturing-use product that legally could be used
to make an end-use, food-crop pesticide. But if an end-use product's label
specified it was for use only in ways that involved no food/feed exposure and
no repeated human exposure, the subchronic oral dosing study would not be
required to evaluate the product's safety; and if a manufacturing-use
product's label states that the product is for use only in making end-use
products not involving food/feed use or repeated human exposure, that
subchronic oral study would not be relevant to the evaluation of the
manufacturing-use product either.
If a registrant of a currently registered manufacturing-use or end-use
product wishes to avoid the costs of data compensation [under FIFRA Section
3(c)(1)(D)] or data generation [under Section 3(c)(2)(B)]'for "generic" data
that is required only with respect to some use patterns, he may elect to delete
those use patterns from his labeling at the time he re-registers his product.
An applicant for registration of a new product under this Standard may
similarly request approval for only certain use patterns.
Data Compensation Requirements under FIFRA 3(c)(1)(D)
Under FIFRA Section 3(c)(1)(D), an applicant for registration, re-
registration, or amended registration must offer to pay compensation for
certain existing data the Agency has used in developing the Registration
Standard. The data for which compensation must be offered is all data which is
described by all the following criteria:
(1) the data were first submitted to EPA (or to its predecessor agencies,
USDA or FDA), on or after January 1, 1970;
(2) the data were submitted to EPA (or USDA or FDA) by some other
applicant or registrant in support of an application for an
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experimental use permit, an amendment adding a new use to a
registration, or for re-registration, or to support or maintain in
effect an existing registration;
(3) the data are relevant to the Agency's decision to register or re-
register the applicant's product under the Registration Standard,
taking into account the applicant's product's composition and intended
use pattern(s);
(4) the data are determined by EPA to be valid and usable in reaching
regulatory conclusions; and
(5) the data are not those for which the applicant has been exempted by
FIFRA Section 3(c)(2)(D) from the duty to offer to pay compensation.
(This exemption applies to the "generic" data concerning the safety of
an active ingredient of the applicant's product, not to "product
specific" data. The exemption is available only to applicants whose
product is labeled for end-uses for which the active ingredient in
question is present in the applicant's product because of his use of
another registered product containing that active ingredient which he
purchases from another producer.)
An applicant for re-registration of an already registered product under
this Standard, or for registration of a new product under this Standard,
accordingly must determine which of the data used by EPA in developing the
Standard must be the subject of an offer to pay compensation, and must submit
with his application the appropriate statements evidencing his compliance with
FIFRA .Section 3(c)(1)(D)'.
An applicant would never be required to offer to pay for "product specific"
data submitted by another firm. In many, if not in most cases, data which are
specific to another firm's product will not suffice to allow.EPA to evaluate
the applicant's product, that is, will not be useful to the Agency in determin-
ing whether the applicant's product is registrable. There may be cases, how-
ever, where because of close similarities between the composition of two or
more products, another firm's data may suffice to allow EPA to evaluate some or
all of the "product specific" aspects of the applicant's product. In such a
case, the applicant may choose to cite that data instead of submitting data
from tests on his own product, and if he chooses that option, he would have to _
comply with the offer-to-pay requirements of Section 3(O(1)(D) for that data.
Each applicant for registration or re-registration of a manufacturing-use
product, and each applicant for registration or re-registration of an end-use
product, who is not exempted by FIFRA Section 3(c)(2)(D), must comply with the
Section 3(c)(1)(D) requirements with respect to each item of "generic" data
that relates to his product's intended uses.
A detailed description of the procedures an applicant must follow in
applying for re-registration (or new registration) under this Standard is found
in the Guidance Package for this Standard.
Obtaining Data to Fill "Data Gaps"; FIFRA 3(c)(2)(B)
Some of the kinds of data EPA needs for its evaluation of the properties
and effects of products to which this Standard applies have never been
submitted to the Agency (or, if submitted, have been found to have deficiencies
rendering them inadequate for making registrability decisions) and 'nave not
been located in the published literature search that EPA conducted as part of
preparing this Standard. Such instances of missing but required data are
referred to in the Standard as "data gaps".
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FIFRA Section 3(c)(2)(B)f. added to FIFRA by the Congress in 1978,
authorizes EPA to require registrants to whom.a data requirement applies to
generate (or otherwise produce) data to fill such "gaps" and submit those data
to EPA. EPA must allow a reasonably sufficient period for this to be
accomplished. If a registrant fails to take appropriate and timely steps to
fill the data gaps identified by a section 3(c)(2)(B) order, his product's
registration may be suspended until the data are submitted. A mechanism is
provided whereby two or more registrants may agree to share in the costs of
producing data for which they- are both responsible.
The Standard lists, in its summary second chapter, the '^generic" data gaps
and notes the classes of products to .which these data gaps pertain. The
Standard also points out that to be registrable under the Standard, a product
must be supported by certain required "product spe::fic" data. In some cases,
the Agency may possess sufficient "product specific" data on one currently
registered product, but may lack such data on another. Only those Standards
which apply to a very small number of currently registered products will
attempt to state definitively the "product specific" data gaps on a 'product by
product' basis. (Although the Standard will in some cases note which data that
EPA does possess would suffice to satisfy.certain "product specific" data
requirements for a category of products with closely similar composition
characteristics.)
As part of the process of re-registering currently registered products, EPA
will issue Section 3(c)(2)(B) directives requiring the registrants to take
appropriate steps to fill all identified data gaps —.whether that'data in
question is "product specific" or "generic" — in accordance with a schedule.
Persons who wish to obtain registrations for new products under this
Standard will be required to submit (or cite) sufficient "product specific"
data before their applications are approved. Upon registration, they will be
required under Section 3(c)(2)(B) to take appropriate steps to submit data
needed to fill "generic" data gaps. (We expect they will respond to this
requirement by entering into cost-sharing agreements with other registrants who
previously have been told they must furnish the data.) The Guidance Package
for this Standard details the steps that must be. taken by registrants to comply
with .Section 3(c)(2)(B).
Amendments to the Standard
Applications for registration which propose uses or formulations that are
not presently covered by the Standard, or which present product compositions,
product chemistry data, hazard data, toxicity levels, or labeling that do not
meet the requirements of the Standard, will automatically be considered by the
Agency to be requests for amendments to the Standard. In response to such
applications, the Agency may request additional data to support the proposed
amendment to the Standard, or may deny the application for registration on the
grounds that the proposed product would cause unreasonable adverse effects to
the environment. In the former case, when additional data have been
satisfactorily supplied, and providing that the data do not indicate the
potential for unreasonable adverse effects, the Agency will then amend the
Standard to cover the new registration.
Each Registration Standard is based upon all data and information available
to the Agency's reviewers on a particular date prior to the publication date.
Tnis "cut-off" date is stated at the beginning of the second chapter. Any
subsequent data submissions and any approved amendments will be incorporated
into the Registration Standard by means of addenda, which are available for
inspection at EPA in Washington, D.C., or copies of which may be requested from
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he Agency. When all the present "data gaps" have been filled and the
ubmitted data have been reviewed, the Agency will revise the Registration
tandard. Thereafter, when the Agency determines that the internally
aintained addenda have significantly altered the conditions for registration
nder the Standard, the document will be updated and re-issued for publication.
While the Registration Standard discusses only the uses and hazards of
roducts containing the designated active ingredient(s), the Agency is also
oncerned with the potential hazards of some inert ingredients and impurities.
ndependent of the development of any one Standard, the Agency has initiated
he evaluation of some inert pesticide ingredients. Where the Agency has
dentified inert ingredients of concern in a specific product to which the
tandard applies, these ingredients will be pointed out in the Guidance Package.
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II. Regulatory Position
This chapter presents the Agency's decision on what Standards of
product composition, toxicity, use, labeling, and packaging are
required for the pesticide active ingredient in question. The
decision complies with the rules and regulations (40 CFR 162)
used to implement the Federal Insecticide, Fungicide, and
Rodenticide Act, as amended (FIFRA), and with the Agency's
present regulatory policies. There are different requirements
for manufacturing-use chemicals and for each type of end-use
formulation which present a significantly different set of
hazards. This Registration Standard is based upon all data and
information on 4-aminopyridine available to the Agency's
reviewers as of December 23, 1979.
Two companies have submitted data in support of their
registration of 4-aminopyridine products: Phillips Petroleum
Company of Bartlesville, Okla. and Avitol Corporation of Tulsa,
Okla. These data may be cited by other registrancs or
applicants for registration, when appropriate, to support the
registration(s) of their own product(s) provided they have
offered and agreed to pay compensation as required by FIFRA
Sections 5(c)(1)(d) and 3(c)(2)(d). Anyone wishing to cite data
submitted by Avitrol Corporation or Phillips Petroleum Company
must offer and agree to pay compensation to Avitrol Corporation
since Phillips Petroleum Company sold all 4-aminopyridine
registration rights to Avitrol Corporation in 1972 and has
requested not to receive compensation offers.
Manufacturing-Use
The Agency has reviewed all data available to it. Although
incomplete, these data indicate that manufacturing-use 4-
aminopyridine is suitable for registration because it does not
meet or exceed the risk criteria leading to a Rebuttable
Presumption Against Registration [Chapter 40, Section 1o2.119a)
of the Code of Federal Regulations]. Data gaps have been
identified; when these data are supplied, the Agency will again
review the registration status of this compound.
In order to be covered under this Standard, a manufacturing-use
4-aminopyridine product must comply with the following
standards. A manufacturing-use 4-aminopyridine product
must contain 4-aminopyridine as an active ingredient.
Intentionally added inerts present in quantities greater than
0.10/&, by weight of the total product, must consist of food or
feedstuffs only. Manufacturing-use 4-aminopyridine products may
fall into Toxicity Categories I through IV for the following
acute effects:
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Acute Oral Toxicity;
Acute Dermal Toxicity;
Acute Inhalation Toxicity;
•'••
Primary Eye Irritation; and
Primary Dermal Irritation
Labels for manufacturing-use products must include the
following:
1. The intended end-use of products formulated from
manufacturing-use products must be stated on the
manufacturing-use products' label. All manufacturing-use 4-
aminopyridine products must therefore carry the following
statement on the label: For Formulation into End-Use
Products Intended only for Bird Control.
2. All manufacturing-use 4-aminopyridine products must
carry the following warning on the label, under the "Hazards
to Wildlife" section:
This pesticide is toxic to birds and fish.
Do not discharge into lakes, streams, ponds
or public water unless in accordance with
an NPDES permit. For guidance contact your
Regional Office of the EPA.
3. All manufacturing-use 4-aminopyridine products must
carry the following statement of practical treatment on the
label.
If swallowed:
If the patient is unconcious, maintain
breathing and heartbeat (CPR:
cardiopulmonary resuscitation). Contact
your local Poison Control Center,
hospital of physician immediately.
If patient is conscious, induce vomiting
with syrup of ipecac (if not available
stimulate the back of the throat with
finger). Never give anything by mouth
to an unconscious person. Contact your
local Poison Control Center, hospital
or physician immediately.
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4. Manufacturing-use product labels must comply with the
requirements of 40 CFR 162.10 regarding toxicity hazard
warnings, first aid statements, and label format, including
placment of hazard warnings on the label, type size and
color, etc.
To be covered under this Standard, all applicants for
registration or re-registration of technical and formulation
intermediate products must agree to cite or submit the following
information on the physical/chemical composition of each
proposed product. Listed after each' data gap is the section of
of the Proposed Guidelines which describes that type of data and
when it is required [43 FR, No. 132, 29696 of July 10, 1978; and
43 FR, No. 163, 37336 of August 22, 1978].
Product Chemistry Guideline Section
For All Manufacturing-Use Products
1. Density or specific gravity 163.61-8Cc)(8)
For Technical
2. Chemical Identity 163.61-3
Process
4. Product Analytical Methods 163.61-7
and Data
5. Solubility 163.6l-8(c)(4 )
6. Octanol/Water Partition 163.61-8(c)(6)
Co-efficient
7. pH-Aqueous solution 163.6l-8(c)(11)
4-Aminopyridine Formulations
In order to be covered under this Standard, an end-use, ready-to-
use bait or dust 4-aminopyridine product must contain 4-
aminopyridine as an active ingredient. All 4-aminopyridine
ready-to-use bait and dust products, regardless of the Toxicity
Categories assigned for acute effects, are classified as
restricted use pesticides and must consequently bear the label
statement: "For sale to and use only by Certified Applicators
or persons under their direct supervision."
In addition, 4-aminopyridine formulated products must comply
with the following standards.
Ready-to-use Baits
1. Intentionally added inerts present in quantities greater
than Q.10%, by weight of the total product, must consist of
food or feedstuffs only.
2. When registered for use in agricultural crops, the
product must not exceed 0.03%, by weight of the total
product, 4-aminopyridine. The product may consist of 3.02
or less 4-aminopyridine per treated granule if it is
diluted, prior to packaging, at a ratio of 1 treated
granule to 99 untreated granules.
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3. When registered for the control of house sparrows,
cowbirds, blackbirds, or pigeons at nesting and roosting
structures, the product must not exceed 0.52, by weight of
the total product, 4-aminopyridine.
4. When registered for the control of crows at nesting and
roosting structures or for the control of starlings in
cattle feedlots, the product must not exceed 1.05», by
weight of the total product, 4-aminopyridine.
Dusts
1. Intentionally added inerts must consist of food or feed
stuffs only.
2. When registered for the control of Herring gulls at
nesting and roosting structures and at sanitary landfills,
the product must not exceed 25%, by weight, 4-aminopyridine.
3. When registered for the control of starlings in cattle
feedlots, the product must not exceed 50%, by weight, 4-
aminopyridine.
Labels for 4-aminopyridine formulated products must include the
following:
1. All 4-aminopyridine formulated products must bear the
following statement of practical treatment on the front
panel of the label:
If swallowed:
If the patient is unconcious, maintain
breathing and heartbeat (CPR:
cardiopulmonary resuscitation). Contact
your local Poison Control Center,
hospital or physician immediately.
If patient is conscious, induce vomiting
with syrup or ipecac (if not available
stimulate the back of the throat with
finger). Never give anything by mouth
to an unconscious person! Contact your
local Poison Control Center, hospital
or physician immediately.
2. Each 4-aminopyridine formulated product must carry on
the label toxicity hazard warnings and first aid statements
appropriate to the Toxicity Categories assigned to that
product for acute effects [refer to 40 CFR 162.10] with the
following exception. If registrants of 4-aminopyridine dust
products do not agree to provide or cite data on the
teratogenic or mutagenic potential of 4-aminopyridina [Refer
to Toxicology Chapter], all 4-aminopyridine dust products,
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regardless of the Toxicity Categories assigned for acute
inhalation toxicity and acute dsrmal toxicity, must require
applicators to wear protective clothing including long
sleeves, gloves, and respirators.
3. 4-aminopyridine formulated products must include the
following warnings under the "Hazards to Wildlife" section:
a. For all products
This product is toxic to birds and fish. Do not
contaminate water by cleaning of equipment or
disposal of wastes.
b. For products intended for, use in agricultural
crops.
Do not allow bait to remain in unprotected places
after control measures are completed.
c. For ready-to-use bait products containing greater
than". 3.0% (per treated granule) 4-aminopyridine
and all dust products.
Pick up and dispose of dead birds by burial.
4. All 4-aminopyridine formulated products must include the
following under the section for Use Restrictions:
a. For all products
Before application in your .area, consult endangered
species personnel of the U.S. Fish and Wildlife
Service to ensure that endangered and rare bird
species are not likely be adversely affected by use
of this product.
b. For, all products except those intended for the
control of. Herring gulls
Investigate local laws that may prohibit the use of
any toxic chemical in bird control.
For all products
LProduct Name]Is a poison with flock alarming
properties used for the control of
(type of birds) in such a way that a. part of a
flock may react and frighten the rest away. Birds
that react and alarm a flock usually die.
Do not use where food (grain or meat) might become
contaminated.
d. For all products, intended, for use in agricultural
crops
This product must be applied in accordance
with 40 CFR Part 170.
-12-
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Registrants may amplify the above statement on
labels or labeling by stating the requirements of
40 CFR Part 170 or additions thereto if they
choose.
For pretreated baits
Do not feed to livestock or poultry.
Do not mix with grain for livestock or poultry.
For dust products
Keep away -from livestock, poultry, and pets.
For products intended for, use in cattle
feed lots
Keep bait off the ground, out of reach of
cattle.
5. All formulated 4-aminopyridine products must specify al'.
prebaiting methods on the label, under the section
"Prebaiting Directions". If the product is intended for us<
at sanitary landfills or at target species' nesting and
roosting sites the directions must include the following
statement.
This product must not be applied where
nontarget birds feed. Careful
observation of the birds' feeding habits
must therefore be made to establish
proper feeding locations and to
determine that no nontarget birds
are feeding on the prebait.
6. All 4-aminopyridine ready-to-use bait products intended
for use in agricultural crops must specify all application
methods and rates on the label, under the section "Baiting
Directions". Baiting directions must include the following
statement:
Confine treatment to areas 50 feet in from field edge.
No application rate in excess of .0144 ounces 4-
aminopyridine per acre on the portion being treated may be
recommended. Directions may not recommend more than four
applications per crop season for corn or more than five
applications per crop season for sunflowers.
If the product is intended for use at sanitary landfills,
cattle feed lots, or nesting and roosting sites, baiting
directions must include the following:
13-
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To obtain minimal mortality the
distribution of [PRODUCT NAME] should be
limited to scattered spot placements
that will provide feeding opportunities
only for the necessary number of target
birds. After the birds' feeding pattern
has been established through prebaiting,
replace untreated bait with diluted
treated bait only at sites where target
birds are actively feeding. Do not
apply treated bait to inactive feeding
sites. Pick up and destroy untreated
bait at the end of each day.
7. All 4-aminopyridine dust products must specify all bait
preparation methods on the label under the section "Bait
Preparation Directions". Bait preparation directions must
include the following statement.
"Materials resembling human food'must be altered in
form by crushing, balling, or pelleting so that they
are not readily recognizable as human food."
8. All 4-Aminopyridine products except ready-to-use baits
intended for use on agricultural crops must specify all
dilution methods and rates on the label under the section
"Dilution Directions." Recommended dilution ratios must
comply with the following:
If the product is intended for the control of pigeons
near nesting and roosting sites, no dilution ratio less
than 1 part treated bait to 9 parts treated bait may
be recommended. A dilution ratio of 1 part treated
bait to 29 parts untreated bait should be recommended
for normal use (i.e. situations where other bird food
is plentiful).
If the product is intended for the control of sparrows,
blackbirds, cowbirds, or crows in nesting or roosting
structures, or for use in cattle feedlots, no dilution
ratio less than 1 part treated bait to 9 parts
untreated bait may be recommended.
If the product is intended for the control of Herring
gulls at sanitary landfills or nesting and roosting
sites, no dilution ratio less than 1 part treated bait
to 10 parts untreated bait may be recommended.
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9. Labels for 4-Aminopyridine formulated products must
comply with the requirements of 40 CFR 162.10 regarding
label format, including placement of hazard warnings on the
label, type size and color, etc.
To be covered under this Standard, all applicants for
registration or reregistration of 4-aminopyridine ready-to-use
bait and dust products must agree to submit or cite the
following information on the physical/chemical composition of
each proposed product. Listed after each data gap is the
section in the Proposed Guidelines which describes that type of
data and when it is required [43 FR, No. 132, 19696 of July 10,
1973; and 43 FR, No. 162,37336 of August 22, 1978].
Product Chemistry Guideline Section
1. Color 163.51-dCc)(1)
2. Odor I63.61-8(c) (2)
3. Density 163.61-8(c) (3)
4. Storage Stability 163.61-8(c)(12)
5. Formation of Unintentional
Ingredients 163.61-5
6. Percentages of Compounds 163.61-6
Pesticid-. Products
All applicants for registration or re-registration of dust
products must also agree to provide or cite an acute
inhalation toxicity study (163.81-3) on a dust formulation.
Two toxicology data requirements for 4-Aminopyridine dust
products are contingent upon label restrictions. Applicants
for registration or re-registration of dust products must
require applicators, by the label, to wear protective
clothing including long sleeves, gloves, and respirators or
they must agree to provide or cite the following studies:
Toxicology
Teratogenicity 163.83-3
Mutagenicity 163.34-111,2,2,4
Although certain 4-aminopyridine products are used to control
birds at public facilities the Agency does not consider this use
a public health use. The Agency is therefore waiving all
efficacy requirements. In support of this waiver, when 4-
aminopyridine products are used to control nuisance birds at
public facilities, the user can readily see the results of the
intended action of the pesticide, thereby eleminating the need
for efficacy data.
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Applicants are hereby advised that if the Agency does not
receive commitments, within the specified time period, from
manufacturing-use producers to fill data gaps identified for
the manufacturing-use material, the registrations of the
manufacturing-use products will be suspended. Formulators m
then bear the burden of supplying the data if they want the
manufacturing use product to be available.
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III. Product Chemistry
Product Chemistry Introduction
FIFRA 3(c)(2)(A) requires the Agency to establish guidelines for registering
pesticides in the United States. Registrants are required to provide
quantitative data on all added ingredients, active and inert, which are equal
to or greater than 0. U of the product by weight.
To establish the composition of products proposed for registration, the Agency
requires data and information not only on the manufacturing and formulation
processes, but also a discussion on the formation of manufacturing impurities
and other product ingredients, intentional and unintentional. Further, to
assure that the composition of the product as marketed will not vary from the
composition evaluated at the time of registration, applicants .are required to
submit a statement certifying upper and lower composition limits for the added
ingredients, or upper limits only for sane unintentional ingredients. Subpart D
suggests specific precision limits for ingredients based on the percentage of
ingredient and the standard deviation of the analytic method.
In addition to the data on product composition, the Agency also requires data
to establish the physical and chemical properties of both the pesticide active
ingredient and its formulations. For example, data are needed concerning the
identity and physical state of the active ingredient (e.g., melting and boiling
point data, vapor pressure and solubility). Data are also required on the
properties of the formulated product to establish labeling cautions (e.g.,
flammability, corrosivity or storage stability). The Agency uses these data to
characterize each pesticide and to determine its environmental and health
hazards.
The number in parenthesis next to the subheadings in the Product Chemistry
Topical Discussions corresponds to the number of the section in the "Proposed
Guidelines for Registering Pesticides in the United States" (43 FR 29696)
which fully explains the minimum product chemistry data requirements.
Topical Discussions
Chemical. Identity. .(163..6.1 -3)
At present there is no acceptable common name for the bird repellent, 4-
aminopyridine (3th Collective Index, 1973). Other chemical names for the.
compound include 4-pyridinamine (9th Collective Index, 1977), gamma-
aminopyridine, and p-aminopyridine. "4-AP" is a commonly used abbreviation
while "Avitrol", "Avitrol 200", "Compound 1861", and "Phillips 1861" are all
trade names.
The Phillips Petroleum Company (no date, 00004019) speculated that 4-
aminopyridine may also exist as a tautoneric form. However, Craig (1968,
05010341) presented an NMR spectral study 'which confirmed the amino structure.
Baer (1943, 05006181) also confirmed the amino structure with U.V. absorption
spectra data. Further characterization of 4-aminopyridine is noted in Appendix
A, Chemical Data Sheet.
-.17-.
