Environmental Protection
Agency
Office of
Pesticides and Toxic Substances
Washington DC 20460
March 1981
x>EPA
6-ethoxy-1,2-dihydro-
2,2,4-trimethylquinoline
Ethoxyquin
Pesticide Registration
Standard
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730R81001
ETHOXYQUIN
Pesticide Registration Standard
Kevin McCormack Project Manager (SPRD1)
Ton Edwards lexicologist (HED)
Arthur Schlosser Environnental Chemist (HED\
William Boodee Residue Chemist (HED)
Ray Kent Residue Chemist (HED)
Ed Fite Wildlife Biologist (HED)
Bruce Sidwell Plant Physiologist (BFSD)
Dan Dickson Product Manager (RD)
Randy Norris Writer-Editor (Branch 2)
March 1981
Office of Pesticides and Toxic Substances
Environnental Protection Agency
401 M Street, SW
Washington, D.C. 20460
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TABLE OF CONTENTS
Page No.
Chapter One
How to Register Under a Registration Standard............1
Chapter Two
Agency ?osition on Ethoxyquin
Regulatory Position on Ethoxyquin...................9
1. Introduction................................9
2.
Description of Che~ical.....................9
Investigation by Other Federal Agencie~.....9
Classification under Minor Use.............10
Regulatory Position for Ethoxyquin.........l0
Regulatory Rationale.......................10
Criteria for Registration Under
this Standard..............................l1
3.
4.
5.
6.
7.
A.
Manufacturing-use Ethoxyquin.............12
1. Acceptable Ranges and Li~tts
2. Required h.heling
B.
Emulsifiable Concentrate Ethoxyquin......1S
1. Acceptable Ranges and Li~its
2. Required Labeling
C.
Impregnated Fruit Wraps..................1R
1. Acceptable Ranges and Li~its
2. Required Labeling
8. Tolerance
Reassessment.....................20
Chapter Three
Data Require~ents and Data Gaps
1.
2.
Manufacturing use Ethoxyquin...............21
Formulated Ethoxyquin Products.............21
Chapter Four
Product Che~istry of Ethoxyquin
A.
B.
C.
D.
Introduction...................................22
Manufacturing-use Ethoxyquin...................22
1. Product Chemistry Profile..................22
2. Data Requirenents..........................23
3. Topical Discussions........................23
Emulsifiable Concentrate Ethoxyquin............25
1. Topical Discussions........................25
I~pregnated Product Ethoxyquin.................26
1. ~opical Discussions........................2~
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Chapter Five
Environmental Fate of Ethoxyquin
A.
Us e Pro f i 1 e . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2 R
B.
Manufacturing-use Ethoxyquin
1. Environmental Fate Profile
2. Exposure Profile
3. Data Requirements and Data
.... .............29
Gaps
C.
. . . . . . . . . . . . . . . . . . .30
Formulations of Ethoxyquin
1. Exposure Profile
Chapter Six
Toxicology of Ethoxyquin
A.
Manufacturing-use Ethoxyquin...................32
1. Toxicology Profile.........................32
2. Data Requirements and Data Gaps............32
3. Topical Discussions........................33
B.
Emulsifiable Concentrate Ethoxyquin............44
1. Toxicology Profile.........................44
2. Topical Disc~ssions........................4S
C.
Impregnated Products...........................47
1. Toxicology Profile.........................47
D.
Information......................47
Supplementary
Chapter Seven
Residue Chemistry of Ethoxyquin
A.
Manufacturing-use Ethoxyquin...................SO
1. Residue Chemistry Profile..................50
2. Data Gaps..................................51
3. Topical Discussions........................51
B.
Formulated Ethoxyquin..........................S3
1. Registration Requirements..................S3
2. Required Labeling..........................53
Chapter Eight
Ecological Effects of Ethoxyquin
A.
Ecological Effects Profile.....................54
Case Bibliography
of the Bibliography...............55
A.
Guide to Use
Section I
Section II
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I
HO\-! TO REGISTER
UNDER A REGISTRATION STANDARD
Organization of the Standard
Purpose of the Standard
Requirenent 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 of 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)(S) that:
"(A)
( B)
(D)
its composition is such as to warrant the proposed claims for it;
its labeling and other material required to be submitted comply
with the requirements of this Act;
it will perform its intended function without unreasonable adverse
effects on the environment; and
when used in accordance with widespread and commonly recognized
practice it will not generally cause unreasonable adverse effects
on the environment."
(C)
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:
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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.
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, 1978 and 43 FR 37336, August 2, 1978), many products
that had already been registered for years were being sold and used without
the same 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».
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 product' 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
documents 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, composition, labeling, and
packaging, and satisfaction of the data compensation provisions of FIFRA
Section 3(c)(I)(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 unreasonab-e 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
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as being competent to use pesticide safely, responsibly, and in accordance
with label directions. A restricted-use pesticide can have other
regulatory restrictions [40 CFR 162.11(c)(S)] 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.
Requirement to 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-registration. 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 29696, July 10, 1978, and 43 FR
37336, August 22, 1978), as applied to the use patterns of the products to
which this Standard applies. Where it appeared that data from a noroally
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 affect for some time and are, the Agency belives, relatively familiar to
registrants. Data which we have found are needed to evaluate the
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registrability of some products covered by the ~tandard 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 ,It 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 manufactur-
ing-use or end-use product, and 'nthout regard to its intended use pattern,
must 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 163.81-1(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
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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 makin~ 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 by 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 I, 1970;
the data were submitted to EPA (or USDA or FDA) by some other
applicant or registant in support of an application for an
experimental use permit, an amendment adding a new use to a
registration, or for registration, or to support or maintain In
effect an existing registration.
they are the kind of data which 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);
the Agency has found the data to be valid and usable in reaching
regulatory conclusions; and
they are not data 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 con-
cerning 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 produ~er.)
(2)
(3)
(4)
(5)
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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 evidencin~ 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 is 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 determining whether the applicant's product is registrable.
There may be cases, however, 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(C)(1)(D) for that data.
Each applicant for registration or re-registration of a manufacturing-
use product, and each applicant for registration or re-re~istration 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 re~istration) 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 have 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".
FIFRA Section 3(c)(2)(B), 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
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to fill the data gaps identified by a section 1(c)(2)(B) order, his
product's registration may be suspended until the data is 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 specific" data. In
some cases, the Agency may posses 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 the 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. This "cut-off" date is stated at the beginning of the
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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 the Agency. t~en all the present
"data gaps" have been filled and the submitted data have been reviewed, the
Agency will revise the Registration Standard. Thereafter, when the Agency
determines that the internally maintained addenda have significantly
altered the conditions for registration under the Standard, the document
will be updated and re-issued for publication.