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Manufacturing, Process (l63.6l:-4)
The Phillips Petroleum Company (Hyden, 1968, 00004143) submitted a description
of the manufacturing process (Appendix B, Manufacturing Process, Confidential)
in 1968. However, Phillips sold its 4-aminopyridine patents to Avitrol
Corporation in 1972. The Agency has no information on the present commercial
method of manufacture, which is conducted solely by Avitrol Corporation.
Two methods of preparing 4-aminopyridine have been discussed in the literature
(Baer, 1943, 05006181). One method involves preparation from chelidonic acid,
through 4-chlorpyridine-2,6-dicarboxylic acid. The second method involves
preparation from pyridylpyridinium dichloride. It is uncertain whether either
of these methods is currently used for coranercial manufacture.
Formation of Unintentional. Ingredients 063.61-5,)
The Phillips Petroleum Company submitted information (Hyden, 1968, 00004148) on
the contaminants of technical 4-aminopyridine but did not support the
information with analytical data (Appendix B, Manufacturing Process,
Confidential). In addition, no information is available on the contaminants
which result from the current manufacturing process of 4-aminopyridine.
Additional data on the formation of unintentional ingredients are therefore
required.
Active Ingredient Limits .in Pesticide Products (163.61-6.)
The technical chemical prepared by Phillips Petroleum Company contained a
minimum of 98£ active ingredient (Hyden, 1968, 00004148). The confidential
formula of the manufacturing use product is described in Appendix C,
Formulation Processes, (Confidential). The formulas of nine products which
appear on the labels are listed in Appendix B, Summary of Label Ingredient v
Statements. Certification of active and inert ingredients is not possible at
this time due to a lack of information on the currently used manufacturing
process for 4-Aminopyridine and the length of time which has passed since the
original submission of formulas for registered products.
Product Analytical Methods and. Data ,(,163.6.1-7,)
Phillips Petroleum (1962, 00003978, 1920, 00004020) submitted a method for
analysis, by U.V. spectrophotometry, of grain seed impregnated with 0.1$ - 3.02
4-aminopyridine. This method was also used to assay their analytical
standard. The EPA Manual (1976) describes a similar U.V. method for use on
solid formulations. This method is adequate for the characterization of 4-
aminopyridine. However, if impurities in the technical material were to be
identified, analytical methods would also be needed for their assay.
Physical/Chemical Properties (.153.61-8.)
Tne following information (Phillips, 00004019, 00004112) applies to the
technical compound except where otherwise noted.
-18-
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Color; White (purified).
Off-white (technical grade).
No color reported for formulated products.
Odor: None (purified).
Slightly musty (technical).
No odor reported for formulated products.
Melting point: 158.9°C, (purified).
155-158 C. (technical).
Solubility: Water — given as both 3% and 12% (free base).
— 50% (HC1 salt).
Acids — soluble as the salts.
Acetone — moderately to very soluble.
Methanol — soluble.
Ether — soluble.
Benzene — soluble.
Soluble in most polar solvents.
These data are not adequate to assess the solubility of 4-aminopyrid^ne.
Solubilities must be expressed in quantitative terms, (g/100ml at 20 C,
or ppm).
Stability: The free base9is moderately stable to light. An aqueous
solution of free base darkens slowly in light. The hydrochloride salt is
light stable.
Qctanol/Water Partition Coefficient: Mone reported.
Physical State: Crystalline solid (technical). The formulation
intermediate is a granular (impregnated grain). The formulated products
consist of granulars (impregnated grains), dusts and pelletized
baits.
Density or Specific Gravity: Not reported.
Boiling. Point: 273-274°C (760 mm Hg, technical).
Not applicable for formulated products.
Vapor Pressure: None reported (technical).
jg£: Basic in reaction (technical).
Storage Stability: Four 0.25% 4-aminopyridine formulations of different
impregnated grains were studied over a period of eight months at 82 F and
140-150T after storage in four different kinds of containers. No 4-
aminopyridine loss was reported. Actual use experiments were carried out
for over a year on four 0.5/5 formulations with the same four impregnated
grains. No loss of 4-aminopyridine was reported in the samples stored in
completely protected feeders. There was a 40-50% loss of 4-aminopyridine
in samples partly exposed to the weather.
-19-
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Flammability: Not applicable.
Oxidizing or Reducing Action: Not reported.
Explosiveness: Not reported.
Miscibility: Not applicable.
Viscosity: Not applicable. .
Corrosion Characteristics: Not reported.
DISCIPLINARY REVIEW
Product Chemistry Profile
Data Gaps
Required Labeling
Product Chemistry. Profile
"Avitrol" is a well-known trade name for 4-aminopyridine. "4-AP" is a commonly
used abbreviation. The technical compound is an off-white crystalline solid
with a slightly musty odor. The hydrochloride salt is stable in light and
soluble in water, acids, and most organic solvents. The°technical compound is
manufactured by the Avitrol Corporation in an integrated formulation system
to produce a 0.3J impregnated grain formulation intermediate and end-use
products.
The manufacturing-use product produced by Avitrol is reformulated into
additional products by the Woodbury Chemical Company and the Huge' Company.
All 4-aminopyridine is ultimately formulated into baits. Most of the end-use
products are ready-to-use baits in which 4-aminopyridine is mixed with a
variety of foodstuffs such as corn, wheat, sorghum, and mixed grains. The
remaining end-use products are dust concentrates consisting of cornstarch
and 25* or 50% 4-aminopyridine. These dusts are used to coat bread or french
fries in order to make finished baits.
Data. Gaps
Listed below are Product Chemistry data needed to obtain registration or
reregistration for 4-aminopyridine products. Listed after each data gap is the
number of the section in the Proposed Guidelines (July 10, 1978, 43 FR, No.
132,29696) which describes that type of data and when it is required.
-20-
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For Technical
1) Chemical Identity —
Complete identification of all impurities
and reaction compounds (if any) in the
technical chemical.
2) Manufacturing Process —
Complete description of the present-day
manufacturing process, including type of
process, equipment, quality control
measures, etc.
3) Product Analytical Methods and Data —
Methods of analysis for identifiable
impurities (if any) in the technical compound.
4) Solubility — in quantitative terms
5) Octanol/Water Partition Coefficient
6) pH — aqueous solution
For Manufacturing.-use. Product:
7) Density
For Formulations .(Readyrto-Use Baits and Dusts,):
8) Color
9) Odor
10) Density
11) Storage Stability (dust and pellets only)
12) Formulation of Unintentional Ingredients —
Theoretical discussion of the formation
of each substance, aside from the active
ingredient and intentionally added inert
ingredients, that might reasonably be
identifiable as being present in the
pesticide product.
13) Percentages of Components in Pesticide Products —
Declaration/certification of limits for all
active and inert ingredients.
Guideline Section
163.61-3
163.61-4
163.61-7
163.61-3(0)
163.61-8(c)(6)
163.61-8(c)(8)
I63.61-8(c)(1)
I63.61-8(c) (2)
163.61-8(c)(8)
163.61-8(0)(12)
163.61-5
163.61-6
Required Labeling
The ingredient statement will list the active ingredient as:
4-aminopyridine ...._%
Additional labeling may be.required following review of physical/chemical
properties data provided at the time of registration or reregistration.
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Product Chemistry Bibliography
05006181 Baer, J.E. (19*18) Alkyl Polysulfide and 4-aminopyridine and
Related Compounds [Doctoral Dissertation]. Philadelphia, Pa:
University of Pennsylvania. (Twenty-one unpaged figures)
05010341 Craig, J.C., Jr.; Pearson, D.E. (1968) NMR proof of the structure
of 4-aminoquinolines and pyridines. Journal of Heterocyclic
Chemistry 5(5):631-637.
00004143 Hyden, S. (1968) Bird Management Process: LDG-123-68P. (Unpub-
lished study received Jul 17, 1968 under unknown admin, no.;
prepared by Nepera Chemical Co., submitted by Phillips Petro-
leum Co., Bartlesville, Okla.; CDL:103068-A)
00004112 Phillips Petroleum Company (no date) Technical Data Sheet: Phillips
Avitrol 200 (1861). (Unpublished study received 1968 under un-
known admin, no.; CDL:221959-B)
00004019 Phillips Petroleum Company (no date) [Identity, Physical and
Chemical Properties, and Formulations of Avitrol]. (Unpublished
study received Jul 13, 1970 under 1F1013; CDL:093322-D)
00003978 Phillips Petroleum Company (1962) Determination of 4-aminopyridine
in Grain Seed: Ultraviolet Spectrophotonetric Method. Method
PK-62R dated Jan 12, 1962. (Unpublished study received Aug 13,
1963 under 224-EX-1; CDL: 122741^A)
00004020 Phillips Petroleum Company (1970) Determination of 4-aminopyridine
in Grain Seed Ultraviolet Spectrophotonetric Method.
(Unpublished study including letter dated Jun 26, 1970 from
A.M. Schnitzer to U.S. Food and Drug Administration, Pesticides
Branch, Reference Standards Section, received July 13, 1970
under 1F1013; CDL:093322-F)
Standard. References
Chemical Abstracts Service (1973) Chemical Abstracts 8th collective
index, Vols 66-75 (1967-1971), American Chemical Society.
Chemical Abstracts Service (1977) Chemical Abstracts 9th collective
index, Vols 76-85 (1972-1976), American Chemical Society.
U.S. Environmental Protection Agency (1976) Manual of chemical
methods for pesticides and devices. Washington, D.C.
U.S. Environmental Protection Agency (1978) Proposed Guidelines for
the registering of pesticides in the United States.
Federal Register., 43 (132) 29696 - (July 10, 1978).
-22-
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IV. Environmental Fate
Use Profile
4-aminopyridine is the active ingredient in several federally
registered pesticide products. It is currently registered for
the control of nuisance and depredatory birds such as
blackbirds, crows, cowbirds, starlings, gulls, and common
grackles. Application sites include field corn, sweet corn, and
sunflower fields, and urban and agricultural premises. Between
330 and 350 pounds of 4-aminopyridine are produced yearly
(Avitrol, 1980, personal communication). Approximately 104
pounds are used on agricultural crops and approximately 240
pounds are used on agricultural premises and in urban areas.
All 4-aminopyridine is ultimately formulated into baits. The
baits are placed in areas where large numbers of nuisance or
depredatory birds congregate. The baits work by causing the
birds that eat them to utter distress calls which serve to scare
the rest of the flock away. Birds that eat the treated bait
usually die.
Registered 4-aminopyridine products which are .used on crops
are 3% pretreated baits. The baits are mixed prior to
application at a ratio of one treated particle to 99 untreated
particles. The mixture actually applied therefore contains
0.032 4-aminopyridine. Current label directions call for the
application of one pound of bait per total acre applied to one-
third of an acre at a time, resulting in a rate of 3 Ibs/acre on
the treated portion. When applied to sunflowers, only areas of"
15 or more acres are treated. Succeeding applications are made
on previously untreated areas so that the material is eventually
spread over the entire area. Labels direct product users to
make applications to corn fields "when bird damage becomes
apparent" and to make applications to sunflower fields "when
bird damage reaches 200 freshly damaged heads, or when at least
200 feeding target birds are observed in a field". Treatments
are made a maximum of four times per season in corn fields and a
maximum of five times per season in sunflowers.
Other registered formulations include 50% and 252 4-
aminopyri.dine dusts and pretreated bait formulations containing
from 0.022 to 1 % active ingredient. These formulations are used
for the control of nuisance birds at urban nesting and roosting
sites, cattle feedlots and sanitary landfills. Current use
directions call for scattered spot placements of untreated bait
followed by placements of treated bait after feeding patterns at
the bait sites have been established. Labels for 4-aminopyridine
products used at urban facilities direct applicators to place
the baits at the appropriate feeding sites, in high locations
on buildings and ledges. Labels for 4-aminopyridine products
used at cattle feedlots direct applicators to place the bait in
elevated feeders, out of reach of farm animals.
Products containing 4-aminopyridine are restricted use
pesticides registered for sale to and use only by certified
applicators or persons under their direct supervision. These
-23-
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products are not for sale to the general public.
Topical. Discussions
Numbers in parentheses next to topical discussion subheadings
correspond to the number of the section in the proposed
Guidelines (U.S. Environmental Protection Agency, 1978) which
explains the minimum data requirement of that topic.
AVITROL 200R
4-Aminopyridine
Physico-Chemical. Transformation (1 63.. 62.-7.)
(A) Hydrolysis. 1.63.62-7(b)
Hydrolysis data are required in most cases, to support the
registration of manufacturing-use products, regardless of the
intended end uses of products formulated from the manufacturing-
use product. These data are not required for 4-aminopyridine,
however, because the chemical is a minor use pesticide with a
total yearly production of less than 350 pounds. Should yearly
production of 4-aminopyridine reach 25,000 pounds, hydrolysis
data on the technical chemical will be required.
(B) Photolysis 163..62-7(c)
Photodegradation studies in water are required, in most cases,
to support the registration of formulated products intended for
terrestrial uses. Studies in soil are required in most cases to
support the registration of formulated products intended for
crop uses. These studies are not required for 4-aminopyridine,
however, because residues of 4-aminopyridine are not expected to
reach significant levels in soil or water as a result of
application of 4-amiminopyridine formulated products (Metabolism-
Soil and Exposure Profile below).
Metabolism, 163.62.-8
Data on metabolism are required to determine the nature of
pesticide residues and their availability to rotational crops,
to help in the assessment of potential disposal and reentry
hazards, and to assist in predicting the persistence and extent
of residue accumulation.
(A) Soil l63.62-8(b,c.)1
Aerobic metabolism studies are required to support the
registration of all formulated 4-aminopyridine products intended
for terrestrial uses. Anaerobic soil metabolism studies are
-2'4-
-------
required to support the registration of all formulated products
intended for field and vegetable crop uses.
Of three soil metabolism studies submitted, two were considered
valid. Starr and Cunningham (1975, 05003185) investigated the
degradation of 4-aminopyridine, as measured by COp
evolution, in various soil types (loamy sand, sandy loam, loam,
and sandy clay loam) under aerobic and flooded conditions. In
alkaline soil under aerobic conditions, 4-aminopyridine, when
applied at 10 ppm, exhibited half-lives ranging from 3 months in
loamy sand to 32 months in sandy clay loam. Extensive
degradation to C02 occurred after a lag period of over 7
days. However, under flooded conditions, very little «Q.5%)
[ C] 4-aminopyridine degradation was detected within the same
period.
14
Rates of metabolism of [ C] 4-aminopyridine in soil under
aerobic conditions increased with increasing organic matter.
When metabolized in two^slightly acidic (pH 5.6-5.8) loam soils
containing 16£ clay, [ C] 4-aminopyridine was degraded to
COp faster (t 1/2 = 8 months) in the soil with 5.0% of
organic matter than it was in the soil with 2.9% organic
matter (t 1/2 = 22 months).
Rates of metabolism also increased with increasing soil pH. The
amount of COp recovered over a 3-month period was minute
(0.352) for a highly acidic loam (pH 4.1), but was much greater
(4.88X) for an alkaline sandy clay loam with similar levels of
organic matter and clay. In these l^sts, degradation of 4-
aminopyridine was measured only by COp recovery. No
attempt was made to identify intermediate degradation products.
Bettf§ et al. (1976, 05003407) investigated the degradation of
[2- C] 4-aminopyridine (10 ppm) in sandy loam, fine loamy
sand, and clay soils under aerobic and flooded conditions.
Under aerobic conditions, the half-lives of 4-aminopyridine
ranged from 8 months in the clay soil to 32 months in the sandy
loam soil. A lag period of 20 days occurred before extensive
degradation to COp was observed. Under flooded conditions,
the half-lives of 4-aminopyridine ranged from 8 months in the
clay soil to approximately 10 months in the sandy loam soil.
These half-lives are based on CC^ evolution. No
intermediate degradation products were detected in extracts from
soils under either aerobic or flooded conditions.
The studies by Betts et. al (1976, 05003407) and Starr and
Cunningham (1975, 05003135) show that 4-aminopyridine residues
would be fairly persistent in soil, but they do not fully
characterize 4-aminopyridine soil metabolism. No additional
studies are needed, however, because of the following:
1) Only a small amount (approximately 104 Ibs) of 4-
aminopyridine is used on crops yearly. Accumulation in
soil, based on the maximum allowable use, together with
available data, should not exceed 1.6 mg per square
meter.
-25-
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2) When applied at cattle feedlots, 4-aminopyridine
treated baits will be placed off the ground, out of
reach of cattle. Therefore, very little direct-soil
contact is expected.
3) Similarly, no significant direct-soil contact is expected
from urban uses.
4) Since the total amount of 4-aminopyridine applied yearly in
all landfills is less than 10 Ibs, residue levels in
soil resulting from this use are expected to be very small.
In addition, at the site of application, any residues
which might accumulate would not be expected to be available
to rotational crops.
In summary, the lack of significant 4-aminopyridine residues
available to rotational crops eliminates the need for fully
assessing 4-aminopyridine soil metabolism.
(B) Microbiological. Studies. 163 .62-8.(f.)
Data on the effects of microbes on pesticide degradation and the
effects of pesticides on microbes are required in most cases to
support the registration of formulated products intended for
terrestrial use.
(1 ) MicrpbiologicalrEffeots of Microbes on. Pesticides. 163^.2.-
One study (Betts, et al, 1976, 05003407) on the ability of soil
microorganisms to metabolize 4-aminopyridine was reviewed. In
the study, pure cultures of Asperg.illus n.iger , Pseudpmonas
f luorescens, Ent.erobac.ter aerogenes „ Streptomyces griseus, and
Agrobacterium tumefaciens failed to metabolize 4-aminopyrdine
when incubated in the presence of the compound at concentrations
of 10 and 100 ug/ml for 5-6 days. Microbiological rates in the
pure cultures were not retarded by the pesticide. These data
cannot be considered conclusive however, because too few species
of microorganisms were examined and culture conditions were not
varied enough.
(2) Microbiological, - Effects of. Pesticides on Microbes 163.62-
8,(f.).(77 '
Preliminary data on the effects of 4-Aminopyridine on microbes
were reviewed. The study by Betts et. al. (1976, 05003407)
indicated that the growth of A_^ nig.er , P^ f luorescens, E_.
aerogenes, S_._ griseus. and A^ tumefaciens was not retarded
when incubated in the presence of 4-aminopyridine at
concentrations of 10 or 100 ug/ml for 5-6 days. These data
cannot be considered conclusive, however, because too few
species of microorganisms were examined.
Although the data discussed above are inconclusive, no
additional microbiological studies are required because 4-
aminopyridine soil residues potentially available to rotational
crops are expected to be insignificant (Metabolism-Soil above)
-26-
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-------
Table I. Leaching of I CH-Aminopyr Id ine (10 ppm) from soil columns after elution with 7 Inches of water over 20 days.3
Soil
A
B
C
D
E
F
G
H
Sol 1 type
Loamy sand
"i Sandy clay loam
f ,
?"•'" Sandy clay loam
* Loam
Loam
Loam
__ Sandy loam
[" Loam
(paste)
7.8
7.7
7.6
7.6
5.8
5.6
5.6
4.1
Organic
matter
(*>
2.9
4.0
1.9
2.5
2.9
5.0
4.0
1.4
Sand
(*>
Alkal Ine sol Is
77
61
47
59
Acidic soils
46
50
53
31
Silt
<*>
16
19
27
30
38
34
33
44
Clay
(%)
7
20
26
11
. 16
16
14
25
Radioactivity
recovered from
leachate
<*>
0.18
0.02
0.09
0.01
<0.01
—
—
—
Radioactivity
remaining in
upper Inch oi
- so 1 1 co 1 umn
95
99
98
— c
>99
>99
>99
>99
a Adapted fifom Starr and Cunningham (MRID 05003185; KRID 00004001).
Percent ofe'total recovered from soil columns.
c Not measured.
-28-
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immobile in soils.
Because the experimental soils were leached with less than half
the amount of water recommended by the Proposed Guidelines,
these studies would not be considered adequate to assess the
leaching potential of a major crop use chemical. However, since
the total amount of 4-aminopyridine applied yearly is quite
small, residue levels in soil are expected to be insignificant
(See 2A above). Therefore, no additional data on the leaching-
potential of 4-aminopyridine are required.
(B) Adsorption/Desorption. 165.62.-9(d.)
A laboratory study using radioisotopic or nonradioisotopic
analytical techniques is required, in most cases, to support the
registration of products intended for terrestrial uses. These
data are not required for 4-aminopyridine because accumulation
of 4-aminopyridine in soil is expected to be insignificant.
(C) Terrestrial Field. Dissipation 1 63 .62-.VO(b)
A field dissipation study under actual use conditions is
required, in most cases to support the registration of
formulated products intended for terrestrial uses. This study
is not required for 4-aminopyridine because accumulation of 4-
aminopyridine in soil is expected to be insignificant.
Accumulat.ion 163 . 62-J 1
Data on accumulation are required to determine accumulation in
food webs.
(A) Rotational Crops. 1 63 .62-11 (b )
Rotational crop studies are required, in most cases, to support
the registration of formulated products intended for
field/vegetable uses. 4-Aminopyridine residue levels in
soil available to rotational crops are expected to be
insignificant (approximately 1.6 mg/m ). Consequently, no
significant residues of 4-aminopyridine are expected to occur in
rotational crops, thus eliminating the need for 4-aminopyridine
rotational crop studies.
(B) Fish l63.62-1.1.(d,)
This laboratory study employing radioisotopic or nonradioiso-
topic analytical techniques is required in most cases to support
the registration of formulated products intended for terrestrial
and field/vegetable crop uses. A fish accumulation study is not
required for 4-aminopyridine, however, because residues in
aquatic systems are not expected to result from current uses of
the formulated products.
DISCIPLINARY REVIEW
Environmental Fate Profile
Exposure Profile
-29-
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Environmental, Fate Profile
Residue levels of 4-aminopyridine in soil resulting from
terrestrial application of 4AP formulated products are expected
to be very low. The following discussion characterizes the
fate of 4-aminopyridine in soil were it to accumulate in soil.
4-aminopyridine is fairly persistent in soil. Under aerobic
conditions, 4-aminopyridine exhibited half-lives ranging from 3
months to 32 months in a variety of soils. A lag period of 7-20
days was required before extensive degradation to carbon dioxide
occurred. Under flooded conditions half-lives ranged from 3
months in clay soil to 10 months in sandy loam soil.
The rate of aerobic soil metabolism of 4-aminopyridine increases
with increasing organic matter. Of two slightly acidic loam
soils studied, the soil with 5% organic matter degraded the
compound to carbon dioxide almost three times faster than
the soil with 2.95£ organic matter. Soil pH also influences 4-
aminopyridine metabolism. Recovered carbon dioxide was almost
negligible for a highly acidic loam (pH 4.1) but was somewhat
greater for alkaline sandy clay loam with similar levels of
organic matter and clay. Degradation of 4-aminopyridine was
measured only by carbon dioxide recovery; no attempt was made to
identify intermediate degradation products.
The rate of microbial degradation of 4-aminopyridine appears to
be slow. Several common soil microorganisms, Aspergillus niger,
P.seudomonas fluorescens., Strep.tomyces griseus, and Agrobacterium
tumefaciens, were unable to degrade the chemical within 120
hours. 4-aminopyridine appears to have no effect on microbial
growth. Microbial growth rates in pure cultures were not
retarded by the pesticide at concentrations of 10 and 100
micrograms/ml. These results are inconclusive however, and the
ability of microorganisms to degrade 4-aminopyridine as well as
the effect of the pesticide on microbes remains uncertain.
Available data on the mobility of 4-aminopyridine suggest that
the compound does not leach significantly in soil. When soil
columns containing acidic loam or sandy loam soils (pH 4.1-5.8)
were eluted with water over a 20-day period, greater than 99J of
the applied compound remained in the top inch of soil. Low
quantities of 4-aminopyridine were found in the leachate of one
of the acidic soils (less than 0.01& of the initial application)
and in all of the alkaline soils (0.09-0.18%).
Because 4-aminopyridine strongly adsorbs to the soil, it will
remain near the soil surface, where maximim microbial
degradation is likely to occur. However, the rate of microbial
degradation is, at best, rather slow. Therefore, any 4-
aminopyridine residues present in soil will probably persist for
a considerable period. Because 4-aminopyridine appears to be
tightly held to soil under most or all circumstances examined,
migration of the chemical from the site of application will be
minimal.
-30-
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Exposure Profile
For persons involved in the dilution, mixing, and application of
4-aminopyridine products, there is little chance of oral
exposure except through accidental ingestion. 4-Aminopyridine
is registered for use on food crops but 4-aminopyridine residue
levels in the crops should be insignificant, so there is
very little possibility of dietary exposure to 4-aminopyridine
for the general public.
Because 4-aminopyridine ready-to-use bait formulations consist.
of grains, such as corn and wheat, impregnated with 4-
aminopyridine during the manufacturing process, no occular or
inhalation exposure to these formulations should occur. There
is a chance of dermal exposure, but applicators would be exposed
to only very small amounts of active ingredient. Applicators
who handle dust formulations, may receive dermal and inhalatlonal
exposure because the bait preparation process involves manual
mixing of the active ingredient with bait material. The use of
protective clothing, including long sleeves, gloves, and
respirators during the handling of dust formulations, will
essentially eliminate all but accidental dermal, occular, and
inhalation exposure to dust products.
Due to the nature of 4-aminopyridine formulations, the potential
for contamination of nontarget sites by drift is negligible.
The extremely low rates at which 4-aminopyridine is applied to
crops and to sanitary landfills, and the lack of direct soil
contact with formulations applied to cattle feedlots and urban
areas should prevent significant 4-aminopyridine accumulation in
soil. 4-Aminopyridine is not expected to be present in ground
water or surface water as a result of terrestrial application of
4-aminopyridine formulated products.
The potential for exposure to 4-aminopyridine formulations is
greatest for nontarget wildlife, specifically, grain-feeding
birds. The greatest risk to migratory birds will occur during
the fall migration period when finches and other small seed-
feeding birds may ingest lethal doses of the pretreated baits
applied to corn and sunflower fields. Observations (McCann,
1980, //0015005) indicate, however, that in areas where 4-amino-
pyridine is most often used (the midwest) most migratory birds
will pass through after the corn is harvested. In addition,
field'reports (Besser and Cummings, 1975 #0000479) indicate that
in a year of normal maturation of sunflowers baiting will be
completed before most finches, sparrows and other birds migrate.
-31-
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Environmental Fate Bibliography
00004079 Besser, J.F.; Cummings, J.L. (1975)..Avitrol FC Corn
Chops - 99 Baits for protecting sunflower from
blackbirds in North Dakota, Minnesota, and South
Dakota: (Report of study #59, work unit DF-
102.3). (Unpublished study received Nov. 11, 1975
under 11649-15; prepared by U.S. Fish and Wildlife
Service, Denver Wildlife Research Center,
submitted by Avitrol Corp., Tulsa, Okla.; CDL
223451-1)
05003407 Betts, P.M.; Giddings, C.W.; Fleeker, J.R. (1976)
Degradation of 4-aminopyridine in soil. Journal
of Agricultural and Food Chemistry 24(3):571-574.
GS0015005 McCann, J.A. (1980) Registration standards Phase I
qualitative use assessment for 4-aminopyridine.
U.S. Environmental Protection Agency, Office of
Pesticide Programs (Internal document)
00004001 Starr, R.I.; Cunningham, D.J. (1970) Translocation and
Degradation of 4-Aminopyridine in Corn Plants—Its
Movement and Degradation in Soil Systems: .[Third
Periodic Report, Avitrol Concentrate].
(Unpublished study received April 24, 1970
under 224-EX-3; prepared by U.S. Fish and Wildlife
Service, Denver Wildlife Research Center,
submitted by Phillips Petroleum Co.,
Bartlesville, Okla.; CDL: 12.2744-H)
05003185 Starr, R.I.; Cunningham, D.J. (1975}4Leaching and
degradation of 4-aminopyridine C in several
soil systems. Archives of Environmental
Contamination and Toxicology 3(1):72-83.
Standard Reference
U.S. Environmental Protection Agency (1973) Proposed
Guidelines for Registering Pesticides in the
United States. Federal Register, 43 (132) 29696
(July 10, 1978)
-32-
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V. Ecological Effects
Ecological Effects Topical. Discussions
Effects on Avian Species (163.7.1-1,2,4.5)
Effects on avian species can be measured by acute, subacute, reproduction, and
field studies. The. studies required for a particular chemical depend upon the
use pattern of the chemical and the results of particular tests.
Acute Effects: The minimum data required for establishing the acute
toxicity of 4-aminopyridine are results from avian single-dose oral ID™
studies using technical 4-aminopyridine. Test species should be either
wild waterfowl (preferably the mallard duck) or upland game birds
(preferably the bobwhite quail or the ring-necked pheasant).
Two valid studies on the acute effects of 4-aminopyridine on a variety of
species were available for review. Table 1 summarizes the results of these
studies.
Table 1. Studies on the Acute Toxicity
£f Technical 4-Aminopyridine t£> Avian Species
Author
Schafer,
et al,
1975 '
(05003186)
Schafer
et al, •
1973
(0500319D
Species
Blackbilled
magpie
Yellowbilled
magpie
Sparrow hawks
Quelea
House Sparrow
Red-winged
blackbird
Test
Substance
Technical
Technical
Technical
Technical
Technical
Technical
Results
Oral LD5Q =2.4 mg/kg
Oral LD5Q =2.4 mg/kg
Oral LDco =5.6 mg/kg
(4.2 iu7.5 mg/kg)
Oral LDqn =5.6 mg/kg
50
30
Oral LE£n =7.5 mg/kg
Oral LDg = 2.4 mg/kg
While neither of these studies alone fulfills the Proposed Guideline
(US. Environmental Protection Agency, 1978) requirement for the avian
single dose oral ID™, the studies taken together provide sufficient
information to characterize 4-aminopyridine as highly toxic to avian
species. Consequently, no further acute avian toxicity studies are required.
Subacute Effects: The minimum data required for establishing the subacute
toxicity of 4-aminopyridine in birds are as follows: Avian dietary LCC
studies for one wild waterfowl species (preferably the mallard duck)
one upland gamebird species (preferably the bobwhite quail or the ring-
neck pheasant).
-33-
-------
Three valid studies were available for review on this topic.
summarizes the available subacute data.
Table 2. Studies _on the Subacute Toxicity
of Technical 4-Aminopyridine Jto A vian Species
Table 2
Test
Author
Schafer
et al,
1975
(05003186)
Schafer &
Ma-king, 1974
(00004083)
Fink & Reno
1976
(GS-0015-004)
Species
Coturnix
Quail
Mourning
Dove
Coturnix
Quail
Coturnix
Quail
Mallard
Duck
Substance
Technical
Technical
Technical
Technical
Technical
Results
.LCqn = 447 ppm
t239 - 714 ppm)
LCr.n = 316 ppm
T100 - 1000 ppm)
LCq0 = 479 ppm
^354 - 645 ppm)
LC50 > 316 ppm
LCen = 722 ppm
X547.3 - 952.5 ppm)
Based on this .information, 4-aminopyridine can be characterized as
moderately toxic to upland game birds and waterfowl.
Avian. Reproduction: Avian reproduction toxicity studies on technical
4-aminopyridine are necessary if the pesticide is persistent in the
environment, if it is stored or accumulated in plant or animal tissues, if
its use is such that nontarget birds may be exposed repeatedly or
continuously to sublethal doses (especially before breeding season), or
if available test information indicates that avian reproduction may be
adversely affected by use of the pesticide.
Schafer et. al. (1975, 05003186) conducted an avian reproduction study on
coturnix quail. The effects of chronic and single-dose exposures were
studied. In the chronic feeding test, 4-aminopyridine was incorporated
into the diet at concentrations of 31.6, 100, and 316 ppm. No significant
differences in egg production or hatchability were found through the F1
generation. Further generations were not studied. In the single exposure
study, a dose of 5.66 mg/kg 4-aminopyridine did not affect egg production
or hatchability.
The preferred test species was not used in this study nor was egg shell
thickness measured. In addition, the study was carried out for only four .
weeks instead of the preferred ten week period, only three concentrations
were administered instead of the preferred four, and fewer birds than the
preferred number were tested. Despite these deficiencies, the study
demonstrated for coturnix quail that no adverse reproductive effects will
result from a chronic dose of 316 ppm or a single dose of 5.62 mg/kg. In
view of these results, the high acute avian toxicity of the compound, and
-34-
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the method of use of the compound (distribution of discrete bait granules),
it is unlikely that birds would consume sublethal doses that would
adversely affect reproduction. No additional avian reproduction studies
are required.
Special Studies : Several special toxicity studies on both technical 4-
aminopyridine and formulated products were available for review.
Schafer et al. (1970, 00003998) found no observable effects at 31.6 and
100 ppm dietary levels after 30 days of feeding 4-aminopyridine to mourning
doves. However, at the next level, 316 ppm, 5Q% mortality occurred. This
study further confirms previous LCcQ studies.
Schafer et al. (1973, 05003191) also conducted a study to determine the
acute dermal LDcn for quelea and house sparrow. The value determined was
greater than 100 mg/kg for both birds. This LDcn value indicates that 4-
aminopyridine is only slightly toxic when applied dermally to birds.
Several avian feeding studies on the formulated product were available for
review for 4-aminopyridine. Table 3 summarizes these results.
Table 3. Avian Feeding Studies
on. the Formulated Product
Author Species Results
Schafer & Mourning Both 2% and 3% baits were lethal after a 7
Lockyer Doves day feeding period. The baits were
no date, diluted at a ratio of 1:99.
(00003999)
Besser, Bobwhite No toxic .effects were seen at 1:99 dilution
1963 Quail ratio of the 3% active ingredient bait.
(00004101)
Schafer & Bobwhite All birds died at the 1:29 dilution ratio of
Marking, 1974 Quail the 3% active ingredient bait.
(00004033)
Schafer & Starlings LCc-n > 1.78 mg/kg/day
Marking, 1974 ou
(0004033)
Schafer et al. (1974, 00003965) designed a secondary poisoning study which
included blackbilled magpies, sharp-shinned hawks, red-tailed hawks, and
American kestrels. The birds exhibited no symptoms of intoxication, nor
any gross pathological changes when fed birds killed with 3% baits.
Secondary poisoning toxicity appears to be nonexistent for 3% (per treated
granule) products. However, no data were available to determine the
potential for secondary poisoning of avian predators from 25% or 50% dusts
or from pretreated baits containing greater than 3% (per treated granule)
4-aminopyridine.
-35-
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Besser and Currming (1975, 00004079) conducted a field study in which
searches for dead nontarget and target birds were made in North Dakota,
Minnesota and South Dakota sunflower fields treated with 4-aminopyridine.
In one part of the study, two relatively small areas (35.65 and 51.5A) were
searched intensively, along with nearby shelter belts and pastures. During
the search, 253 target and 42 nontarget birds were found dead. Crackles
and redwings accounted for 231 (902) of the dead target birds. Slate-
colored juncos and Harris sparrows accounted for 26 (62%) of .the dead non-
target birds.
The second part of the study involved an 18,000 acre area of which only 128
acres were searched. The search in this area disclosed a total of 32 dead
birds: 29 target birds (all black birds), 2 nontarget birds (1 mourning
dove and 1 song sparrow) and 1 unidentified birti. The authors reported
that the ratio of target to nontarget species found closely agreed with
findings of searches made in heavily damaged fields during the previous six
years. (Besser and Cummings, 1975, (00004079).
Effects on Aquatic Organisms. (163.72-1,2,3,4,5,5)
Effects on aquatic organisms are measured by a variety of tests, including fish
acute LCCQ'S, acute toxicity tests on aquatic invertebrates and estuarine and
marine organisms, and embryolarvae and life cycle studies. The types of tests
required depend on the pesticide use pattern and the results of previous
tests.
Fish Acute LQt-n: The minimum data required, in most cases, for •
establishing the acute toxicity of 4-aminopyridine to fish are results from
96 hour exposure studies on one coldwater species (preferably rainbow trout)
and one warm water species (preferably bluegill), using technical 4-
aminopyridine. Valid data on two species were available for review on this
topic. The acceptable acute toxicity data are summarized in Table 4.
-36-
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Table 4. Studies on the Acute Toxicity
of Technical 4-Aminopyridine _to Fr-eshwater Fish
Author
Schafer &
Marking,
1974
(00004033)
Schafer 4
Marking,
1974
(00004033)
Warmwater
Fish
Species
Channel
Catfish
17°C
22°C
Bluegill
17°C
22°C
Hardness
very soft
soft
hard
very hard
soft
soft
very soft
soft
hard
very hard
soft
soft
Results
LC5Q=4ppm
(3.2-5. Oppm)
LC(-Q=4ppm
(3T4-4.7ppm)
LCc0=4ppm
(3?6-4.5ppm)
LC.or2.43
(2?2-2.8ppm)
LCqn=4.36ppm
(3.9-4.8ppm)
LC(-0=5.80ppm
(5T2-6.4ppm)
LCcrQ=3.40ppm
(3.0-3.9ppm)
LC53=4.41ppm
(3.3-5. 1ppm)
cn-
(2?3-3.5ppm)
LC«-Q=3.20ppm
(2?7-3.8ppm)
LCc-Q=5.60ppm
(4T80-6.5ppm)
LCcQ=7.56ppm
(6?3-9.1ppm)
Based on these results, 4-aminopyridine can be characterized as moderately
toxic to warmwater fish. Although no- data on coldwater fish were submitted,
none are required for 4-aminopyridine formulated products because 4-
aminopyridine residues should not occur in water as a result of application of
the formulated products. In addition, because 4-aminopyridine is a minor use
pesticide that has a total yearly production of less than 350 pounds, an
acute toxicity study on coldwater fish is not required for manufacturing-use 4-
aminoyridine. In further support of this data waiver, a valid study was
available on warmwater fish species which provides sane basis for determining
the toxicity of 4-aminopyridine to fish. However, should yearly production of
4-aminopyridine reach 25,000 pounds, an LCcQ for coldwater fish will be
required to support the registration of manufacturing-use 4-aminopyridine
products.
-37-
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Effects on Mammals
Special mammalian toxicity studies on technical 4-aminopyridine can be required
under circumstances described in Sec. 163.71(d) of the Proposed Guidelines. .
One valid study was available on this topic. Schafer (1971, 00003965) designed
a secondary poisoning study in which a beagle-coyote hybrid, one beagle, and
ten white laboratory rats were fed redwing blackbirds contaminated with 4-
aminopyridine. The largest dose consumed by a rat in these experiments was 1
redwing blackbird which had been dosed at a rate equal to 300 mg/kg. The 300
mg/kg dose fed to the blackbird was equal to 57 mg/kg or 3.4 LDcg doses for
the rat. The highest dose given to a dog was 10 redwings which had been dosed
at a rate of 150 mg/kg. The dose given to the 10 redwings was equal to 3.22
mg/kg, twice the dogs' LD50dose. Neither the rats nor the dogs exhibited
symptoms of intoxication Or any gross pathological changes. This study
indicates that the hazard to mammals from secondary poisoning is minimal.
Phytotoxici.ty
Two valid studies (Starr and Cunningham, 00004037; 1974, 05003440) on phyto-
toxicity were available for review. Data from the studies showed that corn
germination was unaffected at 1 ppm (the highest level tested), and that both
corn and sorghum growth were unaffected in a 100 ppm solution of technical 4-
arainopyridine.
Acute Toxicity .to Aquatic Invertebrates (l63:.72-2)
A determination of the EC™ or LC,-g for an aquatic invertebrate is
required, in most cases, to support the registration of all manufacturing-use
products. These data are not currently required for 4-aminopyridine, however,
because it is a minor use pesticide (refer to above discussion on Fish Acute
"V-
DISCIPLINARY REVIEW
Ecological Effects Profile
Ecological Effects Hazard Assessment
Data Gaps
Required Labeling
Ecological Effects Profile
Acute oral LA-g and dietary LCcn data indicate that 4-aminopyridine is
acutely toxic to several avian species including magpies, sparrowhawks, house
sparrows, and red-winged black birds. It is moderately toxic to upland
gamebirds and wild waterfowl. Results of an avian reproduction study suggest
that adverse avian reproductive effects resulting from ingestion of sublethal
doses are unlikely.
LCj-Q values for two warmwater fish species indicate that 4-aminopyridine is
moderately toxic to these species. Cold water species were not tested.
-38-
-------
Available data on the effects of feeding birds contaminated with 4-
arainopyridine to avian predators and mammals suggests that secondary poisoning
of mammals is unlikely to result fron use of this compound and secondary
poisoning of avian species is unlikely to result from use of 52 or less
pretreated baits. The only phytotoxicity data available indicate that 4-
aminopyridine is not significantly toxic to corn or sorghum. One ppm does not
affect seed germination in corn and a 100 ppm solution does not affact the
growth of corn or sorghum.
Ecological, Effects Hazard Assessment
Although 4-aminopyridine is acutely toxic to some bird species and at least
moderately toxic "to others, the hazard to* nontarget migratory birds from 3.03
(per treated granule) 4-aminopyridine ready-to-use baits applied to
agricultural crops is slight. Most nontarget migratory birds are expected to
pass through corn areas after the crop is harvested. In addition, in a year of
normal maturation of sunflowers, all sunflower baiting will have been completed
prior to the period during which most nontarget birds migrate. Migratory
nontarget birds may still be killed occasionally however, due to variations in
the time of. migration and in the time of crop harvest.
Mourning doves and bobwhite quails, which are nonmigratory species, may
potentially be exposed after each application of ready-to-use baits to corn and
sunflower fields. However, when the 3% (per treated granule) baits are applied
to fields at a ratio of one treated granule to 99 untreated granules, the
likelihood of a nontarget bird picking up more than 1 treated granule is small.
At the 1:99 dilution ratio and the current application rate, only about 200
treated granules per acre are applied to corn and sunflower fields. One
3.0& 4-aminopyridine granule is not expected to be lethal to either doves
or quails. In addition, 28-40 day- LCcg dietary studies show that
4-aminopyridine has no cummulative toxic effect; several sublethal doses have
no greater effect than a single sublethal dose. Therefore, it appears that in
the field, the 1:99 dilution ratio reduces the hazard to doves and quails
although sublethal doses may intoxicate these and other birds, leaving them
more vulnerable to predation. Available data indicate, however, that if a 1:29
dilution ratio were used in the field, high dove and quail mortality could
result (see Table 3).
The hazard to nontarget birds from 4-aminopyridine pretreated bait and dust
products applied to cattle feedlots, sanitary landfills, and urban buildings
should be slight, since these formulations are restricted to use only in areas
where target birds are feeding. Secondary poisoning of mammals is not
expected to occur as a result of application of any 4-aminopyridine product.
Neither is secondary poisoning of avian predators expected to occur as a result
of application of 3.0£ or less (per treated granule) 4-aminopyridine ready-to-
use baits. Due to a lack of data, however, the potential for secondary
poisoning of avian predators from ready-to-use baits containing greater than
~3.Q% 4-aminopyridine (per treated granule) and from dust products, cannot be
determined. Adverse avian reproductive effects resulting from sublethal doses
of 4-aminopyridine are unlikely.
-39-
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4-aminopyridine residues in water, resulting from terrestrial application of
4-AP formulated products, are expected to be insignificant. But assuming the
"worst possible case" (i.e. direct application to water which is prohibited by
label restrictions), at the current maximum application rate of .0144 oz. per
acre the amount expected in an acre of water six inches deep is well below the
•LCcQ of 2.43 ppm and 2.82 ppm for channel catfish and bluegill sunfish.
Thas 4-no
Thas, 4-aminopyridine formulated products do not present a hazard to fish.
As indicated by the Environmental Fate Chapter, residues of 4-aminopyridine in
soil are expected to be insignificant. Therefore, terrestrial plants including
corn and .sunflowers, are not expected to be adversely affected by application
of 4-aminopyridine formulated products.
Required Labeling
The following labeling requirements are made on the basis of the available
ecological effects data:
Manufacturing, 4-aminopyridine:
Do not discharge into lakes, streams, ponds or public waters unless in
accordance with an NPDES permit. For guidance, contact your regional office of
EPA.
For All Formulations:
For use only by certified applicators or persons under their direct
supervision.
This pesticide is toxic to birds and fish. Wildlife feeding on treated bait
may be killed.
Do not contaminate water by cleaning of equipment or disposal of waste.
Before application in your area, consult endangered species personnel of the
U.S. Fish and Wildlife Service to ensure that endangered and rare bird species
are not likely to be adversely affected by use of this product.
For Pre-treated Baits
Do not allow this material to remain in unprotected places after control
measures are completed.
For Ready-to-Use Bait Products Containing Greater than 3% (per-treated
particle) 4-aminopyridine and For All Dust Products
Pick up and dispose of dead birds by burial.
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For Products Intended for Use at Sanitary. Landfills, Cattle Feed Lots, or
Nesting and Roosting Sites;
This product must not be applied where nontarget birds feed. Careful
observation of birds feeding habits must be made to establish proper feeding
locations and to determine that no nontarget birds are feeding on prebait.
Pick up and destroy uneaten bait at the end of each day.
For Products Intended for the Control of Herring Gulls
(Larus argentatus)
Herring Gulls ( Larus argentatus ) are protected by law and treaty. Both
Federal and State permits are required to control these birds.
For All Products Intended for Use in Agricultural Crops
Confine treatment to areas 50 feet in from field edge.
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Ecological Effects Bibliography
00004101 Besser, J.F. (1968) Compilation of Information on the Chronic
Toxicity of 4-aminopyridine to Pheasant, Cxiail and Starlings.
(Unpublished study received Mar 2, 1973 under 11649-12; prepared
by U.S. Fish and Wildlife Service, Denver Wildlife Research
Center, submitted by Avitrol Corp., Tulsa, Okla.; CDL:120117-A)
00004079 Besser, J; Cummings, J.L. (1975) Antrol FC Corn Chops - 99 Baits
for protecting Sunflowers from Blackbirds in North Dakota,
Minnesota, and South Dakota (Report of Study No. 59, Work Unit
DF-102.3). Unpublished study received November 11, 1975 under
11649-15; prepared by U.S. Fish and Wildlife Serviced, Denver
Wildlife Research Center, submitted by Avitrol Corp, Tulsa,
Ckla; (DL:223451)
GS0015004 Fink, R.; Reno, F.E. (1976) Eight-day dietary LC™ - Mallard.
duck. (Unpublished study received February 9, 1980 under 11649-
12; pepared by Hazleton Laboratories America, Inc., submitted
by Avitrol Corp., Tulsa, Qkla.; (DL:223451-I)
05003186 Schafer, E.W.; Brunton, R.B.; Lockyer, N.F. (1975)
The effects of subacute and chronic exposure to
4-aminopyridine on reproduction in coturnix quail. Bulletin of
Environmental Contamination and Toxicology 13(6):758-764.