While the Registration Standard discusses only the uses and hazards of
products containing the designated active ingredient(s). the Agency is also
concerned with the potential hazards of some inert ingredients and
impurities. Independent of the development of anyone Standard, the Agency
has initiated the evaluation of some inert pesticide ingredients. Where
the Agency has indentified inert ingredients of concern in a specific
product to which the Standard applies, these ingredients will be pointed
out in the Guidance Package.
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II
REGULATORY POSITION ON ETHOXYQUIN
1.
Introduction
This chapter is the central part of the Registration Standard.
It presents the Agency's regulatory position and rationale based
on an evaluation of all registered products con~aining ethoxyquin
as the sole active ingredient, or in mixtures with the same use
patterns as described in this Standard. After describing the chemical,
the review of ethoxyquin by the Food and Drug Administration, and
the discussion of ethoxyquin's classification as a minor use chemical,
this chapter presents the regulatory position and rationale, the
criteria by which applicants for registration of ethoxyquin products
will be approved, including discussion of specific labeling considera-
tions, and tolerance reassessment. Thus, this chapter contains all of
the Agency's requirements for continued registration of ethoxyquin
products and new product registrations that are covered by the Standard.
Discussions of the data upon which this regulatory position is based
are presented in each of the disciplinary chapters, IV through VIII.
2.
Description of Chemical
Ethoxyquin is the generic naQe for 6-ethoxy-l,2-dihydro-2,2,4-
trimethylquinoline, used to control scald in apples and pears; as a food
preservative (21 CFR 172.40) to inhibit color changes in select spices; as
a food additive in animal feeds (21 CFR 573.380) and in select dehydrated
forage crops (21 CFR 573.400). Scald is a physiological disorder of fruit
which results in discoloration (browning) of the large areas of the fruit,
usually rendering it unfit for the fresh ~arket. The disorder is super-
ficial in nature, but the cosmetic effect is a significant factor in
downgrading fruit during inspection and culling.
Only the pesticidal uses of ethoxyquin will be addressed in this
Standard. Ethoxyquin is also known by the following trade names:
Santoquin, Santoflex AW, Niflex D, Stop-Scald, and Deccoquin.
3.
Investigation by Other Federal Agencies
It is significant to note that the Food and Drug Administration (FDA)
is currently evaluating ethoxyquin as a food additive under its Cyclic
Review Program. Ethoxyquin is one of 258 direct food additives which are
scheduled to undergo review in order to evaluate their potential hazard,
if any, in human food.
The review currently has 55 color additives, 258 direct additives,
and 1332 flavors which are now in Phase II, or safety profile evaluation.
An "index of concern" is assigned each chemical, based on review of all
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toxicity datil <1v;lilable on eacn subsumce. 0ie evaluation of etnoxyqllin
and assignrnent of a corresponding "incex of concern" is schedulen to be
cornpleted in Octoher lO~l.
A review of the FDA data files revealed no rn~jor ~<1ta gaps
nor any significant inconsistencies in scientific references \~en cornpared
to the nata base cornpiled by EPA.
4.
Classification Under Minor Use
~.ow market volume chemicals (usually those wi.th less than 250,000 Ihs.
active ingredient used per year) and formulated procucts (usually those
with less than 25,000 Ibs. active ingredient per year) from 1Thich exposure
is expected to be minirnal based on use p<1ttern, available data, and other
considerations may be classified by EPA as having rninor use status.
Estirnates m2de hy EPA staff indicate that production of ethoxyquin
during the rnost recent five year period is less than 30,000 pounds of
active ingredient in all formulated products per year. These estimates
are !lased on International Trade ComrniRsion data, Departrnent of Cornmerce
data and other published sources, as well as contacts \lith industry
representatives farniliar with this rnarket.
Accordingly, ethoxyquin is classified as a rninor use chemical. As a
result, many data requirenents, particularly in the areas of Toxicology,
Ecological Effects, and Environmental Fate have been waived in this
Stancard. Haiving these requirements is i1 resul t of a thorough revie1-l
of the uses and subsequent potentia] exposure ~o hurnans and \Jildlife,
prin<1rily through the food chain, \~ich indicate exposure to he nininal.
5.
Regulatory Position for Lthoxyquin
Ethoxyquin as described in this Standard may be registered for sale,
distribution, reformulation and use in the United States. The Agency has
considered the limited arnount of scientific data obtained from the open
literature as of Feb. 11, 1980, and the data submitted by the registrants
lip through the time of publication of this Standard. In view of this
information, the Agency finds that none of the risk criteria found in
section lA2.11(a) of Title 40 of the U.S. Code of Federal Regul<1tions
have been met or exceeded by ethoxyquin, and that etnoxyquin does not
appear to cause an unreasonable adverse effect uith proper lanel
directions and precautions.
Ethoxyquin pronucts currently registered nay be reregistered unc1er
this Standard subject to the conrlitions imposed by this St?ndard.
~leH products may he registered under this Standard and are subject to
the same requirenents.
6.
Regulatory R<1tion"le
The Agency has reviewed the rlata available to it on ethoxyquin.
Based on this revie\J, the information on ethoxyquin's use patterns,
nethods of application, anc the liMited poundage active ingredient
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r.1arketerl per year, the Agency has concluded that ethoxyquin products
currcntly registered r.1ay be re-registered in accorrlance uith the criteria
set forth below.
a. ~mnufacturing-Use Ethoxyouin
Data on physical ~nd chemical properties and ~cute toxicity are
required for all ethoxyquin Manufncturing-use products to establish
the physical ann cher.1ical properties and the ~cute toxicity of the
active ingredient.
b.
Forr.1ul~ted Ethoxyquin
Enulsifiable concentrate ethoxyquin and inpregnated fruit ~ITaps may
be registered for use in the United States.
The registration is dependent upon filling the dat? gaps
listed in the Tables in Chapter J anrl identified in the disciplinary
chapters for EC cthoxyquin anrl upon neeting standards for nondor.1estic use.
The outdoor (spray) uses of ethoxyquin are reportedly no longer
practiced, but this use still appears on the label. L8ck of data on the
fate of ethoxyquin in thc environnent and its toxicity to non-target orga-
nisr.1s are the basis for Ecological Effects and Environr.1ental Fate data
requirenents in Chapter 3. Removal of this use fror.1 the label Hill reduce
significantly this r.1ajor route of exposure. This reduction, coupled ~lith
the low probability of accidental spills, flooding, and unintentional dis-
charge of uastes Hill enable uaiving of these di1ta requirentnts.
7-
Criteria for Registration Under This Standard
To be suhject to this ~ti1ndarcl ethoxyquin products r.1Ust r.1eet the
folloHin~ conditions:
1. The product r.1Ust r.1ect conposition st:mdarc1s specifien in this Chapter;
2. The pro(luct must r.1eet ilcute toxicity 1 imits specified in this Chapter;
J. The product r.1ust r.1cet the labeling standards specified in this Chapter.
In addition, applicants for registration or reregistration of
ethoxyquin products subject to this Standard nust cOr.1ply uith all terns
an1 conditions described in this Standard including connitnent to fill cata
gaps accor~ing to the tir.1e schedule spccifiecl by the A~ency and, uhen
applicable, offer to pay cOr.1pcnsation to the extent required hy Sections
3( c) (l )(D) and 3( c)(2 )CD) of the Federal Insecticide, Fungicide and
Rodenticide Act [FIFP~1, as ~r.1ended, 7 U.S.C. 11n(c)(1)(D) and 1JA(c)(2)(D).