00003999 Schafer, E.W.; Lockyer, N. (no date) The Effects of DRC-1327 Baits
on Mourning Doves. (Unpublished study received Dec 18, 1970
under 224-EX-3; prepared by U.S. Fish and Wildlife Service,
Denver Wildlife Research Center, submitted by Phillips Petroleum
Co., Bartlesville, Okla.; CDL:122744-E)
00003998 Schafer, E.W., Jr.; Brunton, R.B.; Lockyer, N. (1970) The Chronic
Toxicity of DRC-1327 to Mourning Doves: Preliminary Report
No. 16--W. J. DF-T02.2. .(Unpublished study received Dec 18,
1970 under 224-EX-3; prepared by U.S. Fish and Wildlife Ser-
vice, Denver Wildlife Research Center, submitted by Phillips
Petroleum Co., Bartlesville, Okla.; CDL:122744-D)
00003965 Schafer, E.W., Jr.; Brunton, R.B.; Lockyer, N.F. (1974) Hazards to
animals feeding on blackbirds killed with 4-aminopyridine baits.
Journal of Wildlife Management 38(3):424-426. (Also in unpub-
lished submission received Apr 10, 1975 under 11649-10; submit-
ted by Avitrol Corp., Tulsa, Okla.; CDL.-115276-B)
05003191 Schafer, E.W., Jr.; Brunton, R.3.; Lockyer, N.F.; De Grazio, J.W.
(1973) Comparative toxicity of seventeen pesticides to
the Quelea , house sparrow, and red-winged blackbird.
Toxicology and Applied Pharmacology 26(1):154-157.
00004033 Schafer, E.W., Jr.; Marking, L.L. (1974) Long Term Effects of 4-
Aminopyridine Exposure to Birds and Fish. (Unpublished study
received Nov 11, 1975 under 11649-15; prepared by U.S. Fish and
Wildlife Service, Wildlife Research Center in cooperation with
Fish Control Laboratories, submitted by Avitrol Corp., Tulsa,
Okla.; CDL:225255-C)
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00004057 Starr, R.I.; Cunningham, D.J. (no date) Phytotoxicity. (Unpublished
study received Jan 3, 1973 under 1F1013; prepared by U.S. Fish
and Wildlife Service, Denver Wildlife Research Center, submitted
by Phillips Petroleum Co., Bartlesville, Okla.; CDL:091757-R)
05003440 Starr, R.I.; Cunningham, D.J. (1974) Phytotoxicity, absorption,
and translocation of 4-aminopyridine in corn and sorghum
growing in treated nutrient cultures and soils. Journal of
Agricultural and Food Chemistry 22(3):409-413.
00003985 U.S. Fish and Wildlife Service, Denver Research Laboratory (no date)
Toxicity of Avitrol to Bluegill and Channel Catfish at Selected
Water Qualities and Temperatures: Table. (Unpublished study
received May 18, 1971 under 224-EX-3; prepared in cooperation
with La Crosse Fish Control Laboratory, submitted by Phillips
Petroleum Co., Bartlesville, Okla.; CDL:122743-F)
Standard Reference
U.S. Environmental Protection Agency (1978) Proposed Guidelines for
Registering Pesticides in the United States. Federal Register,
43 (132), 19696.
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VI. Toxicology
Toxicology Topical. Discussions
The following topical discussions describe available toxicity data on technical
4.-aminopyridine and its formulations and state whether the data are adequate
for Agency regulatory purposes. Agency acceptance depends on the adequacy of
test substances used to represent a product on which toxicity data are required
and on the adequacy of the toxicity test procedures used to satisfy Agency
requirements.
Because 4-aminopyridine ready-to-use bait and dust formulations are dilutions
of the technical chemical with foodstuffs, the toxicity of a particular
formulation depends directly on the concentration of the active ingredient
present in that formulation. Therefore, when no data specific to formulations
were available, toxicity categories were based on extrapolation from data
available on the technical chemical.
Test procedures in several toxicity tests submitted for 4-aminopyridine did not
meet proposed Agency guideline requirements. Some of those tests were
determined to be adequate, however, for Agency regulatory purposes. The
judgments made are included in the following topical discussions.
Numbers in parentheses next to topical discussion subheadings correspond to the
number of the section(s) in the Proposed Guidelines of August 22, 1978 (U.S.
Environmental Protection Agency, 1978) which explain(s) the minimum data that
the Agency usually requires in order to adequately assess a pesticide's
toxicology.
Acute Oral Toxicity (163.81-1)
The minimum data requirement for testing acute oral toxicity (LDc-n) of 4-
aminopyridine is one test on the technical chemical, preferably using the
laboratory rat.
Technical; Ives (1962, 00004024) conducted a study in which laboratory rats
and dogs were administered 4-aminopyridine hydrochloride, in capsule form
by gavage. The LD5Q was 28.7 mg/kg(S.D. =0.6 mg/kg) for the rat and 3.7
mg/kg (S.D. =0.6 mg/kg) for the dog; both species showed very steep dose
response curves. This study meets Agency requirements for an acute oral
toxicity test and is adequate to place technical 4-aminopyridine in
Toxicity Category I, indicating.a very high acute oral toxicity hazard.
Formulations: Ives (1962, 00004024) conducted a second acute oral toxicity
study in which a .53% granular formulation was administered to dogs and
swine in their feed. The ID™ for dogs was 2300 mg of formulation/kg
which is equivalent to 12.6 mg of active ingredient/kg. The LDcg for the
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swine was 3**00 mg of formulation/kg which is equivalent to 18 mg of
a.i./kg. This study does not meet Agency requirements for an acute oral
toxicity test because too few animals were used in the experiments. Taken
alone, therefore, the results cannot be considered conclusive. However,
the data in this study support the results obtained (Ives, 1962, 0004024)
with the technical material. The difference between the dog LD^g
determination (3.7 mg/kg) from the technical material and the dog ID™
determination from the .532 granular formulation is most likely due K5 the
route of administration. LD.-Q values are generally higher when
substances,*are administered ?n feed than when they are introduced directly
into the animals' stomachs by gavage. Based on extrapolations from
data on the technical chemical, formulations of 4-aminopyridine are
assigned to the following Toxicity Categories for acute oral toxicity:'
o Formulations containing 25% or more
4-aminopyridine—Toxicity Category I
o Formulations containing 2.5% to 242
active ingredient—Toxicity Category II
o Formulations containing less than 2.5%
active ingredient—Toxicity Category III
Acute Dermal.. Toxicity (163.81-2)
Technical: The minimum data requirement for testing the acute dermal
toxicity (LDco) of 4-aminopyridine is one test on the technical
formulation, preferably using the albino rabbit. The acute dermal LDcn of
4-aminopyridine hydrochloride is 327 mg/kg (S.D. = 54.3 mg/kg) for male
rabbits (Ives, 1962, 00004024). Animals exhibited signs of ataxia,
hyperpnea, salivation and tremors. No gross pathlogical changes were noted
in any tissues or organs examined. Although data on female rabbits were not
submitted, the Agency considers the available data sufficient to assess
the acute dermal toxicity of technical 4-aminopyridine. Based on this
study, technical 4-aminopyridine is assigned to Toxicity Category II for
dermal effects.
Formulations: No data specific to 4-aminopyridine formulations were
available for assessing acute dermal toxicity. Based on extrapolation from
data available on the technical chemical, formulations of 4-aminopyridine
are assigned to the following Toxicity Categories for acute dermal toxicity:
o Formulations containig 65% or more
4-aminopyridine — Toxicity Category
II.
o Formulations containing 6.5% to 64$ —
Toxicity Category III.
o Formulations containing less than 6.5%
active ingredient-Toxicity Category IV.
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Acute Inhalation Toxicity 063.81—3.)
A determination of the acute inhalation toxicity is required to support the
registration of a manufacturing use product and a formulated product if:
1) The product is a gas:
2) Tne product produces a respirable vapor; or
3) 20 percent or more of the aerodynamic equivalent of the product is
composed of particulates not larger than 10 microns in diameter.
Neither 4-aminopyridine manufacturing use products nor ready-to-use bait
formulations meet any of the conditions listed above. Therefore, no inhalation
testing of these products is necessary. Dusts, however, meet condition 3.
In order to develop proper labeling dust formulations must be tested for acute
inhalation toxicity. The minimum data requirement is one test, using the
albino rat, of a 50% a.i. dust.
Acute. Delayed Neurotoxicity (.163.8.1-7)
Acute delayed neurotoxicity data are required if the active ingredient,
or any of its metabolites, degradation products, or impurities cause esterase
depression or are structurally related to a substance that induces delayed
neurotoxicity. 4-Aminopyridine does not cause esterase depression nor is it
structurally related to a substance that is known to induce delayed
neurotoxicity. Therefore no testing is required for the technical formulation
or any of its registered products.
Primary Eye Irritation (163.81-4)
The minimum data requirement for evaluating 4-aminopyridine eye irritation '
potential is one test on the technical chemical, preferably on the albino
rabbit.
Technical: One study (Ives, 1962, 00004024) on primary eye irritation was
' reviewed. In the study, 10 mg of 4-aminopyridine hydrochlorids were
instilled into the eyes of albino rabbits. At 1 hour, iritis and
conjunctival irritation were noted; these irritations disappeared by day
7. Although less 4-aminopyridine than the amount recommended by the.
Proposed Guidelines (U.S. Environmental Protection Agency, 1978) was
instilled into the rabbits' eyes, the Agency considers the data adequate to
assign technical 4-aminopyridine to Toxicity Category III for primary eye
irritation.
Formulations: No data specific to formulations were available. Based on
extrapolation from data available on the technical chemical, all 4-amino-
pyridine formulations are assigned to Toxicity Category III.
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Primary Dermal Irritation (,163.31-5)
The minimum data requirement for evaluating the dermal irritation potential of
4-aminopyridine is one test on the technical formulation, preferably on the
albino rabbit.
Technical: Ives (1962, 00004024) observed rabbits after 5.0 mg of 4-
aminopyridine hydrochloride were applied to abraded and intact skin. He
observed no signs of irritation, either at 24 hours or 72 hours. Although
less 4-aminopyridine than the amount recommended by the Proposed Guidelines
was applied, the Agency considers the data adequate to assign technical 4-
aminopyridine to Toxicity Category IV for primary dermal irritation.
Formulations: Phillips Petroleum Co. (no date, 00004137) submitted a study
'in which granular 4-aminopyridine (amount unspecified) was applied to the
clipped skin of rabbits on 10 consecutive days. Each application remained
in place for 18 hours but no signs of irritation were observed. Because
the amount of 4-aminopyridine applied to the skin was not specified, this
study cannot be considered adequate for assessing the primary irritation
potential of 4-aminopyridine formulations. However, it does support data
available on the technical chemical. Therefore, based on this study and
the data on the technical chemical, 4-aminopyridine is assigned to Toxicity
Category IV for primary dermal irritation.
Subchronic Oral. Toxicity (1,63.82r1)
The minimum data requirement for assessing the subchronic oral toxicity of 4-
aminopyridine is one test in each of two mammalian species, a rodent and a
nonrodent, on the technical chemical.
Technical: No subchronic oral tests on 4-aminopyridine were available. In
one 90-day study, (Kohn et al., 1968, 00004026) rats were given dietary
levels of 3, 30, and 300 ppm 4-aminopyridine hydrochloride (calculated as
free base). No gross or microscopic pathologic findings of significance
were noted. In the group given 300 ppm, all surviving animals were
hyperirritable to noise and touch throughout the test. No other abnormal
behavioral reactions occurred. Blood and urine analyses of rats given the
high dose showed no significant changes. Female rats given 300 ppm showed
elevated brain weight (p<0.05); male rats showed elevated liver weight
(p<0.05) when given the same dose. This study is an adequate subchronic
oral test in rats.
A subchronic study was also conducted on dogs (Cervenka and Vega, 1968,
00004027). The study was informative, although it was conducted for 90
days instead of the desired 180 days. 4-aminopyridine hydrochloride was
given in the diet at 0.1, 1.0, and 2.0-3.25 mg/kg/day (corresponding to
200, 2,000 or 4,000 - 6,500 ppm, calculated in terms of the free base). At
the highest dose, dogs exhibited salivation and muscular weakness but
developed no abnormal lesions. No dose-related trends occurred in mean
organ weights, but male and female dogs given the two highest doses showed
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decreased brain weights. Blood and urine values were comparable in treated
and control animals.
In summary, rats and dogs in the 90 day studies showed no significant
pathologic changes in any organ or tissue. In both rats and dogs brain
weight was affected, but examination of the brain revealed no abnormalities.
Formulations: No significant subchronic oral toxicity effects were observed
in tests of the technical chemical. Therefore, none should result from
exposure to 4-aminopyridine formulations. No subchronic oral toxicity
testing specific to ready-to-use baits or dusts is required.
Dermal Sensitization (163.8.1-6)
Subchronic 21-Day Dermal Toxicity (163.82-2)
Subchronic 90-Day Dermal Toxicity (153.52-3.)
Dermal sensitization data and subchronic dermal toxicity data are required if
repeated skin contact with a pesticide is expected under conditions of use.
Applicators who handle 4-aminopyridine manufacturing-use products, or any dust
or pretreated bait product which falls into Toxicity Category I or II for
dermal toxicity, will be required to wear protective clothing, including
gloves, thereby greatly reducing the potential for repeated skin contact.
Applicators who handle pretreated baits which fall into Category III or IV for
dermal toxicity will not be required to wear gloves, since they are unlikely to
be exposed to the active ingredient in sufficient quantities for dermal
sensitization or subchronic toxicity problems to develop. Because of the lack
of significant dermal exposure, no subchronic dermal toxicity or dermal
sensitization testing is required for 4-aminopyridine.
Subchronic Inhalation Toxicity Q63.32r4)
Data from a subchronic inhalation toxicity study are required to support the
registration of each manufacturing-use product and formulated product which
has been identified as toxic from the results of acute inhalation testing and
whose use may result in repeated inhalation exposure. Because of the nature of
4-aminopyridine manufacturing-use products and ready-to-use baits, no
inhalation exposure to these products is expected. Short term inhalation
exposure to dusts may occur if applicators do not wear respirators. However,
based on available information on the use pattern of 4-aminopyridine dust
products, significant repeated inhalation exposure to dusts is not expected
to occur even if respirators are not worn. Therefore, subchronic inhalation
toxicity testing is not required.
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Subchronic Heurotoxicity (163.32-5)
Data from a subchronic neurotoxicity evaluation are required to support the
registration of each manufacturing-use product and formulated product
containing an active ingredient which induced neuropathy or delayed
neurotoxicity in acute tests. A subchronic neurotoxicity study is not required
for 4-aminopyridine because no neuropathy or delayed neurotoxicity was observed
in acute tests. In addition, significant repeated exposure to 4-aminopyridine
is not expected to occur.
Chronic Fe.eding (.163.3.3-1.)
Qncogenicity -yfr3«83riO''
Reproduction (1 6.3.. 133-4 J
Metabolism (163'. S5-11
Chronic feeding, oncogenicity, metabolism, and multi-generation reproductive
studies are usually required if use of a pesticide is likely to result in
repeated human exposure over a significant portion of the human life span or if
a use requires a tolerance or an exemption from a tolerance.
Although significant prolonged exposure to handlers and applicators of 4-
aminopyridine is unlikely, the fact that 4-aminoypridine has a tolerance of
•0.1.ppm for both corn and sunflowers would normally indicate that long-term
studies are necessary. However, the Agency believes that residue levels in
crops resulting from either translocation of 4-aminopyridine to food crops or
from the direct application of 4-aminopyridine to growing crops will be lower
than the tolerances set (see Residue Chemistry Chapter - Residues in corn
and sunflowers). Therefore, because dietary intake of 4-aminopyridine is
expected to be negligible and because prolonged human exposure is unlikely, the
long-term studies listed above are not required for 4-aminopyridine.
Teratology (163.83-3)
Teratogenic studies on the technical chemical, using two mammalian studies,
are required if the pesticide's use requires a tolerance or an exemption from a
tolerance or if its use may result in exposure to human females. No
significant dietary or chronic exposure to 4-aminopyridine is expected (see
Residue Chemistry .Chapter and above discussion on long-term studies). In
addition, no significant (including short-term) dermal exposure is expected
to result from the application of pretreated baits (see Dermal Sensitization
Topical Discussion). However, if applicators of 4-aminopyridine dusts do not
wear protective clothing, including long sleeves, gloves, and respirators,
short-term inhalation exposure and dermal exposure to dusts will occur.
Therefore, unless applicators of dust formulations are required, by the label,
to wear protective clothing including respirators, the teratogenic potential of
4-aminopyridine must be determined.
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Mutagenicity
Mutagenicity testing will be required for 4-aiiinopyridine unless applicators of
dust formulations are required by the label to wear protective clothing
including respirators (see above discussion on teratology).
The following studies represent the minimum requirements for data on the
potential heritable effects of a 4-aminopyridine.
1. A mammalian in-vitr.o point mutation test.
2. A sensitive sub-mammalian point mutation test. (Bacteria, fungi, insect.)
3. A primary DNA damage test (i.e. sister chromatid exchange or unscheduled
DNA synthesis).
4. A mammalian in-vitro cytogenetics test. If this test suggests a positive
result, a dominant lethal or heritable translocation test may be required.
After results from these test systems and other toxicology disciplines have
been considered, additional testing may be required to further characterize or
quantify the the potential genetic risks.
Although the Agency's mutagenic testing requirements are not final, the
standards for these tests should be based on the principles set forth therein
(43 FR 37336 August 22, 1978). Protocols and choices of test systems should
be accompanied by'a scientific rationale. Substitutions of test systems for
those listed above will be considered after discussion with the Agency.
The requirements should be considered an interim guide and not final Agency
policy. However, the Agency does consider the above testing scheme to be a
reasonable minimum requirement.
Pharmacological. Effects
In Vivo Effects: 4-Aminopyridine produced prolonged increases in the
blood pressure of cats (Fastier, 1958, 05004214). The cats' blood pressure was
increased an average of 50 mm Hg following administration of 1 mg/kg of 4-
aminopyridine intravenously. It remained elevated by 20 mm Hg up to 30 minutes
after 4-aminopyridine adminstration. Barbituate hypnosis in mice was
antagonized 302 by 5 mg/kg of 4-aminopyridine (Vohra et al. 1969, 05003184).
These effects indicate involvement of the autonomic nervous system.
In the rat brain and spinal cord, 4-aminopyridine stimulated release of
norepinephrine but not 5-hydroxytryptamine or dopamine (Anden annd Leander,
1979, 05003729). 4-aminopyridine did not stimulate norepinephrine by
electrical stimulation. This suggests an effect on the electrical
conductivity of the nerve membrane.
In Vitro Effects: In isolated skeletal and smooth muscle preparations,
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4-aminopyridine increases twitch tension and reverses the nondepolarizing
neuromuscular blockade. Inhibition of membrane potassium conductance by
4-aminopyridine prolongs the presynaptic spike, allowing an increase in
acetylcholine release at the presynaptic membrane. The mechanism of action of
4-aminopyridine at the neuromuscular junction is calcium-dependent, and it
probably acts by affecting calcium permeability of the presynaptic membrane.
Dose-dependent positive inotropic responses (contractions) were produced by
4-aminopyridine in guinea pig ileum (Moritoki et al., 1978, 05003154) and
canine tracheal muscle (Kann.an and Daniel, 1978, 05005155). The positive
inotropic effect of 4-aminopyridine was reduced when treated with a combination
of phenoxybenzamine (an alpha blocker) and propranolol (a beta blocker)
(Leander et al., 1970, 05003158). When phentolamine, another alpha-blocker,
was used instead of phenoxybenzamine, no reduction in the effect of 4-amino-
pyridine was observed. This suggests that 4-aminopyridine does not have an
agonistic effect on alpha-receptors.
In superfused guinea pig ileum, 4-aminopyridine decreased contractile responses
stimulated by carbachol by more than 50£ (Fastier, 1958, 05004214).
Contractile responses were increased in the presence of choline or by
anticholinesterase agents such as physostigmine (Al Haboubi et al., 1978,
05005379) and neostigmine (Al Haboubi et al., 1978, 05006379). Atropine, a
cholinergic antagonist (Kannan and Daniel, 1978, 05003155, Al Haboubi, 1978,
05005379, Moritoki et al., 1978, 05003154) antagonized the contractile
response to 4-aminopyridine. Because initiation and potentiation of
contractile responses were blocked by atropine and tetrodotoxin and increased
by cholinesterase inhibitors, it is suggested that the effect of 4-amino-
pyridine is the result of indirect cholinergic action. The action of 4-amino-
pyridine appears to be Ca - dependent (Al Haboubi et al., 1978,
05006379). 4-aminopyridine potentiated by eight times the tension of muscle
twitch evoked by phrenic nerve stimulation in the presence of tubocurarine
(Bowman et al., 1977, 05003160). In the presence of 4-aminopyridine, extremely
high doses of curare were required to abolish twitches. These data indirectly
support the conclusion that the mechanism of action of 4-aminopyridine is on
the presynaptic membrane.
In summary, 4-aminopyridine selectively blocks membrane potassium conductance
in both nerve and muscle. Inhibition of membrane potassium conductance
prolongs the presynaptic action potential, resulting in an increase in the
amount of neurotransmitter released at the presynaptic membrane. The mechanism
of 4-aminopyridine is calcium-dependent, probably acting by increasing the
influx of calcium ions during the nerve terminal action potential.
Clinical Effects
4-aminopyridine increases transmitter release from the nerve terminals,
probably by increasing calciun permeability of-the nerve terminal membrane.
4-aminopyridine has been shown to restore neuromuscular transmission in
myasthenia gravis, Eaton-Lambert syndrome, and pancuronium-linconycin
neuromuscular blockage in man.
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In six patients with myasthenia gravis, intravenous adminstration of 10 to 20 mg
of 4-aminopyridine caused a marked improvement in clinical status (Lundh et
al., 1979, 05003494). Similar improvements were reported for two Eaton-Lambert
syndrome patients (Lundh et al., 1977,Q05004217, Agoston et al., 1978,
05003173). Electrophysiological examination before and after intravenous
injection of 4-aminopyridine revealed some improvement in all eight patients
discussed above. Results suggest that 4-aminopyridine may be a valuable drug
in the treatment of myasthenia gravis and myasthenic syndrome, sometimes
associated with Eaton-Lambert syndrome.
Clinical Side Effects
In six adult patients with myasthenia gravis, intravenous administration of 10-
20 mg of 4-aminopyridine produced perioral paraesthesia within seconds (Lundh
et al., 1979, 05003494). The paraesthesia disappeared within a few minutes of
4-aminopyridine administration.
In a clinical study of 57 surgical patients, no signs of central nervous system
stimulation were observed after single intravenous doses of 0.15, 0.35, or 0.50
mg/kg of 4-aminopyridine (Miller et al., 1979, 05004966). After a single
intravenous administration of 10 to 20 mg, four of six patients experienced a
temporary sensation of unsteadiness during walking, lasting 0.5-2 hours
(Lundh et al., 1979, 05003494). However, no objective signs of disturbed gait,
posture, or coordination were observed.
Miller et al. (1979, 05004966), Lundh et al. (1977, 05004217), and Lundh et al.
(1979, 05003494) reported no significant changes in blood pressure or heart . '
rate after administration of 4-aminopyridine. Agoston et al. 1978, (05003178)
reported a slight decrease in heart rate but no changes in blood pressure in an
Eaton-Lambert syndrome patient given up to 120 mg/day of 4-aminopyridine for
120 days (Lundh et al., 1977, 05004217). No changes in routine blood tests of
liver or kidney function were observed in this patient.
These studies demonstrate that intravenous adminstration of single doses of 4-
aminopyridine at 0.5 mg/kg or repeated dosing of up to 120 mg/day for 20 days
produced no adverse effects in hunans.
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DISCIPLINARY REVIEW
Toxicology Profile
Toxicology Hazard Assessment
Data Caps
Required Labeling
Toxicology Profile
Technical 4-amir.opyridine
The very low acute oral LDcQ in both laboratory rats (28.7 mg/kg) and dogs
(3.7 mg/kg) indicate a hign acute oral toxicity in humans. The acute dermal
toxicity in male rabbits (LDt-g = 327 mg/kg) suggests a moderate dermal
toxicity in humans. Technical 4-aminopyridine is expected LO produce only
mild, short-term eye irritation in humans, based on studies conducted with
rabbits. Mild eye irritation lasting less than 7 days was noted when this
compound was instilled into rabbit eyes. Technical 4-aminopyridine is not
expected to cause skin irritation in humans. No sign of skin irritation was
noted when 4-aminopyridine was applied to intact and abraded rabbit skin.
Adequate subchronic 90-day oral toxicity data were available for technical 4-
aminopyridine. No significant pathologic changes in any organ or tissue and no
compound-related effects in blood or urine in rats and dogs were noted.
However, at high doses (2.0-3.25 mg/kg/day) brain weight in dogs was affected,
although examination of the brain revealed no abnormalities. The no-observable-
effect level (NOEL) was 3 ppm in rats and 200 ppm (.1 mg/kg/day) in dogs.
4-aminopyridine. Formulations
Very little data specific to any of the formulations of 4-aminopyridine were
available. Based on extrapolation fron data available on the technical
compound, formulations of 4-aminopyridine are assigned LO the following
Toxicity Categories:
Actus Oral Toxicity: o Formulations containing 25% or more
4-aminopyridine—Toxicity Category I
o Formulations containing 2.5% to 24%
active ingredient—Toxicity Category II
o Formulations containing less than 2.57=
active ingredient—Toxicity Category III
Acute Dermal Toxicity: o Formulations containing 65% or more
4-aminopyridine—Toxicity Category II
o Formulations containing 6.5% to 64%
active ingredient—Toxicity Category III
o Formulations containing less than 6.5%
active ingredient—Toxicity Category IV
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Primary Eye Irritation: Ail formulations—Toxicity Category III
Primary Dermal Irritation: All formulations—Toxicity Category IV
No data were available for assessing the acute inhalation toxicity to humans of
4-.aminopyridine dust formulations.
Hazard Assessment
4-Amir.opyridine Formulations
The 'Exposure Profile' which appears in the Environmental Fate Chapter
indicates that there is little chance of oral exposure to 4-aminopyridine
formulations, except through accidental ingestion. Dietary exposure from
residues in corn and sunflowers is expected to be insignificant. Accidental
ingestion of 4-aminopyridine can result in serious poisoning, and in some cases
death. The severity of the poisoning is dependent upon the concentration of
active ingredient in the formulation swallowed.
No inhalation exposure to ready-to-use baits will occur, due to the nature of
these formulations. Inhalation of dusts may occur, however, if applicators do
not wear respirators. No inhalation toxicity hazard assessment can be made for
4-aminopyridine dusts because of the lack of data. Similarly, the potential
for teratogenic or mutagenic effects resulting from inhalation exposure cannot
be determined because of a lack of data.
Because the applicator will be required to wear gloves, there should be no
hazards resulting from dermal exposure to any 4-aminopyridine dust or
pretreated bait product which falls into Toxicity Category I or II for dermal
toxicity. Applicators who handle pretreated baits which fall into Category IV
will not be required to wear gloves and may be exposed on a short-term basis to
very small amounts of 4-aminopyridine. The hazard is slight, however, since
such products have very low dermal toxicities. Accidental occular exposure may
occur while handling dusts. Eye exposure to either the 5Q% or the 25* dust
formulation is expected to produce only mild, short-term eye irritation.
Since chronic exposure to 4-aminopyridine for either the applicator or the
.public will not occur, no oncogenic reproductive or general chronic effects are
expected to result from use of 4-aminopyridine products.
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Data Gaps
The following are gaps in the Toxicology data base needed to adequately support
a Registration Standard for 4-aminopyridine. Listed after each gap, is the
section in the proposed Guidelines (U.S. Environmental Protection Agency, 1978)
which describes that type of study and when it is required.
Technical 4-aminopyridine Guideline Section
No data requirements
4-aminopyridine Dusts
Acute inhalation toxicity study 163.81-3
Registrants of dust formulations must agree to provide or cite the following
studies, OR_ to adhere to label requirements for protective clothing discussed
in the Required Labeling Section of this chapter.
i
Teratogenicity (2 species) 163.83-3
Mutagenicity 163.84-1,2,3,4
Required Labeling
Each 4-aminopyridine product must bear label statements appropriate to the
Toxicity Categories assigned to that product for each acute effect (Refer to
{162.10 of 40 CFR, 1978) with the following exception: Labels on all 4-
aminopyridine dust products, regardless of the Toxicity Categories assigned,
must require applicators to wear protective clothing including long sleeves,
gloves, and respirators.
To help prevent accidental oral ingestion, dust product labels must also bear
the requirement, "Bait materials resembling hunan food must be altered in form
by crushing, balling, or pelleting so that they are not readily recognizable as
hunan food.
\
Despite precautions, accidental oral ingestion may still occur. Consequently,
the following statement of emergency treatment must be.included on the label of
all 4-aminopyridine manufacturing-use, and formulated products:
IF SWALLOWED: If the patient is unconscious, maintain breathing and heart beat
(CPR: cardiopulmonary resuscitation). Contact your local Poison Control
Center, hospital or physician immediately.
If patient is conscious, induce vomiting with syrup of ipecac (if not available
stimulate the back of the throat with finger). Never give anything by mouth to
an unconscious person! Contact your local Poison Control Center, hospital or
physician irnnedlately.
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Toxicology Bibliography
Agos ton , 3.; V.'esrd-sn , T. von; Westra, P.; Broekert,
1>7
0-5006373
05003729
05003160
00004027
05004214
00004024
05003155
00004026
05003153
05004217
05003494
Effects of 4-aminopyridine in Eaton Lambert syncroine. British
Journal of Anaethesie 50(4):333-335.
Al-!h>boubi, H.A.; Bovraan, W.C.; Houston, J. ; Savage, A.G. 1973.
Effects of 4-aminopyridine on the isolated
parasympathetically-innervated oesophagus of che.domestic fowl
chick. Journal of Pharmacy and Pharmacology 30(3):517-513.
Anaen, M.E.; Leander, S. 1979. Effects of 4-aminopyridine on the
turnover of mor.oamines in the central nervous system of the
rat. Journal of Neural Transmission 44(i/2):1-12.
Eownan, W.C.; Khan, H.H.; Savage, A.O. 1977. Sane antagonists of
cantrol-ane sodium on the isolated diaphragm muscle of the rat.
Journal of Pharmacy and Pharmacology 29(10):516-625.
Corvenka, H.; Vega, 3.M. 1963. Ninety-Day Subacute Oral Toxicity
of Canpounc 1361 (4-Aminopyridine)—Beagle Dogs: Project Number
777. (Unpublished study received Dec 30, 1963 under IF'iOlj.;
prepared by Lifestream Laborstories, Inc., submitted by Phillips
Petroleum Co., Bartlesville, Okla.; CDL:091 /56-G)
Fastier, F.N.; McDowall, M.A. 1953. A comparison of the
pharmacological properties of the three isorneric
aminopyriaines. Australian Journal of Experimental Biology
jo:365-371.
Ives, M. 1962. Report to Phillips Petroleum Company: Toxicity
Studies on Compound 1361 Hydrochloride. (Unpublished study
received Dec 30, 1963 under 1F1013; prepared by Industrial Bio-
Test Laboratories, Inc., submitted by Phillips Petroleum Co.,
Bartlesville, Okla.; CDL:C91756-3)
Kannan, M.S.; Daniel, E.E. 1973. Formation of gap junctions by
treatment in vitro with potassium conductance blockors.
Journal of Cell Biology 73(2):333-343.
Kohn, F.E.; Cervenka, H.; Kay, D.L.; Vega, 5.H. 1563. 90-Day Sub-
acute Oral Toxicity of Canpounc 1361 (4-Amir.opyridine): Albino
Rats: Project lium'oer 333. (Unpublished study received Dec 30,
1963 under 1F101j; preparec by Lifestrean Laboratories, Inc.,
submitted by Phillips Petroleum Co., Bartlesville, Okla.; CDL:
091756-F)
Lzander, S.; Arner, A.; Johansson, 3. 1977. Effects of
4-ejfiinopyridine on mechanical activity ana r.oracrenaline
release in the rat portal vein in vitro . European Journal of
Pharmacology 46(4):351-361.
Lundh, H.; Nilsson, 0.; Rosen, I. 1977. 4-Aminopyridine—a new
arug tested in the treatment of Eaton-Lambert syndrome.
Journal of Neurology, ','eurosurgery, and Psychiatry
40(10:1109-1112.
Lundh, H.; 'liisson, 0.; Rosen, I. 1979. Effects of
4-anir.opyridine in myasthenia gravis. Journal of Neurology,
Meurosurgery, and Psychiatry 42(2):171-175.
-56-
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05004305
05003154
OUOC41J7
05005134
Millar, R.D.; Booij, L.H.D.J.; Agoston, S.; Crul, J.F. 1979.
4--Aminopyridine potentiates neostigmine and pyridostigmine in
win. . Anesthesiology 50 (5): 416-420.
,-ioritoki, H.; Takei, M.; ."Jakarnoto, N.; Ishida, Y. 1973. Actions
of arninopyridines on guinea-pig ilaurn. Archives
Internationales de PharmacodynaT.ie et de Therapie 252(1):28-41.
Phillips Petroleum Conpany no date. Percutaneous Tests on Rabbits
with Grain Containing 1361, 4-Aminopyridine as the Hydrochlo-
riae. (Unpublished study received Oct 5, 1966 under unknown
admin, no.; CDL:103074-A)
Vohra, M.M.; Pradhan, 3.N.; Jain, P.C.; Chatterjee, 3.K.; Anand,
i*. 1365. Synthesis and structure-activity relationships of
sane atninopyridir.es, imidszopyridines, and triazolopyriaines.
Journal of Medicinal Chemistry 3(5):295-504.
-57-
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Standard References
Tiii3 40 -Prot»ct,ior; of the Environment 40 CFR, 1370,. Cods of
Federal Regulations. Chapter i -Environmental Protection
Agency. Washington, D.C.: U.S. Government Printing Office.
U.o. Environmental Projection Agency 197G. Proposed Guidelines for
for registering P-asticidas in the United States. Haajrc
Evaluation: Human and Domestic i\r.irr.als. 43 Feder-al Register,
(153) 5/336. (August 22, 1973)
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VII. Residue Chemistry
Topical Discussions
the Proposed Guidelines for residue chemistry have not been published.
Accordingly there are no citations for guidelines corresponding to the types of
residue chemistry data normally required to support individual registrations.
In general, however, the Agency must have sufficient data for each proposed
product to be assured that the residues of the parent chemical and its
metabolites have been quantitatively and qualitatively identified.
Plant. Metabolism of 4-aminopyridine:
Data are required to examine the metabolism of 4-aminopyridine in the crop to
which it is applied. The available information on this topic is summarized by
crop.
Corn: The amount of information available on the metabolism of 4-
aminopyridine in plants is limited. There is one report in the published
literature (Starr and Cunningham 1975, 05003202) regarding the
degradation of 4-aminopyridine in corn. Young corn plants were exposed to
10 ppm of 4-aminopyridine in nutrient solution for^ days. TLC-
autoradiography of the acetone extracts showed no C-radioactivity
other than parent compound in roots or shoots. A study (Starr and
Cunningham 1966, 0004039) of the absorption of 4-aminopyridine from soil or
nutrient solution bjf^variously aged corn plants demonstrated that older
plants absorb less C-4-aminopyjjidine than younger plants. 2-month old
corn plants absorbed much less C-radioactivity from soil at 10 ppm than
from nutrient solution. Corn plants at three months showed that detectable
radioactivity in an ear of corn and in the uppermost 2 feet of stalk
resulted fron exposure to nutrient solution at 5 ppm. The first tbjjee 12-
inch sections of the stalk contained 1.4, 0.074, and 0.004 ppm of C-
equivalent to 4-aminopyridine respectively. Nutrient solution exposure is
much greater than exposure under field conditions. Therefore, residues of
4-aminopyridine in corn under field treatments are expected to be
considerably lower.
In summary, the only residue of 4-aminopyridine found in corn plants was
the compound itself. No metabolites of 4-aminopyridine were detected. No
C-radioactivity was detected in corn grain after nutrient solution
exposure. Based upon this information, the low application rate, and the
field residue data discussed below, residues of 4-aminopyridine are not
expected in corn grain under normal use conditions.
Sunflowers: There are no available reports of the metabolism of 4-
aminopyridine in sunflower plants. Cunningham (1975, 00004088) studied the
absorption of 4-aminopyridine by sunflower plants from soil treated at an
exaggerated rate of 20 applications. The concentration in the soil was
0.02 ppm. However, during the 8 weeks of growth, there was no observable
difference between treated and control plants in the amount of C-
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radioactivity in sunflower leaves, stems and stalks, and flower plus
leaves. This information indicates that residues of 4-aminopyridine or its
metabolites would not be expected in sunflower plants under field
conditions.
Other. Plants: The metabolism and degradation of 4-aminopyridine in
sorghum plants were reported by Starr and Cunningham (1975, 05003202).
Acetone extracts of young sorghum plants exposed to 5 ppm 4-AP in nutrient
solution fgr one week followed by one week without exposure, contained 3
distinct C- containing degradation products. The th^e degradation
products contained from 0.5? to 4.4? of the recovered C [recovery
ravage 83? to 95?]. The degradates were not identified or characterized
other than by reportednRF values in a specific TLC procedure. More than
90? of the recovered C was in the parent compound, as shown by TLC-
autoradiographic procedures. When more mature plants were tested, only low
levels of unidentified C-radioactivity were reported in sorghum seeds
and heads, following nutrient solution exposure at 5 ppm. This stu^y
suggests that some 4-aminopyridine plant metabolism occurs, since C-
radioactivity was less easily recovered from older plants than from younger
plants.
Animal Metabolism:
Data on animal metabolism are required if residues are found in animal food or
feed items. Sullivan (1970, 00004030), reported that in vitro beef and chicken
liver honogenates showed no observable degradation of "^aminopyridine during 24
hours of incubation. Although this study would not fulfill an animal
metabolism data requirement, additional data are not needed since residues of
4-aminopyridine are not expected in animal food and feed items (see above).
Analytical Methods:
Because 4-aminopyridine is used on crops, an analytical method for detecting 4-
aminopyridine residues in treated crops is required. The method must be valid
and specific for 4-aminopyridine, without interference from other pesticides
which may be applied to these crops.
Several methods for the extraction, cleanup, and estimation of 4-aminopyridine
concentrations have been reported. One method (Peterson, 1971, 05003193) was
considered to be inadequate due to lack of information regarding the
fortification samples. However, further development and modification of-
Peterson's method were reported by Sullivan (1970, 00004030) and Phillips
Petroleum Company (no date, 00004016). These improvements make this method
valid for the extraction, cleanup, and estimation of residues of 4-
aminopyridine in treated corn. The method is as follows:
Fresh whole corn plant is chopped up into small particles and air dried to
constant weight. An aliquot is blended with acetonitrile containing 3%
ammonium hydroxide. After filtration, the acetonitrile solution is shaken just
to dryness. The residue is transferred to a separatory funnel which is shaken
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vigorously for 5 minutes with n-butyl acetate and 0.1 N HC1, and the phases are
allowed to separate. The aqueous phase is transferred to another separatory
funnel, and is shaken again with n-butyl.acetate. The phases are allowed to
separate and both n-butyl acetate phases are discarded. The aqueous phase is
transfered to a third separatory funnel. It is adjusted to pH 11 with 10$
sodium hydroxide and n-butyl acetate is added. The phases are allowed to
separate and the aqueous phase is discarded. The organic phase is passed
through anhydrous sodium sulfate with additional n-butyl acetate. The solvent
is reduced just to dryness and the residue is quantitatively transferred to a
graduated centrifuge tube with redistilled acetone. 'The acetone solution is
reduced to 1 ml or less for gas chronatography under the following conditions:
Colunn — Chromosorb 103
Temperature ' ' — 228 C
Helium carrier flow — 15 at 40 psi = about 100 ml/min
Sensitivity — 1 x 30
Inlet — 250°C
Transfer . ~ 250°C
Furnace — 900 C
Detector — Nitrogen conductivity detector
The minimum level detectable by this procedure is 10 nanograms or 0.1 ppm for
100 gram samples (fresh weight). The recovery of 4-aminopyridine from 4
control samples fortified at 0.1 ppm ranged from 70? to 80 %, while at 0.4 ppm
the recovery in one control sample was 86%'(Sullivan, 1970, 00004030).
The analytical method described above was used to report the residues of
4-aminopyridine in field treated samples of corn. It was also the method
published in the Pesticide Analytical Manual, Vol. II, for the determination of
4-aminopyridine residues in corn. The method has been subjected to thorough
analytical research for accuracy and sensitivity in EPA laboratories.
The same method is considered adequate for residues of 4-aminopyridine in
sunflower seeds although a high degree of scatter of recovery values has been
reported (Copeland, 1972, 00004050). Attempts to modify the method to improve
the recovery from sunflower seeds were reported by Peterson (1974, 00004048;
1975, 05003192). Due to the high content of oil and cellulose material, the
modifications were thought to be necessary to allow the extraction of 4-
aminopyridine fron sunflower seeds. These modifications are described below:
Seeds and plant tissues are ground to 30 mesh and extracted with n-butyl
acetate and sodium hydroxide. The 4-aminopyridine is partitioned from n-
butyl acetate into water under acidic conditions and is cleaned up by passing
through a weakly acidic cation exchange resin (Amberlite IRC-50) using
hydrochloric acid as regeneration solvent. The residue is. repartitioned
between n-butyl acetate and water containing either sodium hydroxide or
hydrochloric acid. The residue is analyzed on GLC using flame ionization
detection or electrolytic conductivity detector. ,The GLC column material is 3/°
Carbowax 20M and 0.1% potassium hydroxide on Chromosorb 750.. The lower limit
of detector linearity is 10 nanograms. Recovery is reported at 50$ to 70%.
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In addition to the gas liquid chronatographic detection system, procedures for
TLC identity confirmation and semiquantitative estimation of 4-aminopyridine
residues are reported by Sullivan (1970, 00004007; 1970, 00004030), Starr
(no date, 00004126), Schafer and Starr (1969, 00004011), and Phillips Petroleum
Company (no date, 00004029).
Residue Data —- Crops:
Data on 4-aminopyridine concentrations in treated crops are required to assure
that residues are below tolerance values under actual field conditions. Field
residue data are expected to reflect the residues resulting from the registered
uses in regard to dosage rates, modes of application, numbers and timing of
treatments, formulations used and geographical areas.
Field Corn: One valid study (Sullivan, 1970, 00004030) reported traces of
4-aminopyridine in field corn receiving up to 5 applications of a 1 pound
per acre treatment. Traces of 4-aminopyridine in whole corn plants were
reported to be less than the minimum detectable residue, 0.1 ppm. There
were no differences between the control samples and treated samples.
Sweet Corn: A report of uncertain validity (Peterson, 1974, 00004100),
showed corrected residues of 4-aminopyridine at 0.03 ppm maximum in ears of
sweet corn. The accuracy of this information cannot be determined because
the analytical method was not adequately described.
Sunflowers: There is one report of residue data for 4-aminopyridine in
sunflowers receiving both label rates and exaggerated dosages, (USDI, no
date, 1015-002-01). At label rates of up to 5 applications, there were no
detectable differences between control and treated values. All residue
values were less than 0.01 ppm. At exaggerated rates totaling 12.6 pounds
of bait per acre in 13 treatments, treated seed samples showed 0.05 ppm of
4-aminopyridine while control samples showed 0.008 ppm.
Estimated Residues in Corn and Sunflowers: In addition to residue data for
corn and sunflowers, a variety of calculations or estimates have been made
of the residues of 4-aminopyridine that would be expected based on
application of active ingredient at the rates indicated on product labels.
These calculations are based upon the characteristics of the formulated
product and use pattern. The formulated product is applied as a
heterogenous mixture of 1% (by weight) treated bait particles and 99% (by
weight) untreated bait particles. The treated bait particles contain 3%,
by weight, active ingredient. The bait formulation applied contains 0.03%,
by weight, 4-aminopyridine. At one pound of bait per acre, per treatment,
the amount of active ingredient 4-aminopyridine applied to the crop is
0.0003 Ibs per acre.
One report (Phillips Petroleum Company, no date, 00003993) stated that the
yield of corn and fodder is 40,000 pounds per acre. Based on this
assumption and three applications of 0.0003 pounds active ingredient per
acre, the maximum concentration of 4-aminopyridine in corn and grain would
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be 0.0225 ppm if all the applied 4-aminopyridine were absorbed and
translocated. However, testimony presented (Phillips Petroleum Company, no
date, 00004017) contended that 80% to 9555 of the bait granules reach the
ground. Assuming that 103 of the particles lodged in the plant during
three applications, the average residue in corn grains and fodder would be
0.0023 ppm.
Another report (Phillips Petroleum Company, no date, 00004022) estimated
from particle weight and plant yield per acre that the concentration of 4-
aminopyridine in a corn plant would be 6.6 x 10~ g/g of corn plant if
one active treated particle lodged in one corn plant weighing 2.5 pounds.
Similar estimates were made for sunflower seed, based upon yield of seed
and plants per acre. Assuming 3 and 4 applications, residues in sunflower
plants would be 0.0225 ppm in good sunflower crops (40,000 pounds of plants
per acre) and 0.052 ppm in poor crops (23,000 pounds per acre) (Avitrol, no
data, 00004049).
A study (Swindle, 1973, 00004039) was conducted to observe the actual number
of bait granules lodging in sunflower seed heads or other portions of the
plant. Calculations based on the maximum observed number of granules per acre,
estimated the residues of 4-aminopyridine in sunflower seeds to be 0.01V ppm,
assuming complete adsorbtion and translocation.
This information, together with plant metabolism data, the estimates of
residues, and the actual residue data, provide sufficient information on
residues of 4-aminopyridine in corn and sunflower seeds. Based upon these
data, residues of 4-aminopyridine at method sensitivity (0.1 ppm) are not
expected in either corn or sunflowers.