11
-------
The following registrants have submitted data in support of ethoxyquin
registrations, and have not waived their rights to compensation for
this data: Monsanto Che;ICal Company, St. Louis, Missouri, and Crown-
Zellerbach Corporation, San Francisco, California.
A.
Manufacturing-use Ethoxyquin
1.
Acceptable Ranges and Limits
a.
Product Composition Standard
To be registered under this Standard, manufacturing-use ethoxyquin
must comply with the product composition standards developed in the
Product Chemistry chapter (Chapter IV) of this document. Therefore,
manufacturing-use ethoxyquin products with any percentage of active
ingredient with appropriate certification of limits are acceptable under
this Standard.
b. Acute Toxic! ty Limits
The Agency will consider registration of manufacturing-use ethoxyquin
products in the following toxicity categories:
Toxic! ty Category
I II III VI
Acute Oral Toxici ty YES YES YES YES
Acute Dermal Toxicity YES YES YES YES
Acute Inhalation Toxicity YES YES YES YES
Primary Eye Irritation YES YES YES YES
Primary Dermal Irritation YES YES YES YES
c. Use Patterns
To be covered under this Standard, manufacturing-use ethoxyquin must
be formulated into end-use anti-oxidants which are intended for
nondomestic indoor or outdoor food uses. For purposes of this Standard,
the term "non-domestic" means applications or uses other than those
outlined in 40 CFR Sec. 162.3(m).
Data in this Standard that satisfy registration requirements may
be cited if the applicant establishes that the proposed product is
12
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substantially similar to anoth~r product for '~ich the Agency has
received acceptable acute toxicity tests. Data may be cited provided
compensation has been offered to the submitter(s) of the data as
explained in Chapter I of this Stnndard.
2.
Required Labelin~
All manufacturing-use ethoxyquin products must bear appropriate
labeling as specified in 40 CFR In2.10.
a.
Use P~ttern Statenents
All manufacturin~-use ethoxyquin products must list on the label the
intended end-uses of formulated products produced from the manufactllring-
use products. In ~ccordance uith data to be submitted or cited, all
ethoxyquin product labels must bear one of the follo\ling stntements:
"For formulation into End-use products intcndeci Only for non-
Donestic, Outdoor Food Use"; or
For formulation into End-use products intended Only for ~on-
Domestic, Indoor Food Use", or
For formulation into End-use pronucts intenned Only for ~~on-
Domestic Indoor or Outdoor Food Use".
For purposes of this Standard, the term "Hon-dot:1estic" means applications
or uses other than those outlined below [See 40 CFR In2.3(m)1.
The tem "domestic application" means application of a pesticide
directly to hut:1Rns or pets, or application of 11 pesticide in, on or
around a11 structures, ~eh{cles or areas associated ,dtb the household
or home life, patient care areas of health related institutions, or areas
,.,here children spend time including but not limited to:
(1)
Gardens, non-commercial greenhouses, yards, patios, houses,
pleasure marine craft, ~obile homes, campers ane recreational
vehicles, non-comt:1ercial campsites, hone suimming pools and
kennels;
(2)
Articles, objects, devices or surfaces handled or contacted
by humans or pets in all structures, vehicles or areas listed
Rbove;
13
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(3)
Patient care areas of nursing homes, mental institutions,
hospitals, and convalescent homes;
(4)
Educational, lounging and recreational areas of preschools,
nurseries and day camps.
Presented below are the types of statements which must
manufacturing-use ethoxyquin labels. See 40 CFR 162.10 for
required labeling for manufacturing-use products.
appear on
specific
b.
PRECAUTIONARY STATEMENTS
Hazards to Humans and Domestic Animals
May irritate eyes, nose, throat, and skin.
Avoid contact with skin, eyes and clothing.
First Aid Statement
In case of contact, immediately flush skin or eyes with plenty of
water. Get medical attention if irritation persists. Wash
thoroughly after using.
Environmental Hazards
Do not discharge into lakes, streams, ponds, or public waters un-
less in accordance with an NPDES permit. For guidance, contact
your regional office of EPA.
Directions for Use
It is a violation of federal law to use this product in a manner
inconsistent with its labeling. Refer to technical bulletin.
Storage and Disposal
Prohibitions
Do not contaminate water, food, or feed by storage or disposal.
Open dumping is prohibited.
Pesticide Disposal
Pesticide or rinsate that cannot be used according to
tions must be disposed of according to state or local
under the Resources Conservation and Recovery Act.
label ins truc-
procedures
14
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Container Disposal
Triple rinse (or equivalent) and offer for recyclin~ or recondittonin~
or dispose of in a sanitary landfill or by approverl stnte and local
procedures.
B.
Enu1sifiab1e Concentrate Ethoxyqutn
Applicants for registration or reregistration of for~ulated
ethoxyquin products are re~in~ed that since no ~anufacturin~-use prorluct
(~UP) is currently registered, for~u1ators of end-use products are
responsible for providing the data required on the ~anufacturin~-use pro-
duct in orrler to comply with the Agency's Proposed Registration Standards
Data Requirements as outlined in Chapter 3.
1.
Acceptable Ran~es and Li~1ts
a.
Product Composition Standard
The Agency uill consider for registration e~u1sifiable concentrate
products which contain ethoxyquin as the sole actiNe in~redient if the
products neet the acute toxicity standards for nondomestic use, and if the
inert ingredients have been cleared un~er 40 CFR 180.1001. The Product
Chenistry, P~sidue CheMistry and Toxicology data ~ust be supplied by the
fo~ulators of end-use ethoxyquin products.
b.
Acute Toxicity Limits
The Agency ~~ll consider registration of any e~ulsifiah1c concentrate
(EC) product for non-domestic use in the fo1lo'~ing categories:
TOXICITY CATEGORY
I II III IV
Acute Oral Toxici ty amendment required* YES YES YES
Acute Demal Toxici ty amend~ent required* YES YES YES
Acute Inhalation Toxicity a~endnent required* YES YES YES
Primary Eye Irritation amendment required* YES YES YES
Prinary De rma 1 Irritation amend~ent required* YES YES YES
*(Arnendnent to the Stancard)
15
-------
c.
Use Patterns and Application Methods
To be registered under this ~tandarrl» rc products of ethoxyquin may be
used only as anti-oxidants on apples and pears.
The Agency finds that currently registered dosa~e rates and
application methods ar~ acceptable pending submission of required
chemistry data listed in the manufacturing use section of this Standard.
2.