Residue Data ~ Processed, Commodities:
Data on residues in processed commodities are required if residues are found in
the raw agricultural commodity. There are no data available for residues of 4--
aminopyridine in processed ccmmodities. However, since residues of 4-amino-
pyridine do not occur in the raw agricultural commodities (corn, corn fodder
and forage, and sunflower seeds), residues of 4-aminopyridine should not occur
in processed commodities derived from these raw agricultural products.
Therefore, residue data on processed commodities are not required.
Residue Data -- Meat, Milk, Poultry,, and Eggs
Data on residues in meat, milk, poultry, and eggs are required if residues are
found in animal food or feed items. Based upon residue data on agricultural
commodities, significant residues of 4-aminopyridine are not expected to occur
in animal food or feed items. Residues of 4-aminopyridine would not be
expected in meat, milk, poultry or eggs from animals consuming feed or food
items treated with 4-aminopyridine according to label directions. Therefore,
data on residues in meat, milk, poultry and eggs are not required to support
currently registered uses of 4-aminopyridine.
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DISCIPLINARY REVIEW
Residue Chemistry Profile
Tolerance Reassessment
Data Gaps
Required Labeling
Residue Chemistry, Profile
At the sensitivity of the method no residues of 4-aminopyridine are likely to
be found in corn grain, corn fodder and forage, sweet corn (including popcorn)
or sunflower seeds when products are used according to label directions. In
addition, calculation of maximum possible residues in these commodities based
on the low dosage rates indicates that residues should not result from the
label maximums of five applications per year for sunflowers and four
applications per year for corn. Since no residues of 4-aminopyridine at method
sensitivity are expected in the raw agricultural products, no data are needed
for processed commodities or for meat, milk, poultry or eggs.
Available plant metabolism data indicate that sane metabolism occurs, with
three metabolites isolated (but not identified or characterized) in sorghum
plants. No metabolites were found in corn. 4-aminopyridine is absorbed and
translocated in corn plants from nutrient solution, but less so from soil.
Based on this absorption, translocation and metabolism information, plant
uptake of 4-aminopyridine is not expected to be significant in. corn and
sunflowers.
There were no available studies of animal metabolism of 4-aminopyridine. When
4-aminopyridine was studied in vitro in beef and chicken liver homogenate
systems, there was no observable metabolism. These data would not fulfill an
animal metabolism data requirement, but additional data are not needed because
4-aminopyridine residues are not expected in animal food and feed items.
Tolerance Reassessment
The Theoretical Maximum Residue Contribution (TMRC) for 4-aminopyridine in corn
(all types) and sunflower is 0.0033 mg/day for a diet of 1.5 kg. This amount
is 4.233 of the Acceptable Daily Intake which is 0.0015 mg/kg/day. In the
reassessment of this tolerance, calculations were based upon the level of
detection, as were the original tolerances. The Agency does not expect
the Average Daily Intake to result in any unsafe levels of 4-aminopyridine
in the human diet.
Data Gaps
There are no residue chemistry data requirements for non-food uses of 4-amino-
pyridine, nor are there any generic residue chemistry data gaps resulting from
food uses of 4-aminopyridine at present. The registration/tolerance data
requirements for the food uses on corn and sunflowers have been satisfied.
Uses of 4-aminopyridine on raw agricultural commodities other than corn and
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sunflowers would require a validated analytical method, residue data and plant
metabolism data. If residues of 4-aminopyridine were to be found in raw
agricultural commodities other than corn and sunflowers, data on residues of 4-
aminopyridine in meat, poultry and eggs would be required, including
identification of the animal metabolites of 4-aminopyridine.
Required Labeling
Labeling of 4-aminopyridine products must bear a warning or restriction
against use, storage, or disposal of a 4-aminopyridine formulation in a manner
likely to result in contamination of human food items. The bait formulations
intended for use on corn and sunflowers should be limited to a maximum of five
applications per crop season for sunflowers and four applications per crop
season for corn. The specific labeling restrictions for the pretreated bait
formulations necessary to prevent contamination of human or animal foods are:
For all products
Do not use where food (grain or meat) might become contaminated.
Do not contaminate water, food or feed by storage or disposal.
For pretreated baits
Do not feed to livestock or poultry.
Do not mix with grain for livestock or poultry feed.
For products intended for use in cattle, feed lots
Keep treated bait off the ground, out of reach of cattle.
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Bibliography
00004049 Avitrol Corporation (no date) Toxicology: Mathematical Approach:
Consumer Safety from Pesticidal Residues. (Unpublished study
received Apr 30, 1974 under 4F1498; CDL:094836-W)
00004050 Copeland, G.L. (1972) Interim Report: Development and Evaluation of
Methodology to Determine Residues of 4-aminopyridine in Sun-
flower Seeds. Method dated Jul 14, 1972. (Unpublished study
received Apr 30, 1974 under 4F1498; prepared by Hazleton Labora-
tories, submitted by Avitrol Corp., Tulsa, Okla.; CDL:094836-X)
00004088 Cunningham, D.J. (1975) Translocation of 14C-4-aminopyridine in
Sunflowers and Wheat Growing in Treated Soils: (Report of Study
No. 37, Work Unit DF-102.2). (Unpublished study received Apr
28, 1975 under 11649-15; prepared by U.S. Fish and Wildlife
Service, Denver Wildlife Research Center, submitted by Avitrol
Corp., Tulsa, Okla.; CDL:225254-E)
Food and Drug Administration (1978) Pesticide analytical manual.
Volume II. Methods for individual residues. U.S. Department
of Health, Education and Welfare: Washington, D.C.
05003203 Glover, W.E. (1978) Potentiation of vasoconstrictor responses by
3- and 4-aminopyridine. British Journal of Pharmacology
63(4):577-585.
05003193 Peterson, J.E. (1971) A microanalytical method for 4-aminopyridine
in corn plant tissues. Bulletin of Environmental Contamination
and Toxicology 6(1):72-80.
05003192 Peterson, J.E. (1975) A microanalytical method for 4-aminopyridine
in sunflower seeds and plants. Bulletin of Environmental
Contamination and Toxicology 13(6):641-645.
00004048 Peterson, J.E. (1974) Gas Chromatographic Method for 4-aminopyri-
dine in Sunflower Plants and/or Seeds. Method dated Apr 24,
1974. (Unpublished study received Apr 30, 1974 under 4F1498;
submitted by Avitrol Corp., Tulsa, Okla.; CDL:094336-U)
00004100 Peterson, J.E. (1974) Sweet Corn—4-AP Residue Analyses. (Unpub-
lished study received Mar 18, 1975 under 11649-12; prepared by
U.S. Fish and Wildlife Service, Denver Wildlife Research
Center, Section of Chemical Research and Analytical Services,
submitted by Avitrol Corp., Tulsa, Okla.; CDL:094799-1)
00004016 Phillips Petroleum Company (1971) Applicability of Proposed GLC
Analytical Method for 4-aminopyridine Residues in Corn Grain.
Summary of study 093322-B. (Unpublished study received on un-
known date under IF 1013; CDL:093322-A)
00004029 Phillips Petroleum Company (no date) Methodology: [4-aminopyridine].
Includes two undated methods. (Unpublished study received Jan
3, 1973 under 1F1013; CDL:091757-B)
00003993 Phillips Petroleum Company Cno date) Residue Data: 4-aminopyridine
(Avitrol 200; DRC-1327). (Unpublished study received Apr 22,
1969 under 224-EX-3; CDL: 122747-G)
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00004017 Phillips Petroleum Company (no date) Calculations for Amount of
Residue Likely to Migrate to Corn Plant as a Consequence of
Lodging of Bait on Plant during Application. (Unpublished study
including letters dated Mar 24, 1971 and Mar 25, 1971 from
R.N. Smith to Merrill Schnitzer, received June 25, 1971 under
1F1013; prepared in cooperation with U.S. Fish and Wildlife
Service, Div. of Wildlife Research; CDL:093322-B)
00004022 Phillips Petroleum Company (no date) Residue Data: Estimate of
Possible Contamination of Com Plant as a Consequence of Lodging
of an Active Bait Particle in the Plant. (Unpublished study
received Jan 8, 1973 under 1F1013; CDL:091755-D)
00004011 Schafer, E.W.; Starr, R.I. (1969) The Use of Thin-Layer Chromato-
graphy as a Confirmatory Method for the Analysis of 4-amir.o-
pyridine: Progress Report—September 29, 1969. (Unpublished
study received Oct 20, 1969 under 224-EX-3; prepared by U.S.
Fish and Wildlife Service, Denver Wildlife Research Center,
submitted by Phillips Petroleum Co., Bartlesville, Okla.; CDL:
122744-R)
05003440 Starr, R.I.; Cunningham, D.J. (1974) Phytotoxicity, absorption,
and translocation of 4-aminopyridine in corn and sorghum
growing in treated nutrient cultures and soils. Journal of
Agricultural and Food Chemistry 22(3):409-413.
00004039 Starr, R.I.; Cunningham, D.J. (1966) Translocation and Degradation
of 4-aminopyridine in Corn Plants. (Unpublished study received
Jan 3, 1973 under 1F1013; prepared by.U.S. Fish and Wildlife
Service, Denver Wildlife Research Center, submitted by Phillips
Petroleum Co., Bartlesville, Okla.; CDL:091757-T)
05003202 Starr^R.!.; Cunningham, D.J. (1975) Degradation of 4-aminopyridine
- C in corn and sorghum plants. Journal of Agricultural and
Food Chemistry 23(2):279-281.
00004126 Starr, B. (no date) Thin-Layer Chromatography—Avitrol. (Unpublish-
ed study received Apr 15, 1969 under 224-EX-3; prepared by U.S.
Fish and Wildlife Service, Denver Research Center, submitted by
Phillips Petroleum Co., Bartlesville, Okla.; CDL:122745-J)
00004030 Sullivan, J.B. (1970) Final Report: Evaluation of 4-aminopyridine,
Evaluation of the Sponsor's Analytical Method, and Analysis of
Field Samples. Includes method dated May 27, 1970. (Unpublish-
ed study received Jan 3, 1973 under 1F1013; prepared by Hazleton
Laboratories, Inc., submitted by Phillips Petroleum Co.,
Bartlesville, Okla.; CDL.-091757-C)
00004007 Sullivan, J.B. (1970) Progress Report: Evaluation of 4-aminopyri-
dine. Includes method entitled: Thin-layer Chromatography
(Betagram 0). (Unpublished study received on unknown date under
224-EX-3; prepared by Hazleton Laboratories, Inc., submitted by
Phillips Petroleum Co., Bartlesville, Okla.; CDL:122744-N)
00004039 Swindle, K. (1973) Results of Particle Entrapment Experiment. (Un-
published study received Apr 24, 1975 under 11649-15; prepared
in cooperation with U.S. Fish and Wildlife Service and U.S.
Environmental Protection Agency, submitted by Avitrol Corp.,
Tulsa, Okla.; CDL:225254-F)
1015-002 U.S. Department of the Interior, Analysis of 4-aminopyridine
-01 residues on Sunflower seeds and plants.
-67-
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VIII. regulatory ria cion^ie
DC -
-_. v. c;
ysc:; an cemca proper t -3
or reregistration of all 4-aminopyr idino
mcr.ufactur ing-use and formulated products so that the Agency car.
characterize each pesticide. Because 4-aminopyridine is a minor
use pesticide with an annual production of less than 350 pounds,
the following ecological effects and environmental fate studies
arc- not required:
o acute toxicity studies on coldwater fish
and aquatic invertebrates
o a hydrolysis study
o an activated sludge seudy
Studies or the fate of 4-aminopyridine in soil are not r=quired
because, based on available information on the use patterns of 4-
AP end-use products, n-aminopyr idi.ne residues in soil are noc
expected to reach significant levels. Certain chronic
toxicology studies are not required because of ehe following:
1 ) The use pattern is not expected to result in repeated
exposure over a significant portion of one human life
span.
2) Although 4-aminopyr idine has a tolerance of 0. 1ppm for
both corn and sunflowers, human dietary intake from
consumption of these crops is expected to be negligible.
In order to develop proper labeling, acute inhalation toxicity
data are required for the registration or rer egistr ation of all
dust products. Because of the possibility of shore-term
exposure, teratology and rr.utagen ici ty da^a will be required if
applicators of dust products are not required, by the- label, to
wc^r protective clothing, including long sleeves, gloves, and
respirators.
Products t_o b£ Covered Under This Standard
M a r. u f s c t u r i n g -U s e Pr oducts
Having considered all the available information on 4 -
.•iminopyridine manufacturing-use products, the Agency has
ceterr.iined that manufacturing-use U-crninopyricin.c does noc, caus?
unreasonable adverse effects with proper- label directions and
precautions. Therefore, the Agency will accept for r egistration
or r eregistr-a t ion manufacturing-use products with sny percentage
of M-arninopyr idine so long as inert ingredients greater than
1.0",, by weight of tha total product, consist of food or
feed stuffs only.
Fort.-iulateG Products
Th i s 3t :.;nc arc covers only 'ready-to-use bait' and 'dust' type
formulations whose inert ingr rCiiints consist only of food or
ftecstuffs. Products containing o-chor iner-Ls ingredients coulc
have- significantly different properties, ana products in forms
cizli^r than Gusts or ready-to-use bair.s would have significantly
cifferc-n^ application methods not consicered by data available
on the currently registered pr<">aucts. Additional cata
po-rtjin ing c.o x,.-..- produce chemistry, environmental fate,
-68-
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toxicology, residue chemistry and ecological effects of n-2u
formulation types 2nd thtir appliestion methods may be needle
to support the registration of such products.
available data are insufficient to adequately determine the
hazards to humans and wildlife from pretreated bait or dust
products with uses other than those- currently registered,
including use of re-ady-to-use baits on additional crops.
Because such uses could re-suit in increased exposure and in
higher 4-AP residue levels in soil and crops, additional
en v iror.mental fate, residue chemistry and toxicology data would
be required GO support such uses. Specifically, additional
residue chemistry data would be required to establish tolerances
for crops other than corn or sunflowers. The available residue
chemistry data s>-e sufficient to'establish tolerances onlyfor
corn and sunflowers. 4-arninopyridine ready-to use baits may be
applied at a rate of up to .0144 ounces active ingredient per
acre or. trie treated portion of a field a maximum of four times
per year for corn and a maximum of five times per year for
sunflowers without exceeding the established tolerances.
Hazards _to Wildlife
Manufacturing-Use Products
To prevent unauthorized disposal of 4-aminopyridine, all
manufacturing-use 4-aminopyridine products must carry the
following warning on the label:
Do not discharge into lakes, streams, ponds, or public
waters unless in accordance with an NPDE3 permit. For
guidance contact your regional office of EPA.
.For mulcted Products
Although currencly registered 4-aminopyridine ready-to-jse baits
an-d dust products are potentially hazardous to wildlife, the
Agency considers these products suitable for registration
because regulatory actions will help prevent nontarg^t wildlife
exposure and unnecessary target bird mortality. To reduce -
the potential for unreasonable adverse effects on wildlife,
all 4-aminopyridine products will be classified as restricted
use pesticides for use only by certified applicators or
persons undar their direcc supervision. In addition,
formulated products will be restricted to the following
percentages of active ingredient and dilution ratios. Reacy-to-
use bait formulations -nust not exceed i.0,i 4-aminopyridine per
treated granule diluted to .Oj/i 4-aniinopyr idin e per total
product when registered for use in agricultural crops.
Heady-to-use baits must not exceed 0.5/j 4-a:ninopyr idine when
registered to control house sparrows, cowbirds, blackbirds, or
pigeons in che area of nesting and roosting sites, or 1.0,-j 4-
aminopyricine when registered to control starlings in cattle
feedlots, or crows near nesting and costing sites. Dust
formulations must not exceed 50* 4-aminopyridine when registered
to control starlings in cattle feedlots, or- 25,'i 4-aminopyr idin 3
when registered to control Herring Gulls near nesting and
roosting sit^-s and at sanitary landfills. Dilution of bait
before application should be no less than the following:
-69-
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o 1 part treated bait to j parts untreated bait for
pretreatea baits used to control pigeons at nesting
and roosting sites, and for pretreati-c bait and dusc
formulations used in cattle feedlots.
o 1 part treated bait to 10 parts untreated bait for dust
formulations used to.control Herring Gulls at sanitary
landfills and at nesting and roosting sites.
Thi ^-aminopyridine concentrations and trie .-dilution ratios noted
for the various formulations, reflect the maximum concentrations
of active ingredient and the minimum dilution ratios of
currently registered products. Available ecological effects
cata indicate that unnecessary target bird mortality, as well as
an increased hazard to nontarget wildlife would result if
products cor.tair.ea higher percentages of ^-aminopyridine or if
dilution ratios were lowered.
The following label statements', in addition to the restrictions
discussed, above, will help reduce exposure to nontarget birds:
For pretreated baits applieci to agricultural crops:
o Dtfore application in'your area, consult endangered
spe-cies personnel of the U.3. Fish and Wilalife Service
to ensure that endangered ana rare biru species are
not likely to be adversely affected by use of this
product.
o Do not allow bait to remain in unprotectec places after
control measures are completed.
o Confine treatment to areas 50 feet in from field edge.
For products used at sanitary landfills, cattle
feedlots and nesting and roosting structures:
o This product must not be applied where nontarget
bird species feed.
o Careful observation of bird habits must therefore be
made to establish proper feeding locations and to
determine that no nontarget bird species are feeding
on prebait.
Label directions to "Pick up and dispose- of dead birds by
burial" on all dust products and on reacy-to-use bait products
containing greater than 3.0,3 H-aminopyridine per treated granule,
should reduce the potential for secondary poisoning of predatory
wildlife. The label directions."Do not contaminate water by
cleaning of equipment or disposal of wastes11 snould help
eliminate fish anc aquatic organism exposure to significant
quantities of ^-arninopyr idine .
Hazards _to Humans and Domestic Animals
R-; :.icy--to !Js.e Bsit and Dust Products
All '•i-aminopyridine products will be classified as restricted
•JS-. p.-sticic^s and will be handled only by licensed applicators
wno can be expected to comply with label precautions, ana with
directions to -./ear protective clothing. This should greatly
r:;ouc;j th.-:- potential for accidental exposure to 4-AF formulated
products.
In addition, tne following warnings will be included, where
-70-
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priato, on product labels to r-duce the risks f>-o:n
culcir routes of exposure:
For ^cciGcnccl or^i exposure to all products:
o Do rot us~; '.;har£ food (gr^in or ;nea:;) might brcorii.v
con tain ino'ced.
For ciccidantul oral exposure to dust products:
o Gait materials rss-iinbling human food muse be
altered in form by crushing, balling, or pelleting
so that they are nou readily recogr. izsble as food.
For domestic anitnsl =xposurr to pricreatrd bait produce:
o Keep bait off the ground out of r=ach of
-^ •- 4- *- ^ ~
C 3 t -., i.': .
o Do no- feed to livestock or poultry.
o Do rot mix with grain for livestock or poultry.
For domestic animal exposure to ousts products:
o Keep iWciy from livestock, poultry ana pc-ts.
-71-
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APPENDIX A: CHEMICAL DATA SHEET
Chemical Abstracts Chemical Names:
4-Aminopyridine
Other Chemical Names:
gamma-am inopyridine
p-aminopyridine
4-pyridinamine
4-pyridylamine
Structural Formula:
Molecular Formula: ....
C^HrNp free base ' '
CcH~N2Cl hydrochloride salt
Molecular Weight: 94.11'free base ' '
130.58 hydrochloride salt
Chemical Abstracts (CAS) Registry Number:'
504-24-5
Approved Common Name: There is no approved common name at this time.
Other Common Names, Trade Names, or Codes:
Avitrol 200 • •- . '
Phillips 1861
4-AP
WLN: T6NJ DZ
-72-
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APPENDIX B: SUMMARY OF LABEL INGREDIENT STATEMENTS
Three companies, Avitrol, Huge and Woodbury, are the producers of the 26
registered end-use products now on the market. Nine of these products display
the complete ingredient statement of the labels:
i
1. Huge Company: EPA Registration Number 2270-256
4-aminopyridine 0.05 %
Mixed grains* 99.931
HC1 0.019
"Mixture of 1/3 cracked corn, 1/3 whole wheat, and 1/3 milo.
2. Avitrol Corporation: EPA Registration Number 11649-2
4-aminopyridine 1.0 % . .....
Pelletized feed 98.62
HC1 0.38
3. Avitrol Corporation: EPA Registration Number 11649-3
4-aminopyridine 0.5 %
Sorghum 99.31
HC1 0.19
4. Avitrol Corporation: EPA Registration Number 11649-4
4-aminopyridine 0.5 %
Mixed grains 99.31
HC1 0.19
5. Avitrol Corporation: EPA Registration Number 11649-5
4-aminopyridine 0.5 %
Corn 98.62
HC1 0.38
6. Avitrol Corporation: EPA Registration Number 11649-6
4-aminopyridine 0.5 %
Corn Chops 99.31
HC1 0.19
7. Avitrol Corporation: EPA Registration Number 11649-7
4-aminopyridine 0.5 %
Corn 99.31
HC1 0.19
8. Avitrol Corporation: EPA Registration Number 11649-3
4-aminopyridine 1.0 %
Corn 98.62
-73-
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HC1 0.53
9. Avitrol Corporation: EPA. Registration Number 11649-9
4-aminopyridine 0.8 %
Corn chops 79.1
Peanut butter 19.8
HC1 0.3
-74-
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Guide to Use of This Bibliography
Content of Bibliography. This bibliography contains citations of all
che studies reviewed by EPA in arriving at the positions and conclusions
stated elsewhere in this standard. The bibliography is divided into
5 sections: (1) citations that contributed information useful to the review
of the chemical and considered to be part of the data base supporting
registrations under the standard, (2) citations examined and judged to be
inappropriate for use in developing the standard, and (3) standard
reference material. 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, and the published technical
literature.
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. The Agency has sought to identify documents at a level
parallel to a published article from within the typically larger volur.es 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 attempted also to unite basic documents and
commentaries upon them, treating them as a single study.
Identification of Entries. The entries in this bibliography are sorted
by author, date of document, and title. Each entry bears, to the left of
the citation proper, an eight-digit numeric identifier. Tnis number is
unique to the citations, and should be called the "Master Record
Identifier", or "MRID". It is not related to the six-digit "Accession
Number" which has been used to identify volumes of submitted data; see
paragraph 4(d)(4) below for a further explanation. In a few cases, entries
added to the bibliography late in the review may be preceded by a nine-
character temporary identifier. Tnis is also to be used whenever a
specific reference is needed.
Form of the Entry. In addition to the Master Record Identifier (MRID),
each entry consists of a bibliographic citation containing standard
elements followed, in the case of materials submitted to EPA, by a-
description of the earliest known submission. The bibliographic
conventions used reflect the standards for the American National Standards
institute (ANSI), expanded to provide for certain special needs. Some
explanatory notes of specific elements follow:
a. Author . Whenever the Agency could confidently identify one,
tne Agency has chosen to show a personal author. When no individual
was identified, the Agency has shown an identifiable laboratory or
testing facility as author. As a last resort, the Agency has shown
the first known submitter as author.
b. Document Date. When the aate appears as four digits with no
question marks, tne Agency took it directly from the document. When a
four-digit date is followed by a question mark, the bibliographer
deduced the date from evidence in the document. When the date
appears as (19??), the Agency was unable to determine or estimate the
date of the document.
75
-------
c. Ti tie. Tnis is the third element in the citaitnn. In some cases it
has been necessary for tha Agency bibliographers to create or enhance
.£ document oitie. Any such editorial insertions are contained
between square brackets.
d. Trailing Parenthesis. For studies submitted to us in the past, the
trailing parenthesis include (in addition to any self-explanatory
text) the following elements describing the earliest known submission.
(1) Submission Date. Immediately following the word
'received' appears the date of the earliest known
submission.
(2) Administrative ?Jumber. The next element, immediately
following the word 'under', is the registration number,
experimental permit nunber, petition number, or other
administrative number associated with the earliest known
submission.
(3) Submitter. The third element is the submitter, following
the phrase 'submitted by'. When authorship is defaulted to
the submitter, this element is omitted.
(4) Volume Identification. The final element in the trailing
parenthesis identifies the EPA accession number of the
volume in which the original submission ofo the study
appears. The six-digit accession number follows the symbol
'CDL', standing 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.
For example, within accession number 123456, the first
study would be 123456-A; the second, 123456-B;'the 26th,
123456-Z; and the 27th 123456-M.
76
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MRID
05006131
OOCC4101
00004073
OOOu'1035
05003407
0000402/
0000405G
05010341
00004033
GoG015-004
REGISTRATION STANDARD 3I3LICGRAPHZ . ,
Citations Considered to b= Part of the'D^ta Ease Supporting
Registrations Under- the Standard
Biisr, J.E. (1943 )'Alkyl Poiysulfides and 4-Aminopyridine and
Related Compounds [Doctoral.Dissertation]. Philadelphia, Pa:
University of Pennsylvania. (Twenty-oneiunpaged figures)
Bess or, J.F. (1963) Compilation of Information on the : Chronic
Toxicity of 4-Aminopyridine to Pneasant, Quail and Starlings.
(Unpublished study received.Mar 2, .1973 under 11649-12|.prepared
by U.S. Fish and Wildlife Service,.Denver Wildlife Research
Center, submitted by Avitrol Corp., Tulsa, Okla.-; CDL: 120117-A)
Oesser, J.F.; Cummings, J.L. (1.975) Avitrol FC Corn Chops-99 Baits
for Protecting Sunflowers from Blackbirds in North Dakota,
Minnesota, and South Dakota: (Report of Study No. 59, Work Unit
DF-102.5). (Unpublished -study received Nov 11, 1375 under
11549-15; prepared by U.S. Fish and Wildlife Service, Denver
Wildlife Resesrch Center, submitted by Avitrol Corp., Tulsa,
dels.; CDl:223451-I)
Besser, J.F.; Cummings, J.L. (1975) • Avitrol FC Corn, Chops-35 3aits
for Protecting Sunflowers from Blackbirds'.in liorth Dakota,
Minnesota, and South Dakota: (Report of Study Mb. 59, Work Unit
DF-102.3). (Unpublished-study including draft, received Apr 23,
1975 under 11649-15; prepared by U.S. Fish and Wildlife Service,
Denver Wildlife Research, Center, submitted by Avitrol Corp.,
Tulsa,'Okla.; CEL:225254-A) . ' '
Setts, P.M.; Giddings, C.W.; Fleeker, J.R. (1975) Degradation of
4-sminopyridine in soil. .Journal of•Agricultural and Food
Chemistry 24 (3): 571-574. "••••'..
Cervenka, H.; Vega, 3.M. (1953) Ninety-Day Subacute'Oral Toxicity
of Compound 1861 (4-Aminopyridine)—Beagle Dogs: Project Number
777. (Unpublished study received Dec 30, T958 under 1F1013;
prepared by Lifestream Laboratories, Inc., submitted by Phillips
Petroleum Co., Bartlesville, Okla.; CDL:C91755-G)
Copeland, G.L. (1372) Interim Report: Development and Evaluation of
Methodology to Determine Residues of 4-Aminopyridine in Sun-
flower Seeds. Method dated Jul 14, 1972. (Unpublished study
received Apr 30, 1974 under 4F1433; prepared by Uazieton Labora-
tories, submitted by Avitrol Corp., Tulsa, Okla.; CDL:094336-X)
Craig, J.C., Jr.; Pearson, D.E. (1953) NMR proof of the structure
of 4-iminoquinolines and pyridines. Journal of Heterocyclic
Chemistry 5(5):531-637.
Cunningham, D.J. (1975) Transiocation of 14C-4-Aminopyridine in
Sunflowers and Wheac Growing in Treated Soils: (Report of Study
No. 37, Work Unit DF-102.2). (Unpublished study received Apr
23, 1975 under 11549-15; prepared'by U.S. Fish end Wildlife
Service, Denver Wildlife Research Center, submitted by Avitrol
Corp., Tulsa, Okla.; CDL:225254-E)
Fink, R.; Reno, F.E^ (1975) Eight-day dietary LC— - Mallard duck.
(Unpublished study received February 9, 1330 under 11549-12;
prepared by Hazleton Laboratories America, Inc., submitted by
Avitrol Corp., Tulsa, Okia.)
77
-------
00004025
05003195
00004048
00004100
00004325 Ivts, M. (1952) Report to Phillips Petroleum Canpany:-Acute A jl
To::ieity Studies on Compound 1351 Admixed on Grain. (Jnpub-
lished study rece-ivcd Dae 50, 195G under 1F1013; prepared by
Industrial Bio-Test Laboratories, Inc., submitted by Phillips
Petroleum Co., Bartlesvilie,' Okla.; CDL;091756-C)
00004024 Ives, M. (1252) Report to Phillips Petroleum Company: Toxicity
Studies on Compound 1851 liydrochloriue. (Unpublished study
received Dec 50,. 1953 under IF1015; prepared by Industrial Bio-
Tcst Laboratories, Inc., submitted by Phillips Petroleum Co.,
Bartlesvilie, Okla.; CDL:091756-3)
Kohn, F.E.; Cervenka, H.; Kay, D.L.; Vega, S.M. (1963) 90-Day Sub:-
acute Oral Toxicity of Compound 1351 (4-Aminopyridine): Albino
fiats: Project Number 33C. (Unpublished study received Dec 30,
1968 under 1F1013; prepared by Lifsstream Laboratories, Inc.,
submitted by Phillips Petrol-urn Co., Bartlesvilie, Okla.; CDL:
091756-F)
Peterson, J.E. (1971) A microanalytical method for 4-aminopyriUine
in corn plant tissues. Bulletin of Environmental Contamination
and Toxicology 6(1):72~30.
Peterson, J.E. (1974) Gas Chronatographic Method for 4-Aminopyri-
dine in Sunflower Plants and/or Seeds. Method dated Apr 24,
1974. (Unpublished study received Apr 50, 1974 under 4F149G;
submitted by Avitrol Corp., Tulsa, Okla.; CDL:Q943j5-U)
Peterson, J.E. (1974) Sweet Corn—4-AP Rc-sidue Analyses. (Unpub-
lished study received Mar 18, 1975 untie*- 11649-12; prepared by
U.S. Fish and Wildlife Service, Denver Wildlife Research
Center, Section of Chemical Research and .Analytical Services,
submitted by Avitrol Corp., Tulsa, Okla.; CDL:094?99-D
05003192 Peterson, J.E. (1975) A microanalytical method for 4-aminopyridine
in sunflower seeds and plants. Bulletin of Environmental
Contamination and Toxicology 13.(6):641-645.
00004019 Phillips Petroleum Canpany (ho date) .[Identity, Physical and
Chemical Properties, and Formulations of Avitroi]. (Unpublished
study received Jul 15, 1970 under IF 1013; CDL:093322-D)
00004017 Phillips Petroleum Company (no date) Calculations for Amount of Resi-
dua Likely to Migrate to Corn Plant ~.s a Consequence of Lodging
of Bait on Plant during Application, (unpublished study includ-
ing letters dated Mar 24, 1971 and Mar 25, .1971 from R.N. Smith
to Merrill Schnitzer, received Jun 25, 1971 under 1F1015; pre-
pared in cooperation with U.S. Fish and Wildlife Service, Div.
of Wildlife Research; CDL:093322-3)
00004029 Phillips Petroleum Canpany (no date) Methodology: [4-Aminopyrioine].
Includes two undated methods. (Unpublished study received Jan
5, 1975 under 1F1013; CDL:091757-B)
00004137 Phillips' Petroleum Company (no date) Percutaneous Tests on Rabbits
with Grain Containing 1351, 4-Aminopyridine as the Hydrochlo-
rlae. (Unpubiishsa study received Get 5, 1955 unaer unsown
:jcm in. no.; C DL: 103 07 4 -A)
00004022 Phillips Petroleum Company (no date) Residue Data: Estimate of Pos-
sible Contamination of Corn Plant as a Consequence of Lodging of
;:n Active Bait Particle in the Plant. (Unpublished study re-
ceived Jan 3, 1973 under IF 1013; CDL:091755-0)
0000j935 Phillips Petroleum Company (no date) Residue Data: 4-Aminopyridine
(Avitrol 200; DRC-1527). (Unpublished study received Apr 22,
1953 under 224-EX-3; CDL.122747-G)
78
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30004112 Phillips Petroleum Company (no date) Technical Data Sheet: Phillips
• •- Avitrol 200 (1C51). (Unpublished study received 1363 und:ir un-
:
-------
00004126 Starr, B. (no date) Thin-Lay?-;-.1" Chraiiatogrsphy—Avitrol.
(Unpublished study received Apr 15, 1939" under 224-EX-3;
prepared by U.S. Fish end Wildlife Service, Denver- Research
Center, submitted by Phillips Petroleum Co., oartiesvilie,
Okla.; CDL:122745-J)
00004037 Starr, R.I.; Cunningham, D.J. (no date) Phytotoxicity. (Unpublished
study received Jan 3, 1975 under 1F1013; prepared by U.S. Fish
and Wildlife Service-, Denver Wildlife Research Center, submitted
by Phillips Petroleun Co., Bartlesville, Okla.; CDL.-091757-R)
00004039 Starr", R.I.; Cunningham, D.J. (1956) Translocation and Degradation
of 4-Aminopyridine in-Corn Plants. (Unpublished study received
Jan 3, 1973 under 1F1013; prepared by U.S. Fish and Wildlife
Service, Denver Wildlife Research Center, submitted by Phillips
Petroleum Co., Bartlesville, Okla..; CDL:091757-T)
00004001 Starr, R.I.; Cunningham, D.J. (1970) Translocation bnd Degradation
of 4-Aminopyridine in Corn Plants—Its Movement and Degradation
in Soil Systems: [Third Periodic -Report, Avitroi Concentrate!.
(Unpublished study received Apr 24, 1970 under 224-SX-3; pre-
pared by U.S. Fish and Wildlife Service, Denver Wile-life Re-
search Center, submitted by Phillips Petroleum Co., Sartles-
ville, Okla.; CDL:1227^4-H)
05003440 Starr, R.I.; Cunningham, D.J. (1974) Phytotoxicity, absorption,
and trar.slocation of 4-amir.opyriciir.e in corn and sorgaur,
growing in treated nutrient cultures and soils. Journal of
Agricultural and Food Chemistry 22(3);; 409-413.
05003202 Starr, R.I.; Cunningham, D.J. (1975) Degradation of
4-aminopyridine-14C in corn and sorghum plants. Journal of
Agricultural and Food Chemistry 23(2):279-231.
05003135 Starr, R.I.; Cunningham, D.J. (1975) Leaching and degradation of
4-aminopyridir.e-14C in several soil systems. Archives of
Environmental Contamination and Toxicology 3d): 72-33.
00004030 Sullivan, J.3. (1970) Final Report: Evaluation of 4-Arninopyridine,
Evaluation of the Sponsor's Analytical Method, and Analysis of
Field Samples. Includes method dated May 27, 1970. (Unpublish-
ed study received Jan 3, 1973 under 1F1013; prepared by Hazleton
Laboratories, Inc., submitted by Phillips Petroleum Co.,
Sartlesvilla, Okla.; CDL:091757^C)
00004007 Sullivan, J.3. (1970) Progress Report: Evaluation of 4-Aminopyri-
dine. Includes method entitled: Thin-layer chrrmatography
(Eetagram 0). (Unpublished study received on unknown date under
224-ZX-3; prepared by Hazleton Laboratories, Inc., submitted by
Phillips Petroleum Co., Bartlesville, Okla.; CDL:122744-N)
00004033 Swindle, 1C. (1973) Results of Particle Entrapnent Experiment. (Un-
published study received Apr 24, 1975 untie- 11643-13; prepared
in cooperation with U.S. Fish and Wildlife Service and U.S.
Environmental Protection Agency, submitted by Avitrol Corp.,
Tulsa, Okl3.; CDL:225254-F)
iO 1500201 U.S. Department of the Interior (no date) Analysis of 4-Aminopyri-
dine residues on sunflower seeds and plants. Unpublished
document
80
-------
OFFICE CF PESTICIDE PROGRAMS
REGISTRATION STANDARD 3I3LICGRAPHY
Examined and Judged to be Citations inappropriate for Us-:-
in Developing the Standard
HRID
05003173
05006379
05003729
05014933
05003181
;ITATION
00004065
00003964
00004257
000040:34
00004107
00003975
00004131
00004043
00004033
00004063
Agoston, S.; Weerden, T. van; Westra, P.; 3roek-:-rt, A. (1973)
Effects of 4-aminopyridine in Eaton Lambert Syndrome. British
Journal of Anaethesia 50(4):503-335.
Al-Haboubi, H.A.; Bownan, V.C.; Houston, J.; Savage, A.O. (1973)
Effects of 4-aminopyridine on the isolated
parasyrnpathetically-innervated oesophagus of the domestic foul
chick. Journal-of Pharmacy and Pharmacology 30(3):517-513.
Anden, M.E.; Leander, S. (1979) Effects of 4-aninopyridine on ens
turnover of rr.onoamines in the contra! nervous system of the
rat. Journal of Neural Transmission 44(1/2):1-12.
Anden, M.E.; Leander, S. (1979) Turnover of noradrenaline,
dopamine ana 5-hydroxytryptsr,ine in the CMS under the influence
of 4-aninopyridine. Acta Physiologies Scandinavica
105(1):45-45.
Aue, D.H.; Webb, ii.M.; Bowers, M.T.; Liotta, C.L.; Alexander,
C.J.; Hopkins, H.P., Jr. (1976) A quantitative comparison of
gas- and solution-phase basicities of substituted pyridinas
[letter]. Journal of the American Chemical Society
90(3):354-355.
Avitrol Corporation (no date) Durability of Avitrol 200, 4-Amino-
pyridine Hydrochloride on Grain. (Unpublished study received
Get 17, 1973 under 11649-1; CEL:'Q11002-0)
Avitrol Corporation (no cate) Introduction ana Surrmar-y: L^O Document-
ed Reports on Bird Species and Baits]. (Unpublished study
received Apr 10, 1975 under 11549-10; CDL:115276-A)
Avitrol Corporation (no date) Pesticidal Safety: [4-Aminopyridine].
(Unpublished study received Feb 15, 1973 under 11649-12; CDL:
003234-E)
Avitrol Corporation (no date) Pigeon Control with 1351 on a Dewey,
Oklahoma, School Building. (Unpublished study receiver Oct
I/, 1572 under 11649-1; CDL:011002-3)
Avitrol Corporation (no date) Technical Data Sheet: Avitrol. (Unpub-
lished study received Sep 23, 1972 uncbr 11549-EX-5; CDL:
22225C-A)
Avitrol Corporation (no date) The Name, Chemical Identity and Compo-
sition of the Pesticide Chemical: L4-Aminopyriaine]. (Unpub-
lished study received Apr 5, 1973 under 11649-14; CDL:
223313-A)
Avitrol Corporation (no aate) Toxicity Data Summary: 4-Aminopyridine
(Compound 1361; DRC-1327). (Unpublished study received Stp
' 23, 1972 under 11649-EX-5; CDL:222250-D)
Avitrol Corporation (no date) Toxicology: Mathematical Approach:
Consumer Safety from Pistioidal Residues. (Unpublished study
received Apr JO, 19(4 under 4F1493; CDL:094335-W)
Avitrol Corporation (1961) Control of Feral Pigeons with Chemical
1351: Weber Farm, Dewey, Oklahoma, 1961. (Unpublished study
received 'Oct 17, 1973 under 11549-1; CDL:011002-C)
Avitrol Corporation (1963) Gull Tests in Florida, 1953. (Unpub-
tudy received Oct 17, IS^.-uncsr 11649-1; CDL:01 1002-L)
81
-------
Avitroi Corporation (1955) The Control of Gulls with Avitroi 200 on
and Near the Metropolitan Oakland international Air-port. (Un-
published study received Apr 10, 1975 under 11649-10; CDL:
^•1 " '-"-7 ••* T-» \
IjcT/o-F)
Avitroi Corporation (19i'0) Residue Data. (Unpublished study re-
ceived Jul 20, 1972 under 5G1297; CDL:094671-O)
Avitroi Corporation (1972) Reasonable Ground [sic] in Support of
the Petition: [4-Aminopyridinej. (Unpublished study received
Apr 11, 1973 under 11549-EX-3; CDL:095015-D)
Avitroi Corporation (1973) Avitroi Survey: Bird Damage in Pecans.
(Unpublished study received Hay 3, 1973 under 116U9-3; CDL:
220239-B)
A-/itrol Corporation (197-0 Introduction: [4-Aminopyridine]. (Un-
published study received Mar 10, 1975 under 11649-12; C'DL:
094799-A)
Avitroi Corporation (1974) [Avitroi on Sparrows and Pi-
geons]. (Unpublished study received Apr 10, 1975 under 11649-7;
CDL:119797-E)
Avitroi Corporation (1974) Avitroi: Summary Test Results—Gulls.
Summary of studies 115276-D and 115276-F. (Unpublished study
received Apr 10, 1975 under 11649-10; CBL:115275-C)
Avitroi Corporation (1974) Avitroi: Summary Test Results—Pigeons.
(Unpublished study received Apr 10, 1975 under 11649-6; CDL;
113303-E)
Avitroi Corporation (1974) Avitroi: Summary Test Results—Pigeons.
(Unpublished study received Apr 10, 1975 under 11649-7; CDL:
119797-C)
Avitroi Corporation (1974) Avitroi: Summary Test Results—Sparrows.*
(Unpublished study received Apr 10, 1975 under 11649-6; CDL:
119303-C)
Avitroi Corporation (1974) Avitroi: Summary Test Results—Star-
lings, Blackbirds in Feedlots. (Unpublished study received Apr
10, 1975 under 11649-11; CEL:115277-C)
Avitroi Corporation (1974) Summary and Comments—Avitroi Test Re-
sults—1974. Summary of studies Q34799-D through 094739-H.
(Unpublished study including letter dated Feb 23, 1975 from R.M.
Smith to Kelly Swindel, received Mar 13, 1975 under 11649-12;
CDL:094799-3)"
Avitroi Corporation (1975) Avitroi Documentary Report—Structural.
(Unpublished study received Apr 10, 1975 under 11549-7; CDL:
119793-A)
00303363 Avitroi Corporation (1975) Avitroi FC Corn Chops—93 Baits for
Protecting Sweet Corn from Blackbirds in Ulster County, New
York. (Unpublished study including letter datea Sep 12, 1975
from J.E. Forbes to Kelly Swindle, received Feb 1o, 1976 under
11649-12; prepared in cooperation with U.S. Fish and Wildlife
Service; CDL:224248-A)
00004127 Avitroi Corporation (1375) Avitroi: Summary Test Results—Star-
lings, Blackbirds in Feedlots. (Unpublished study received Apr
10, 1Q75 under 11643-5; prepared in cooperation uith Ag Past
Control, Inc., Loyal Pest Control and American Fertilizer, Inc.;
CDL:119311-C)
00004037 Avitroi Corporation (1975) Crop Economics. (Unpublished study re-
ceived Apr 28, 1975 under 11549-15; CDL:225254-D)
000039 i^5
00004134
00004074
00004052
00004094
00004091
00003955
00003977
00004090
00003970
00003959
00004095
00004093
82
-------
05003152
05019579
00004092
05005423
00004070
00004072
00004063
00004057
00004053
05010065
05003161
Babiak, 3.; T-sta, A.C. (1976) Fluorescence lifetime study of
c.minopyridin-is. Journal of Physical Chemistry
' '• .-~\ / 1 -7 N . 1 *"> 'i O 1 ^ r *~
•j-J (11 ;: looJ-1 jv. J.
Bacon, R.G.R.; Hamilton, 3.D. (19/4) Metal ions and complexes in
organic reactions_ Part XVIII__ Structural variations in the
production of polycyclic heterocyelic systems by
iron(II/-promote-d cyclisatior.s of nitro-substituted precursors.
Journal of the Chemical Society, Parkin Transsections 1
16:1370-1975.
Bailay, T.D.; McCill, C.IC., ir.ventors; Reiily Tar anc Chemical
Corp., assignee (1979) Process for substituting and
dequaternizing pyridylethyl quaternary sales of pyridina and
bipyridirs bases. if.S. patent 4,15S,093. Jun 12". 10 p. Int.
C1.-.2? C 07D 213/05; U.S. Cl. 542/455.
Barber, E.H. (1974) Report of the Results Obtained in Pigeon Con-
trol at ths Port of Mew Orleans. (Unpublished study received
Apr 10, 1975 under 11549-7; prepared by Barber Laboratories,
submitted by Avitrol Corp., Tulsa, Okla.; CDL:119797--F)
Batts, B.D.; Spinner, E. (1969) Vibration-spectral unc structural
comparison of the 4-aminopyridir.s cation :;ith the
4-hydroxypyriciinium ion and 4-pyridone. The .protio parent
ions, M- and C-deuteratsd, and M-methylatid ions. Ravelant
j'MR spectral studies. Australian Journal of Chemistry
22(12):2595-25IO.
Baumgardner, R.K. (1952) Chemical Control of House Sparrows in
Sunflower Fields. (Unpublished study received Get 17, 1973
under 11549-1; prepared by Oklahoma State Univ., Research Foun-
dation, Bird Management Project, submitted by Avitrol Corp.,
Tulsa, Okla.; CEL:G11002-W)
Baumgartner, F.M. (1962) Annual Report to Phillips Petroleum Com-*
pany July, 1951-June, 1952: Bird Management Tests. (Unpublished
study received Oct 17, 1973 under 11649-1; prepared by Oklahona
Stste Univ., Dept. of Zoology, submitted by Avitrol Corp.,
Tulsa, Okla.; CDL:011002-Y)
Baumgartner, F.M. (1952) Bird Management Project Progress Report
for September, 1952. (Unpublished study r-aceiv-cd Oct 17, 1973
under 11649-1; prepared by Oklahoma Staue Univ., Research Foun-
dation, submitted by Avitrol Corp., Tul K. , Okla.; CDL:011002-U)
Baumgartner, F.M. (1952) Report on House Sparrow Management at
Southern Great Plains Ficad Station, Woodward, Oklahoma, August
15-17, 1952. (Unpublished study received Oct 17, 1973 under
11549-1; prepared by Oklahoma State Univ., Research Foundation,
submitted by Avitrol Corp., Tulsa, Okla.; CDL:011002-T)
Baumgartner, F.M. (1952) Report bo Phillips Petroleum Company:
Bird Management Tests, January—February, 1952. (Unpublished
study received Oct 17, 1973 under 11549-1; prspared 'by Oklahoma
Stats Univ., Research Foundation, submitted by Avitrol Corp.,
Tulsa, Okla.; C DL:011002-V)
Benoist, J.M.; Ls-m-ignan, M.; Lechat, P. (1959) Study of the
action of 4-aminopyrid.ine on the isolated vas deferens of the
guinea-pig. Pharmacology 2(3):151-160.