Required Labeling
All EC ethoxyquin products must bear appropriate labeling as specified
in 40 CFR 162.10.
PRECAUTIONARY STATEMENTS
a.
Hazards to Humans and DOMestic Aninals
May irritate eyest noset throatt and skin. Avoid breathing
vapors. Avoid contact with skin» eyes and clothing.
First Aid Statement
In case of contact» flush skin or eyes with plenty of uater.
Get medical attention if irritation persists. Wash thoroughly
after using.
Environmental Hazards
Do not apply directly to lakes» streams and ponds.
Do not contaminate water by cleanin~ of equipment or
disposal of "sstes.
Directions for Use
It is a violation of federnl law to use this product in a man-
ner inconsistent with its labeling.
16
-------
Currently Re~lstered Application Rates
APPLES
PEARS
1.50-2.25 lbs. a.i./
100 gal. ~later
Postharvest Dip or
Spray (70r. EC)
1.50-2.25 lbs. a.i./
100 gal. ,,,ater
707, EC
1 part product/
200 parts water
(2,700ppm) 52.2~ EC
1 part product/200
parts water (2,700ppm)
52.2~ EC
1.00 gal. product/
250 gal. water
(2,700ppm) 5970 EC
1.00 gal product/250
gal water (2,700pp~)
59% EC
2.25 lbs. ~.i./100 gal. water (65.5% EC)
b.
GENERAL INFO~1ATIOn
Post-h~rvest applications to fruit (dip or spray) should
include thorough drainin~ of fruit before place~ent in
cold storage. Treat~ent should not exceed 2 or 3 ~in\1tes.
Preharvest spray to trees should be applied within 2 days
of harvest. Application to trees should not he ~ade if
daily maxi~u~ temperature exceeds 85 degrees F. (29.4 C).
I.let or drench a11 fruit.
Stora~e and Disposal
Prohibitions
Do not conta~inate water, food, or feed by storage or
disposal. Open du~ping i5 prohibited.
Pesticide Disposal
Pesticide or rinstate that connot be used according to label
instructions ~ust be disposed of accordin~ to st~te or local
procedures or disposed of under the Resources Conservation and
Recovery Act.
17
-------
Container Disposal
Triple rinse (or equivalent) and offer for recycling or recondition-
ning, or dispose of in a sanitary landfill or by approved state or
local procedures.
General
Consult federal, state or local disposal authorities for
approved alternative procedures.
C.
Impre~n:1ted Fruit Hraps
1.
Acceptable Ranges and Limits
a.
Product Composition ~tandards
To be covered under this Stnndard, fruit ~'T!"aps impre~nated uHh
ethoxyquin with any percent~~e of ingredients are acceptable, provided
residues no greater than 3 ppn. ref.1ain on fruit at time of f.1arket as a
result of their use.
Inert ingredients must be cleared und~r 40 CFR 180.1001.
b.
Acute Toxicitv LiMits
.
The Agency will consider registration of fruit ~~aps if.1pregnated with
ethoxyquin in the following cate~ories:
TOXICITY CATEG0RY
I II III
Acute Oral Toxici ty af.1endment required* YES YES
Acute Demal Toxicity amendment required'" YES YE~
Acute Eye Irritation amendment required* YES YES
Acute Dermal Irritation amencment required* YES YES
>~( Amendment to the Standarrl)
IV
YES
ITS
YES
YES
13
-------
c.
Use Patterns and Application Methods
To be registered under this Standard. products impregnated with
ethoxyquin may be used only as anti-oxidants on apples and pears. The
Agency finds that current formulation rates and application methods are
acceptable under this Standard.
2.
Required Labeling
All impregnated ethoxyquin products must bear appropriate labeling
as specified in 40 CFR 162.10.
Presented below are types of statements which ~ust appear on impreg-
nated ethoxyquin labels. See 40 CFR 162.10 for specific required label-
ing for formulated products.
a.
PRECAUTIONARY STATEMENTS
Hazards to Humans and Do~estic Ani~als
May irritate eyes,
nose.
and throat.
Storage and Disposal
Do not re-use fruit wrap.
Dispose of in trash collection.
Directions for Use
It is a violation of federal law to use this product in a
manner inconsistent with its labeling.
Currently Registered Application Rates
For~ulation
Site
Application-Type/Rate
0.04% a.i.
0.131~ a.i.
Apples
Postharvest wrap. Wrap
fruit within 1 wk. of
harvest.
0.04% a.i.
Pears
(Same as above)
19
-------
b.
General Warnings and Limitations:
Do not use impregnated wraps on fruit
treated with ethoxyquin preharvest or
Prolonged exposure of chemical to air
darkening of the product and staining
which has been previously
postharvest.
or sunlight cay result in
of the fruit.
8.
Tolerance Reassessment
Tolerances have been established for residues of ethoxyquin in or on
raw agricultural commodities as .indicated: 3 ppm in or on apples and
pears (FDA; 40 CFR 180.178).
Ethoxyquin at 150 ppm or less is added directly to animal feeds (21
CFR 573.380) and dehydrated forages (21 CFR 573.400), and tolerances for
residues of ethoxyquin in eggs, meat and meat by-products have been
established to provide for such feed additive use (21 CFR 172.140).
Residues from apple and pear waste are unlikely to contribute a significant
increment of ethoxyquin to the diet of food-producing animals. In addition
pears and apples treated post harvest'with ethoxyqu1n are destined for the
fresh market, and little or no processed waste is expected.
The Theoretical Maximum Residue Contribution (TMRC) of ethoxyquin to
the human diet from pesticidal uses is calculated to be 0.12 mg/kg/l.5
kg.diet. This estimate is based on average adult eating patterns and on
the assumption that each commodity contains residues which meet the
established tolerance level. The TMRC 1s based on the above indicated crop
tolerances, which can no longer be supported with the inadequate data at
hand. There are, however, no data to suggest that maximum dosage rates on
currently registered labels would produce residues that would exceed these
existing tolerances.
In addition, international (CODEX) tolerances of 3 ppm have been
recommended for residues of ethoxyquin in or on apples and pears. The
U.S. has accepted these maximum residue limits (MRL), which are the same
as the U.S. tolerances.
Accordingly, a tolerance reassessment is not possible at this time and
will instead be performed when the necessary residue data for apples
and pears are supplied and reviewed.
20
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III
DATA RF.OUIRENF.HTS AND DATA GAl'S
,
1. ~~nufacturin~ Use Ethoxyquin
Applicants for registration of nanufacturing-usc ethoxyquin products
intende~ to be formulated into acccpt~ble end-uses must cite or subnit
the infornation identified in the nata tables on the physical and chenical
properties, conposition, fate and toxicity of the proposert product. ':'he
Agency \1ill consirter both active and inert in~redients in the determination
of substantially sini1ar products. Before each requirenent is listed the
Section of the Proposed Guidelines ~hich describes the type of data and
uhen it is required (43 FR, No. 132, 29696 of July 10, 1973; and 43 FR,
No. 163, 37336 of August 22, 197C). Applicants for the registration
of nanufacturing-use ethoxyquin nust submit infornation identified as data
gP-ps.