Beresford, R. ; Bills, G.N.3.; Fastier, F.M. (1977) Site of th:;
stimulant action on muscle of such bases ;>s guanidini. jp.d
4-iminopyridine. Hev/ Zealand Medical Journal 36(399)':443.
83
-------
00004021 Bessor, J.F. (1970) A Discussion of the Problem of Blackbird Damage
to Field Corn. (Unpublished study received Jan 2, 1972 uncier
1F1012; prepared by U.S. Fish ;-;nd" Wildlife Service, Denver
Wildlife Research Center, submitted by Phillips Petrol-:urn Co.,
Bartlesville, Okla.; CDL:091757-E)
00004042 Besser, J.F. (1972) '4-Aminopyridine Baits for Protecting Sunflowers
from Blackbirds in Tennessee: (Report of Stuoy Ho. 47, Work Unit
DF-102.2). (Unpublished study received Apr 20, 197'! under
4F1498; prepared by U.S. Fish and Wildlife Service, Denver Wild-
life Research Center, submitted by Avitrol Corp., Tulsa, Okla.;
CDL:094326-L)
00004032 Besser, J.F. (1575) Relationship of Bird Pressure to the Effective-
ness of Avitrol-,(R) FC Corn Chops-99 for Protecting Cropfields
from Blackbirds. Summary of studies 222451-3, 22_>451-I, 222451-
J,-223451-K, 225255-A, 225255-J through 225255-L. (Unpublished
study received Mov 11, 1Q75 under 11543-15; prepared by U.S.
Fish and 'Wildlife Service, Denver Wildlife Research Center, sub-
mitted by Avitrol Corp., Tulso, Okla.; CDL;225255-3)
05017365 Besser, J.F. (1975) 4-Aminopyridine for protecting crops from
birds—a currant review. Pages 11-15, In Proceedings of the
Vertebrate Pest Conference. Vol. 7. Sacramento, Calif.:
California Vertebrate Pest Technical Committee.
000040C5 Besser, J.F.; Cunningham, D.J. (19/4) 1974 Test Results. (Un-
published study received Apr 23, 1375 under 11545-15; prepared
by U.S. Fish and Wildlife Service, Denver Wildlife Research Cen-
ter, submitted by Avitrol Corp., Tulsa, Okla.; CDL:225254-B)
00003995 Besser, J.F.; Mott, D.F. (1970) Field Work with 4-Aminopyridine in
Idaho Cornfields. (Unpublished study received Dec 13, 1970
unaer'224-EX-3; prepared by U.S. Fisn and Wildlife Service,
Denver Wildlife Research Center, submitted by Phillips Petro-
leum Co., Bartlesville, Okla.; CDL:122744-B)
05003953 Bogaert, P.P. van; Snyders, D.J. (1973) Dose-dependent effects of
4-aminopyridine on the electrical activity of cardiac Purkinje
fibres [abstract no. 21]. Pfluegers Archiv. European Journal
of Physiology 272:12.
05004213 Booij, L.H.D.J.; Miller, R.D.; Crul, J.F. (1973) ileostigmine and
4-aminopyridine antagonism of lincomycir.-pancuronium
neurotnuscular blockade in man. Anesthesia and Analgesia,
Current Researches 57(2):216-221.
05004232 Bounan, W.C.; Harvey, A.L.; Marshall, I.C. (1377) The actions of
aminopyricines on. aviar. muscle. ilaunyr.-Schmiedeberg's Archives
of Pharmacology 227(1):99-103.
05002160 Down an, W.C.; Khan, 11.H.; Savage, A.O. (1977) Some antagonists of
dantrolene sodium on the isolated diaphragm muscle of the rat.
Journal of Pharmacy and Pharmacology 29(10):516-525.
05020247 Bowman, W.C.; Rodger, I.W.; Savage, A.O. (1979) Effect of
4-arninopyridine on muscle contractility in the cat. British
Journal of Pharmacology 65(2):465-467.
05003949 Brown, K.L.; Chernoff, D.; Keljo, D.J.; Kullen, R.G. (1972)
Coenzyme B 12 model studies.. Equilibria ana kinetics of axial
ligation of methylaquocobaloxime by primary amines ana
4-subssituted pyridin.es. Journal of the American Cnemical
Society 94(19):6697-6704.
05003159 Burley, E.S.; Jacobs, R.S. (1977) The effects of 4--aninopyridine
on r.iuromuscular transmission in frog sartorius muscle.
Federation Proceedings 25(2):975.
84
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05015251 Hurley, E.S.; Jacobs, R.S. (1973) Effect of 4-aniinopyridir.e (4AP)
on extracellular nerve terminal action potentials (iJTAP) on
frog sartorius muscle-sciatic nerve preparation [abstract no.
523]. Pharmacologist 21(j):244.
050031/7 Chao, H.; Sci'iempp, E. (1977) An X-ray and MQR study of
4-sninopyridine and related aromatic amines. Acta
Crystallographica, Section 3 333(5):1557-1564.
05003556 Christen, D.; Horbury, D.; Lister, D.G.; Palmi;-ri, P. (1975)
Microwave spectra and structure of the an ine group in
3-aminopyridine and 4-aminopyridine: ab initio molecular
orbital calculations of the structure of the ar.ine group in the
aminopyridines. Journal of the Chemical Society, Faraday
Transactions 71:433-446.
05003176 Colton, J.S.; Schauf, C.L.; Colton, C.A. (1975) Effects of the
aminopyridines and sparteine on Myxicola axons and the lobster
neuromuscuiar junction. Biophysical Journal, Supplement
1 " 1 :1 '"I *•>
\ '~\ * I -A,-\ .'
00003336 Coon, R.A. (1971) Avitrol Program: Ohio-Micnigan, 1970. (Unpub-
lished study received Apr 19, 1971 under 224-EX-3; prepared by
U.S. Fish and Wildlife Service, Div. of Wildlife Services,
Ohio Office, submitted by Phillips Petroleum Co., Bartlssvilie,
Okla.; CDL:122743^3)
05019632 Coon, R.A:-(1974) Corn losses from birds reduced with repellent.
Science in Agriculture 21(4):13.
00004030 Cumrnings, J.L.; Besser, J.F.; Mott,.D.F. (1973) 4-Aminopyridine
Baits for Reducing Blackbirds Damage to Ripening Grain Sorghum
in Oklahoma: (Report of Study No. 53A, Work Unit DF-102.3).
(Unpublished study received Mov 11, 1975 under 11549-1:?; pre-
pared by U.S. Fish and Wildlife Service, Denver Wildlife Re-
search Center, submitted bv Avitrol Corp., Tulsa, Okla.; CDL:
223451-J)
05003164 Cumper, C.W.N.; Singleton, A. (1963) The ultraviolet spectra of
aniline, 2-, 3-, and 4-aminopyridines and of sane of their
derivatives in n-hexane 1,4-dioxan, ethanol, and water
solutions. Journal of the Chemical Society, Section 3
6:649-651.
00004113 Custom Cii-imical Specialties' (1353) Avitrol Field Tests. (Unpub-
lished study received 1968 under unknown admin, no. ; prepared in
cooperation with Drown 3: Bryant, Inc. and Soilserv, I-nc., sub-
mitted by Phillips Petroleum Co., Bartlesvillo, OUla.; CDL:
221959-C)
00003995 De Grazio, J.W.; Sesser, J.F.; Cunningham., D.J. (19^9) Project DF-
102: Bird Damage Control Research. (Unpublished stuay received
Dec 13, 1970 under 224-EX-3; prepared by U.S. Fish and Wildlife
Service, Denver Wildlife Research Center, Section of Birds in
cooperation with Sand Lake National 'Wildlife Refuge, submitted
by Phillips Petroleum Co., Bartlesville, Okla.; CDL:122744-A)
0301543,' Do Grvizio, J..W.; Besser, J.F.; De Cino, T.J. ; Guarino, J.L.;
Starr, R.i. (1971) Use of 4-arninopyridint. to protect ripening
corn .from blackbirds. Journal of Wildlife I-ian^g&rntnt
35(3):555-559.
05013435 De Grazio, J.W.; Besser, J.F.; DeCino, T.J.; Guarino, J.L.;
Schafer, E.W., Jr. (1972) Protecting ripening corn from
blackbirds by broadcasting 4-aninopyldin; baits. Journal of
Wildlife Management 36(4):1316-1320.
85
-------
•JU0039/'3 De Grazio, J.V/.; 5^-sser, J.F.; DeCino, T.J.; Gu^rir.o, J.L.;
Schaftr, I.]-!., Jr. (1972) Protecting ripening corn from black-
birds by broadcasting 4-ATiinopyridir.e baits. Journal of Wild-
life i-Lnagement 33(4): 131 5-1320. (Also In unpublished submis-
sion received Jun 21, 1977 under 11649-12; submitted by Avitrol
Corp., Tulsa, Okla.; CDL:2j0555-3)
00004114 De Grazio, J.W.; Besser, J.F.; Guarino, J.L.; West, R.R. (1957)
Annual Progress Report: Wildlife Research Work Unit: Denver
Wildlife Research Center: Calendar Year 1967: Work Unit F-4.1:
Control of Blackbird Damage to Corn in South Dakota. (Unpub-
lished study received Apr 23, 1955 under 224-CX-j; prepared by
U.S. Fish and Wildlife Service, Denver Wildlife Research Cen-
ter, Section of Birds.in cooperation with Sand Lcke National
Wildlife Refuge and South Dakota Dspt. of Game, Fish and Parks,
submitted by Phillips Petroleum Co., Bartlesville, Okla.; CDL:
122745-A)
00004123 Do Grazio, J.W.; Besser, J.F.; Guarino, J.L.; West, R.R. (1959)
Annual Progress Report: Denver Wildlife Research Center: Calen-
dar Year 1968: Project DF-102: Bird Damage Control Re-search:
Work Unit DF-102.3. (Unpublished study received Jan 9, 196cj un-
der 224-EX-3; prepared by U.S. Fish and Wildlife S?rvic.», Den-
ver 'Wildlife Research Center, Section of Birds in cooperation
with Sand Lake National Wildlife Refuge and South Dakota Dept.
of Game, Fish and Parks, submitted by Phillips Petroleum Co.,
Bartl3sville, Okla.; CEL:122745-IO
00004002 De Grazio, J.W.; Besser, J.F.; West, R.R. (1959) Annual Progress
Report: Denver Wildlife Research Center, Calendar Year 1969:
DF-102.3-9. (Unpublished study received Jan 20, 1970 under 224-
iX-3; prepared .by U.S. Fish and Wildlife Service, Denver Wild-
life Research Center, Section of Birds in cooperation with Sand
Lake National Wildlife Refuge, submitted by Phillips Petroleum
Co., Bartlesvills, Okla.; CDL:122/44-1)
U0004116 De Grazio, J.W.; Schafer, E.W., Jr.; Besser, J.F. (1957) Baiting
Experiments. (Unpublished study received May 22, 1967 under
224-EX-3; prepared by U.S. Fish and Wildlife Service, Denver
Wildlife Research Center, submitted by Phillips Petroleum Co.,
Bartlesville, Okla.; CDL: 12274-5--C)
De Grazio, J.W.; Stone, C.P. (1971) South Dakota Field Tests:
Avitrol FC Corn Chips. (Unpublished study received i!ov 19, 1971
under 224--EX-3; prepared by U.S. Fish and Wildlife Service,
Denver Wildlife Research Center, submitted by Phillips Petrol.:-uin
Co., Bartlesville, Okla.; CDL:12274B-B)
De Grazio, J.W.; Stone, C.P. (1972) Project DF-102: Bird D-v^ge
Control Research: Second Periodic Report—Avitrol. (Unpublished
study received Mar 27, 1972 under 224-EX-3; prepared by U.S.
Fish and Wildlife Service, Denver- Wildlife Research Center in
cooperation with Sand Lake National 'Wildlife Refuge, submitted
by Phillips Petroleum Co., Bartlesville, Olcla.; CDL: 122PI3-3)
05019575 Del Bone, J.E.-(1979) An ab initio molecular- orbital study of 2
anc 4-monosubstitut-od pyridines. Journal of the American
Chemical Society 10 I (21 ):6'I34-61C9.
05004634 Desiderl, P.G.; H«inler, D.; Leprl, L. (1973) Differential
voitammstry at solid electrodes: determination of the
amir.opyriaines. Journal of Eltctroanaiyticai Chemistry anc
Interfacial Electrochemistry 37(2):2/5-232.
00003939
00003931
86
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05004219 De Silva, A.J.C.; Lee, C. (19/3) IL'iirrciusculsr and cardiovascular
depression produced -by prolonged exposure, to Polymyxi-r. 3.
Canadian Anaesthetists' Society Journal 25(4): J03-506.
UOOO'IG95 Doibeer, R.A.; Ingrain, C.R. (13/5) 1974 Test.of 4-Arninopyridine
(Avitrol) Efficacy in Pr-eventing Bird Damage to Sweet Corn in
Ohio: Progress Report: January 1, 1974-December J1, 1974: Work
Unit P-F-jj-11. (Unpublished study received Mar 13, 1975 und^r
11549-12; prepared by U.S. Fish and Wildlife Service, Patuxent
Wildlife Research Center, Section of An IT, 31 Depredations Control
Studies, Ohio Field Station, submitted by Avitroi Corp., Tulsa,
Okla.; CDL:094799-H)
00003372 Dolbeer, R.A.; Ingram, C.R.; Seubert, J.L.; Stickisy, A.R., Jr.;
Mitchell, R.T. (1975) 4-Aminopyridine effectiveness in sweet
corn related to blackbird population density. Journal of Wild-
life Management 40(3):554-570. (Also?Ir.?unpubiish£d submission
rscoived Jun 21, 1977 under 11549-12; submitted by Avitrol
Corp., Tulsa, Okla.; CDL:230665-A)
GOOQ4034 Dolbeer, R.A.; Stickiey, A.R., Jr.; Ingram, .C.R. (1974) Efficacy of
4-Aminopyridine in Protecting Sunflowers from Blackbirds in
'Ohio: Progress Report: January 1, 1973—December 31, 1973, Work
Unit P-F-33.1C. (Unpublished study received Jul 22, 1974 under
11:549-15; prepared by U.S. Fish and Wildlife Service, Patuxent .
Wildlife Research Center, Section of Animal Depredations Control
Studies, submitted by Avitrol Corp., Tulsa, Okla.; CDL:226529-A)
05020241 Din-ant, H.I.1.; Lee, C.; Katz, R.L. (1979) 4-Arninopyridine reversal
of ganglion block [abstract]. Anaesthesiology 5K3):263.
03007043 Fairchild, E.J., ed. (1977) .Agricultural Chemicals and Pesticides:
A Subfile of the NIOSH Registry of Toxic Effects of Chemical
Substances. Cincinnati, Ohio: National Institute for
Occupational Safety and Health. (Pagination includes 46 pages
numbered i-xlvi; available from: NTIS, Springfield, VA: PB-274
743)
05004214 Fastier, P.M.; ;
-------
05017026
05004525
05013373
05005337
Garrison, M.V. ; Mott, D.F.; Guellette, M.R.; Holquin, G. (1979) n
tabletac corn bjit to deliver uniform cosage of 4-aniinopyr'idini
to red-winged blackbirds. Journal of Wildlife Management
0500320J
05020055
05003493
05019577
05010T35
00004259
00004143
05004470
05013331
Gillespie, J.I. (1977) Voltage-dependent blockage of the ds-laysd
• potassium current in skeletal muscle by 4-aminopyridine.
Journal of .Physiology 2/3 (2): 64-55.
Gillespie, J.I.; Hutter, O.F. (1975) The actions of
4-aninopyridine on the delayed potassium current in skeijtal
muscle fibres. Journal of Physiology (London) 252(2):70-71.
Girault, G. ; Coustal, 3.;.'Rumpf, P. (1972) Contribution i 1' etude
de derives 'amines de quelques hetcrocycles azotes.
II. — Preparations, absorption dans 1' ultraviolet c
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0004043
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011002-I)
Marqu^rdt, R.E. (1952) Use of 1351 for Bird Control at Psntcx Stor-
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i-iarquirdt, R.E.; Cantrel, K.E. (1953) Bird Control Tests with Chsn-
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Harquardt, R.E.; Cantrel, K.E. (1}53) Herring Gull Tests in Mew
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K.3gal
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00004102 Mott, D.F.; Guarino, J.L. (1972) Investigation of Blackbirds and
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0032G4-A)
00004096 Mo-t, D.F.; Royall, W.C., Jr. (1975) 4-Aminopyridine for Protecting
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lio. 52, Work Uni^ CF-I02.3). (Unpublished study including sta-
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00004051 Mewsom, J.D.; Wilson, R.C. (1973) An Assessment of Crow Control
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00003971 Kewson, J.D.; Wilson, R.C.; Murray, M. (19/3) An Assesanent of Crow
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98
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Palazzolo, R.J. (1963) Report to Phillips Petroleum Company: Toxic-
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Paramount Pest Control Service (1955) Resume of Avitroi Bird Man-
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Parrnenter, R.E. (1957) Final Report: Investigations of the Usabili-
ty of Avitroi 200-D29 as a Pigeon Repellent. (Unpublished study
including preliminary report, received Jan 2, 1963 under 224-12;
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Paul, 3.; Rao, D.-V.R. (1969) Cadmium (II) complexes with
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Parlkov, I.G. ; Chaplinov, P.E. ; Polkovnichenko, P.T. (1974)
Spektrofotonetricheskoe izuchenie 4-aminopidina v
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Peterson, J. (no date) Microanalytical Method Development for
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pyridine: Fourth Periodic Report — July 5, 1959. Includes method
dated Jul 1, 1959. (Unpublished study received Jui 24, 1959 un-
der 224-EX-3; prepared by U.S. Fish and Wildlife Service, Denver
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Peterson, J.E. (1969) Microanalytical Method for 4-Aminopyridinc-.
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100
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' • f I 1 > . 7 1O
G 7 U ;. i - I £.
Pfi.nningsr, K.; Akert, 1C.; Moo*-, H. and 3anc-i, C. (19f2) Tru
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Phillips Pawroliun Company (r.o date) Composition jurd For.nul::tion:
[Avitrol]. (Unpublished study received Jen 3, 1973 under
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Phillips Petr-oleun Company (no date) Compound 1361 Hydrochlorids.
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Phillips Petroleum Company (no date) Formula: Avitrol FC Corn Chops
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Phillips Petroleum Company (no date Laboratory Evaluation of 4-Mino-
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Phillips Petroleum Company (r.o dats) Rsasonable Grounds in Support
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Phillips Pstroieum Company (no date) Residue Data: [4-Amino-z
pyridine (Unpublished study received Jul 17, 1970 under 224-EX-
3~; CDL: 122743-D)
Phillips Petrols-urn Company (no date) Residue Data: Estimate of Possi-
ble Contamination of Corn Plant as a Consequence of Lodging of
an Active Bait Particle in the Plant. (Unpublished study re-
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Phillips Petroleum Company (no date) Results of a Laboratory Tost to
Determine the Rate of Degradation of 4-Atninopyridine in Soil:
Good-67-ojR. (Unpublished study received Hay TJ, 1965 undar
224--EX-3; CDL:122746-D)
Phillips Petroleum Company (no date) Technical Data Sheet: Phillips
Avitrol 200 (I860. (Unpublished study received Jan 17, 1953
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Phillips Petroleum Company (no date) Toxicity Data Summary: 4-/Vnino-
pyridins (Compound 1261; DRC-1327): (Active Component—Avitrol
200 Bird Management). (Unpublished study received Apr- 22, 19o9
under 224-EX-3; CDL: 122747-^)
Phillips Petroleum Company (no date) Toxicology: Consumer Safety
from Pesticidal Residues. Summary of studies 09 1 i'55-3
through 091755-J. (Unpublished study received Dec 30, 1963
under IF 1013; CEL:091756-A)
Phillips Petroleum Company (no date) 4-Amino pyridine Data Sheet:
Properties of U-Aminopyridine (Compound 1351; DRC-b2,7). (Un-
published stucy received Apr 22, 1959 under 224--EX-3; CDL:
122747-A)
Phillips Petroleum Company (no date) 4-Aminopyridine Data Sheet:
Properties of 4-Aminopyridine (Compound 1361; DRC-1327).
(Unpublished study received Jul 17, 1970 under 224-EX-3;
CDL:122743-2)
101
-------
00004122 Phillips Petroleum Company (1953) Ohio Field Evaluation of Aviiroi
200 Used to Discourage Blackbird Depredation, to Field Corn.
(Unpublished study including suimary report, received Apr 15,'
195} under 224-EX-3; CDL:122745-F)
OOOC4130 Phillips Petroleum Company (19-38) Periodic Report for Avitroi FC
Corn Chops Concentrate. (Unpublished study received Sep 33,
1963 under 224-EX-3; CDL: 1227450).
00004129 Phillips Petroleum Company (1953) Toxicity Studies or. Avitrol 200:
(Compound 1361). (Unpublished study received Jan 5, 1959 under
224--EX-3; prepared in. cooperation with Lifestream Laboratories,
Inc.; CDL:122,745-L)
00002992 Phillips Petroleum Company (1959) Effectiveness Data: 4-Aminopyri-
dinfc (Avitrol 200). (Unpublished study received Apr 22, 1969
under 224-EX-3; CBL:122747-F)
00004120 Phillips Petroleum Company (1969) Field Test Project on 4-Amino-
pyridimo (DRC-1327). (Unpublished study received Apr 24, 1970
under 224-EX-3; prepared in cooperation with U.S. Fish
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R-.nr.c-rt, A.J. (no date) Field Tests on Starlings with 1561 at Beard
town, Illinois. (Unpublished study Deceived Get 17, 13/3 under
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Reinert, A.J. (1963) Field Tests on Starlings with 1351 near
Columbus, Ohio. (Unpublished study received Oct 17, 13T3 under
• 11649-1; prepared by Phillips Petroleum Co. in cooperation with
U.S. Fish and Wildlife Service, submitted by Avitrol Corp.,
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Rein-art, A.J. (1963) Crow Control Tests with Avitrol 200 at Fulton,
Arkansas. (Unpublished study received Jul 17, 1370 under
224-EX-2; submitted by Phillips Petroleum Co., Eartlesville,
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Reinert, A.J.; Cantrel, K.E. (1965) Crow Control Tests with Avitrol
200 at Leonard Bend, Texas. (Unpublished study received on Jul
17, 1970 under 224-EX-2; submitted by Phillips Petroleum Co.,
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Reinert, A.L., inventor; Phillips Petroleum Co., assignee (1365)
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Schafer, E.W. (1372?) Acute Toxicity of 4-Amiropyricine to 40 Ani-
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'OQ3234-D)
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