2. Fornulated Ethoxyquin Products
Applicants for re~istration of EC ethoxyquin products nust cite or
submit the information listed in the data tables on the product chenistry
and acute toxicity of the proposed product. In the event that an
applicant establishes that a product is substantially similar to another
pronuct for which the Agency has received acceptable acute toxicity tests,
this rlata may be cited provided conpensation has been offered to the sub-
mitters of these studies. TI-e Agency '''ill consider both active and inert
ingredients in making the deternination of substantially similar procucts.
Applicants for reregistration of impre~nated '~aps must cite or
submit inforMation on the product chenistry of the formulation used to
inpregnate the '~ap.
Applicants are hereby advised that if the A~ency does not rcceivp.
conmitrnents ,,,tthin the ti~e frames specified in the data tables fron
nanufacturing-use ethoxyquin producers to fill data gaps identified for
the nanufacturing-use material, the fornulators must then bear the
burden of supplying the data that would be required to support the re-
registration of their product.
21
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TABLE A
GENERIC DATA. REQUIRFJmNTS AND. DATA GAPS
FOR HANUF ACTURING-USE ETiiOXYQUIN
Guideline
Citation
Name of Test
Are Data
Required?
Test
Substance
Does EPA lIave Data to
Partially or Totjilly
. Satisfy Requirement!
Bibliographic
Citation
Must Additional Data be Submitted
under FIFRA 3(c)(2)(B)! If so. .
IIOnths allowed for subll1salon. .
ENVIRONMENTAL FATE
163. 63-7(b) Hydrolysis Yes
163.62-8(g) Activated Sludge Yes
Metabolism
TOXICOLOGY
Hi3.81-l Acute Oral Yes
Toxicity
163.81-2 Acu te De ma 1 Yes
Toxicity
163.81-3 Acute Inhalation Yes
Toxicity
163.81.,.4 . Prima ry Eye Yes
Irritation
163.81-5 Prima ry De rmal Yes
Irrita tion
163-81-6 Skin Sensitization Yes
Tech. Grade*
Tech. Grade
No
No
Yes**
No**
Tech. Grade* No
Tech. Grade No
Tech. Grade* Yea
Tech. Grade* No
Tech. Grade* No
Tech. Grade* Yes
Yes: 6 months (Sept. 30. 1981)
Yes: 6 IIOnths (Sept. 30. 1981)
Scientific Associates
1960 (HalO 100002202)
No
Yes: 6 months (Sept. 30. 1981)
Yes: 6 IIOnths (Sept. 30. 1981)
Draize. Woodward and
Calvery (HalO 10500474)
No
* Technical Grade of the Active Ingredient
** If the outdoor spray use is dropped from existing labels. the major route of exposure to
non-target organisms will be substantially reduced. This reduction, along with the low
volume use of etboxyquin .on apples and pears, minimal expected exposure. and acceptance
~f the international CODEX tolerances will justify waiving the data requirements for
Hydrolysis. .Activated Sludge requirements are being reserved pending review nad
modification of the testing protocols.
Karch 1981
-------
TABLE A (cont.)
GENERIC DATA REQUIREMENTS AND DATA GAPS
FOR MANUFACTURING-USE ETHOXYQUIN
Guide1h,e
Citation
Name of Test
Are Data
Required?
Test
Substance
Does EPA Have Data to
Partially or Totally
Satisfy Requirement?
Bibliographic
Citation
Must Additional Data be Submitted
under FllRA 3(c)(2)(B)? If so.
months allowed for submission.
163.82-:-1 Subchronlc Oral Yes Tech. Grade Yes
Toxicity
163.82-2 Subchronic (21-day) Yes Tech. Grade Yes
Dermal Toxicity
163.83-1 C1ronlc Feedina Yes Tech. Grade Yes
(See Chspter VI)
(See Chapter VI)
U.S. Agricultural
Research Servic~.
Western Utilization
Research Branch (KilO
'0001923)
Wilson and DeEds (MIlD
'05000474)
Panner end Packer
(HaID '05000S29)
Rudra. Dickerson and
Walker (HRID '05000419)
Hanzal (HaID
'0000192S)
Colorado A&M Uni.
(KRID '00001919)
Gassner. Buss.
Hopwood and Tho.pson
(MRID '05OooS17)
Pascal (review article)
(MIlD '05000412)
*** Although data are not available to reassess tolerances, a new study is not being
required at tbi. thle because of the low volu- use of ethoK}'quin on apples and
pears, uniul apected apo.ure. and acceptance of the international CODEX tolerances.
No
No
No-**
Karch 1981
-------
TAHLE A (cont.)
GENERIC DATA REQUIREMENTS AND DATA GAPS
FOR . MANU!' ACIUIllNG-USE EmOXYQU IN
Guide 11 ne
Citation
Name of Tes t
Are Data
Required?
Test
Substance
Does EPA Have Data "to
Partially or Totally
.Sstisfy Requirement?
Bibl1ogr.phic
Citation
T,
Must Additional Data be Submitted
under FIFRA 3(c)(2)(8)7 ,If so,
months allowed for submission.
163.83-2
163.83-3
163.83-4
Oncogenicity
Yes
Teratogenicity
Yes
Reproduction
Yes
Tech. Grade
Tech. Grade
Tech. Grade
, Yea
Wilson and De Eds (MaID
105000474) .
Telfotd, 1.&. et al.
(HRID 105000428) -
Wilson, R.H. (MaID
100001933)
Isenstein, I\.S.
(MIllD 105000366)
Monsanto Company (MaID
'00001919)
Monsanto Company (MaID
'00001920)
Wilson, R.H. (MaID
100001933)
Wilson, R.B. (HaID
'00001934)
Wisconsin Alumni Ass'n.
(.UlID 100001924)
Amer. Jour. of Anatomy
(MaID '05000428)
Amer. Jour. of Vet. Rea.
(HaID 105000366)
Journal of Food ,nel Ag.
Chemistry (HaID 105000474)
Yea
Yea
No
No
No
Karch 1981
-------
TABLE A (cont.)
GENERIC DATA REQUIREMENTS AND DATA GAPS
FOR MANUFACTURING-USE ETHOXYQUIN
Guideline
Citation
Bibliographic
Citation
Name of Test
Are Data
Required?
Test
Substance
Does EPA Have Data to
Partially or Totally
Satisfy Requirement?
Must Additional Data be Submitted
under FIYRA 3(c)(2)(B)? If so.
months allowed for submission.
Yes
163.84-1-4
Mutagenicity
Yes
Tech. Grade
Joner. P.E. (HiID
'05000385)
Wilson. !959 (HRID
'05000475)
Honsanto (HiID
'00001935)
TerHeulin and Walker
(HiID '05002491)
Skaare. J.V. and Hatstad. I.
(HRID '05012506)
163.85-1
Hetabo1hm
Yes
Tech. Grade
Yes
PRODUCT CHEMISTRY
163.61-8(1) Color Yes Tech. Grade. Yes
163.61-8(2) Odor Yes Tech. Grade No
163.61-8(4) Solubility Yes Tech. Grade No
163.61-8(5) Stability Yes Tech. Grade No
163.61-8(6) Octanol/Water Yes Tech. Grade No
Partition
Coefficient
.3. 61-8( 7) Physical State Yes Tech. Grade Yes
Monsanto Chea. Co.
(HiID 1004X)
Bexolin Chea. Co.
(HiID 10061)
Honsaneo Chem. Co.
(HiID 1004X)
Rexolin Chem. Co.
(HiID 10061)
Technical Grade of the Active Ingredient
No
No
No
Yes I 6 months
Yes: 6 months
Yesl 6 months
Yesl 6 months
No
(Sept. 30.
(Sept. 30.
(Sept. 30.
(Sept. 30.
March 1981
1981)
1981)
1981)
1981) .
-------
TABLE ~ (cont.)
GENERIC DATAREQUIREKENTS AND DAT~ GUS
FOil HAHUFACTUIlING-USE ,E'l'HOXYQUlH
Huae of Test
,
Guideline
Citation
Are Data
Ilequlred'l
Test
Substance
Does UA Have Data to
Partially'or Totally' ,
Satisfy Ilequlre.ent'l '
Bibliographic
Citation
Must Additional Data be Subaitted
under FIFIlA 3(c)(2)(B)'l If 80.
80ntbs allowed for sub818slon.
RESIDUE CHEHISTilY
N.A~**
Degradation Pathway
Yea
N.A.
Ilesiduea on Apples
and Pears from
HAXIHUH rqiacend
uses
Yea
ECOLOGICAL EFFECTS
Tech. Grade
Ko
Yea: 12 8O~hs (March 31. 1981)
Yes: 12 80ntha (March 31, 1981)
163.71-1 Avian Single Yes Tech. Grade. No Yes**
Dose Oral LDSO
163.71-2 Avian Dietary Yea Tech. Grade* No Yea..
LCSO
163.72-1 Fish Acute Yea Tech. Grade* No Yes..
LCSO
. 163.72-2 'Acute ToXicity Yea Tech. Grade. No Ye...
to Aquatic Invertebrates
Tech. Grade
No
* Technical Grade of tbe Active Inaredient
** Data Ilequireaenta are waived because of 1- -rut vol_,
_thode for ethoxyqu1n.
*. N.A. - Hot applicable.
use pstteraa and application
March 1981 . ,
-------
TABLE B
PRODUCT-SPECIFIC DATA REQUIREMENTS AND DATA GAPS
FOR MANUFACTURING-USE ETHOXYQUIN PRODUCTS
Guideline Hue of Test Are Data Test Does EPA Have DAta to Bibliographic
CHat ion Required! Substance Partially or Totally Ci tat ion
Satisfy Require.ent!
PRODUCT CHEMISTRY
163.61-3 Prod. Identity Yes Bach HUP* Ho
and Disclosure
of Ingredients
163.61-4 Description of Yea Bach "UP* Ho
Manufacturing
Process
163.61-5 Disc. of Foraat Yea Each MUP* Ho
of Unint.
IngredienU
163.61-6 Declaration of Yea Each MUP* Ho
Ingredient Li.its
163.61-7 Product Analyt. Yea Each "UP* Ho
Methods and Data
163.61-8(7) Physical State Yes MUl'** Ho
163.61-3(8) Density or Yea MUP** Ho
Specific Gravity
163.61-8(11) pH Yea MUP" Ho
163.61-8(12) Storage Stab. Yea MUP*** Ho
Must Additional Dat. be Submitted
under PIFRA 3(c)(2)(B)! If 80.
80ntha allowed for aub81asion.
Yea: 6 80ntha -(Sept. 30. 1981)
Yea: 6 80ntha (Sept. 30. 1981)
Yes: 6 8Onth. (Sept. 30. 1981)
Ye.: 6 aonths (Sept. 30. 1981)
Yes: 680ntha (Sept. 30. 1981)
Yea: 6 80ntha (Sept. 30. 1981)
Yes: 6 aontha (Sept. 30. 1981)
Yes: 6 80nths (Sept. 30. 1981)
Yea: 6 80ntha (Sept. 30. 1981)
* Each KaRLfacturing-use Product.
Ct* Required for Manufacturing-uae Producta which are not the ..ae as the Technical Grade
for the Active Ingredient. Product Cheahtry data requested in TABLE-A will suffice for
Manufacturing-uae Ethoxyquin because it 1& equivalent to Technical Grade Ethoxyquin.
*** Each 88nufacturing-uae Product or Substantially S1a11ar Product.
March 1981
-------
TABU B (cont.)
PRODUCT-SPECUIC DATA UQUIIlEHEHTS AND DATA GAPS
IOIlIWlUlACTUUJt;-USI ITHOXYQUIR PIODUCTS
GuideUne
Citation
Haae of Teat
Are Data
kquiredl
Teat
Suba talice
Dbea EPA Have Data to
Partially 01' Totally
Satiafy a8quir_ntl
BibUographic:
Citation
Must Additional Data be Subll1tted
under 'URA 3(c)(2)(B)1 If 80.
80ntH allowed for aublliasion.
TOXICOi.oGY
163.81-1 Acute Oral Yea IIDP* Ro
Toxici ty
163.81-2 Acute Demal Yea 1tIJP* Ro
Toxicity
163.81-3 Acute Inhal. ~es MOP** Yea
163.81-4 Pd... Eye Yea 1tIJP** Ro
Irritation***
163.81-5 Prillary Del'88l Yea IIJP** Ro
Irritation
163.81-6 Be mal Yea 1tIJP** Ye.
Senaitization
SdentiUc Aaaodatea. 1960
(MaID 'OOO02~02) .
Dralze. VoocIwarct and
Caber, (MaID 105000474)
* Required for Manufacturing-u.e Producta which are DOt tile -- .. the Technical Grade
of the Active Ingredient. Acute Oral and Dema1 Toxicity data requested in TABU-A will
provide needed data for Manufacturing-u.e Itbo~qin because the KUP ia equivalent to
Technical Grade EtboKJquin.
** Each Hala&facturing-uae Product or SubatantiaUy Sfailar Product.
*** A de80natntion of pH between 1 and 3. or 12 and 14 or a d-aUation of demal irritability
will be sufficient to categori.e a product.. an oculAr irritant. and additional teatiDl will
not be required. .. .
Yea' 6 80ntha (Sept. 1G. 1981)
Yea' 6 8OnW" (Sept. 30. 1981)
Ro
Ye.' 6 80ntH (Sept. 30. 1981)
Ye.: 6 80ntU (Sept. 30. 1981)
110
lfarch 1981
-------
TABLE C
. PRODUCT-SPECIFIC DATA REQUIUHENTS AND DATA. GAPS
10& EMULSIFIABLE OONCENTItATE KTHOXY~IH paODUCTS
Guideline
Citation
Naae of Teat
Are Data
&equiredt
Te.t
Subatane.
Doea IPA Have Data to
Partially or Totally
Satiafy Require.entt
Bibl10lraphic
Citation
.Huat Additional Data be. Subaitted
UDder FIlU 3(c)(2)(B)t If 80.
math. .allowed for .ub81..ion.
PRODUC'l CBEHISTRY
163.61-3 Prod. Identity Yea Each B.C. product* 110
and Di.cloaure
of Inlrediente
163.61-4 Description of Yea Each I.C. l'roduct* No
Manufacturiq
Proce..
163.61-5 Disc. of P01'8Bt Yea Each I.C. Product* No.
of Unint.
Ingredienta
163.61-6 Declaration of Yes Bach E.C. Prodcut* No
Ingredient Limite
163.61-7 Product Analyt. Yea Bach E.C. Product* No
Methode and Data
163.61-8(1) Color Yes Bach B.C. Product* No
163.61-8(2) Odor Ye8 Bach I.C. Product* No
. 163.61-8(7) Physical State Ye8 Bach B.C. Product* No
163.61-8(8) Density. or Ye8 EC** No
Specific Gravity
163.61-8(11) pH Yea EC** No
163.61-8(12) Storage Stab. 1e8 EC** No
Yea: 6 lIIOoth. (Sept. 30. 1981)
Y..: 6 math. (Sept. 30. 1981)
Ye.: 6 math. (Sept.. 30. 1981)
Ye.: 6 motbs (Sept. 30. 1981)
Ye.: 6 80nths (Sept. 30. 1981)
. Ye.: 6 8Ooth. (Sept. 30. 1981)
Yea: 6 80ntha (Sept. 30. 1981)
Yea: 6 8Onth. (Sept. 30.- 1981)
Ye.: 6 80ntbs (Sept. 30, 1981:)
Ye.: 6 IIODtha .(Sept. 30. 1981)
Yea: 6 mntha (Sept. 30. 1981)
* Bach Imulaifiable Concentrate Product.
** Each EIIIulaUiable Concentrate Product or Subataotially SWlar Product
Karch 1981
-------
TABLE C (eont.)
PRODUCT-SPECIFIC DATA BEQUIREHENTS AND DATA GAPS
FOR EHULSlFlAILI mNCENTRATE. I1'UOXYqlJlN PRODUCTS
Gu~deUne
CHat ton
Naae of Teat
Are Data
Required! .
Teat
Sub a tanu
Doea £fA Have Dat~ to
Partially or Totally
Satisfy lequireaent!
Bibliographic
Citation
Huat Additional Data be Subaltted
under FIFiA 3(c)(2)(I)! If so,
8Onth.. al10wecl for subahalon..
c.
TOXICOLOGY
16).81-1 Acute Oral Yea IC. Yea Younger. 1960 (HRIO No
Toxldty 14>0001880)
16].81-2 Acute Denas. Yea IC Yea Younger. 1960 (KiID No
ToxicHy '00001884)
163.81-3 Acute Inbal. Yea IC Yea Scieotlfle Assoclat.., 1960 No
Toxicity (HRID 'CS-0003-4)
163.81-4 Frla. Eye Yea Ie Yea Younger. 1960 (101.10 No
Irritation.. 100001884)
16).81-S Pr 1aa ry De nasi Ye. IC Yea Younger. 1960 (KilO No
Ird taUon 100001884)
163.81;;'6 Demel 'I.. IC Yea See Suppleaentary No
Sensitization Infonastlon Toplca
(Chapter VI)
* Each Zaulatfiable Concentrate Product or Sub.tentlally Slal1ar Product.
u A de80natratlon of pH between 1 and 3. 01' 12 and 14 01' a deaonatl'8t1on of deraa1
InltabUtty will be aufUdent to catelodze a product.. an ocular irdtant,
and additional teatlng will DOt be required.
Hucb 1981
-------
TABLE D
PRODUCT-SPECIFIC DATA REQUIREMENTS AND DATA GAPS
FOR IMPREGNATED ETHOXYQUIN PRODUCTS
Guideline
Citation
Name of Test
Are Data
Required?
Test
Substance
Does EPA Have Data to
Partially or Totally
Satisfy Requirement?
Bibliographic
Citation
Must Additional Data be Submitted
under FIFRA 3(c)(2)(B)? If so,
months allowed for submission.
PRODUCT CHEMISTRY
163.61-3 Prod. Identity Yes Each IMP Product. No
and Disclosure
of Ingredients
163.61-4 Description of Yes Each IMP Product. No
Manufacturing
Process
163.61-5 Disc. of Format Yes Each IMP Product. No
of Unint.
Ingredients
163.61-6 Declaration of Yes Each IMP Product. No
Ingredient Limita
163.61-7 Product Ana1yt. Yes Each IMP Product. No
Methods and Data
163. 61-8( 1) Color Yes Each IMP Product. No
163.61-8(2) Odor Yea Each IMP Product. No
163.61-8(7) Physical State Yes Each IMP Product. No
163.61-8(8) Density or Yea IMp.. No
Specific Gravity
163.61-8(9) Boiling Point Yea IMP.. No
163.61-8(10) Vapor Pressure Yes IMp.. No
163.61-8(11 ) pH Yes IMp.. No
163.61-8(12) Storage Stab. Yes IMp.. No
Yes: 6 months (Sept. 30, 1981)
Yes: 6 months (Sept. 30, 1981)
Yes: 6 months (Sept. 30, 1981)
Yes: 6 months (Sept. 30, 1981)
Yes: 6 months (Sept. 30, 1981)
Yes: 6 months (Sep t. 30, 1981)
Yesl 6 months (Sept. 30, 1981)
Yes: 6 months (Sept. 30, 1981)
Yes: 6 months (Sept. 30, 1981.
Yes: 6 months (Sept. 30, 1981)
Yes: 6 months (Sept. 30, 1981)
Yes: 6 months (Sept. 30, 1981)
Yes: 6 months (Sept. 30, 1981)
~OTE:
If registrants can demonstrate that the material used to impregnate wraps is substantially similar to the technical
or manufacture-use formulations, the toxicology data requirements for the impregnated wraps will be waived.
Each Impregnated Product.
,. Each Impregnated Product or Substantially Similar Product
Karch 1981
-------
TABLE D (cont.)
PRODUCT-SPECIFIC DATA REQUIREMENTS AND DATA GAPS
lOR IMPREGNATED E'l1IOXYQU IN PIlODU=-rS
Guideline
Citation
NaM of Test
Are Data
Bequired!
Test
Substance
Does EPA Have Data to
Partially or Totally
Satisfy &equirement!
Bibliographic
Citation
Must Additional Data be Subaa1tted
under FIFIA 3(c)(2)(B)! If ao.
80nths allowed for sub81ssion.
TOXICOLOGY
163.81-1 Acute Oral Yes IHP* No Yea: 6 Mntha (~ept. 30. 1981)
Toxicity
163.81-2 Acute Deraal Yes IHP No Yes: 6 80ntbs (Sept. 30. 1981)
. Toxicity
163.81-3 Acute Inbsl. Yea IHP No Yes: 6 IIOntha (Sept. 30. 1981)
Toxic! ty.
163.81-4 Prb. Eye Yes IHP No Yea: 6 80ntha (Sept. 30~ 1981)
Irritation**
163.81-5 P.rimary Dermal Yes IHP No Yea: 6 Mntbs (Sept. 30. 1981)
Irritation
163.81-6 Dermal Yea IMP No Yel!: 6 Mntbs (Sept. 30. 1981)
Sensitization
NOTE:
If registrants can demonstrate that the material used to impregnate wraps is substantially similar to the technical
or manufacture-use formulations. the toxicology data requirements for the impregnated wraps will be waived.
* Each Impregnated Product or Substantially Similar Product.
** A demonstration of pH between I and 3. or 12 and 14 or a demonstration of dermal
irritability will be sufficient to categorize a product as an ocular irritant.
and additional testing will not be required.
March 1981
-------
IV
PRODUCT CHEMISTRY
A.
Introduction
FIFRA 3(c)(2)(A) requires the Agency to establish guidelines for regis-
tering pesticides in the United States. The Agency requires
registrants to provide quantitative data on all added ingredients, active
and inert, which are equal to or greater than 0.1% of the product by
ueight. A review of the "confidential statement of formula for the end-use
products of Ethoxyquin indicates that all inert ingredients are cleared
under CFR 40 Part I Sec. 180.1001.
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 some unintentional ingredients. Subpart D of the Proposed
Guidelin~s (43 FR 29696, July 10, 1978) suggests specific precision limits
for ingredients based on the percentage of ingredient and the degree of
accuracy of the analytical method.
In addition to the data on product composition, the Agency guidelines
also require 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, ambient vapor pressure
and solubility). Data are also required on the properties of the
formulated product to establish labeling cautions (e.g., flammability.
corrosiveness or storage stability). The Agency uses these data to
characterize each pesticide and to determine its environmental and health
hazards.
B.
Product Chemistry - Manufacturing-Use Ethoxyquin
1.
Product Chemistry Profile
No manufacturing use products containing ethoxyquin are currently
registered. Applicants for registration of ethoxquin products are
reminded that since no manufacturing use products are currently registered,
the formulators are responsible for supplying the required data
for the manufacturing-use chemical as outlined in Chapter 3.
22
-------
Because it is considered "Confidential Business Information", a
discussion of the specific procedures, equipment, and manufacturing
conditions required for the commercial production of the chemical will not
be included in this standard.
The Farm Chemicals Handbook 1980 shows Monsanto Company, the only
basic U.S. producer of Ethoxyquin, as having discontinued production
of the 701, Emulsifiable Concentrate formulation. Contact with industry
also indicates that, along wit~ the discontinuance of the pre-harvest
spray use, most of the other uses of ethoxyquin with the exception of
the impregnated wraps have been abandoned.
A small amount of data are available on the physical and chemical
properties of technical ethoxyquin. . See Data Tables in Chapter 3.
2.
Data Requirements
Refer to Chapter 3 for Product Chemistry data needed to support
the registration of any manufacturing-use ethoxyquin product. Following
each data requirement is the section in the Proposed Guidelines for the
Registration of Pesticides in the United States (43 FR 29696, July 10,
1978) that describes the type of data required. The applicant for
registration must submit or cite this information.
3.
Topical Discussions
Corresponding to each of the Topical Discussions listed below is the
number of the section in the 'Proposed Guidelines for Registering
Pesticides' in the United States (43 FR 29696, July 10, 1978) which
explains the minimum data that the Agency requires in order to adequately
assess Product Chemistry of manufacturing-use ethoxyquin products. Also
under each of the following topics is a reference to the appropriate
section in the 'Proposed Guidelines'.
Guidelines Section
Ch er.t i c a 1 Id en tIt Y ......................................
Manufacturing Processes ................................
Formation of Unintentional
163.61-3
163.61-4
Ingredients ..........................................
163.61-5
Active Ingredient Limits in
Pesticide Products ...................................
Product Analytical Methods and Data ....................
Physical/Chemical Properties ...........................
163.61-6
163.61-7
163.61-8
Chemical Identity [163.61-3(c)]
The Proposed Guidelines require identifying information including
chemical names, product names, and numerical codes of all substances known
or assumed to be present in pesticide products. See tables in Chapter 3.
23
-------
"EttlOXyqui n" is thc ~eneric n;1r:1C for l)-et1-]oxy-l) 2-<1ihydro-2) 2) 4-
tri~ethyl-quinoline. Ethoxyquin is a derivative of quinoline. Trade
na!':les for Ethoxyquin are: Santoquin, Santoflex !\~7) !~iflex;), Stop-scC1ld,
and Deccoquin. The nane "Ethoxyquin" l1il1 be routinely used in this
standDrd in lieu of other cheMical or trade nanes.
~'anufacturing Processcs r If,lJ>1-4(b) 1
Bccause the route by \l~ich a pesticide is synthesized deterMincs thc
nature Clnc anount of potenti<111y toxic impurities, a cetaiJec cescription
of the nanufacturing process is required.
Fornation of Unintentional Ingrcdients r163.hl-51
Section 1h3.hl-5 of the Proposcd r.uidelines requires registrants of
r.lanufrtcturing-use anr. of forMuL"!ted products to submit a theoretical
discussion of the fornation of unintenr.ed suhst,mces in the product.
A t1:eoretical discussion of the fornation of unintenced suhstances has
not been subnitted for nantlfacturing-use et~oxyquin. Such a discussion is
required for each nanufacturi~g-usc product.
.-kti"e In!";redient Linits in Ppsticjde Products rIAl.hl-h!
The Guidclines require th2t upper and 10l1er lir:lits be establishec for
e;1ch activc ingredient anc cach intentionally ;"!d~cd inert in ;1 pesticide
product. Technical ethoxyquin contains approxinately 05~ of the
pure cheM.ical.
Upper Rnd lower linits havc not becn cst~b]isherl and certificd for
technical ethoxyquin.
Product Analytic;"!1 ~ctho0s and Data rl~1.f,1-71
The Guidelines require subnission of, or refercnce to, analytic?l
nethods for neasuring each i"!ctive inp,redient in a ppsticide product.
Section 16:1.111-7 of the Proposcd Guidelines 3lso require th;1t
applications for registration of ppsticide products contain analytical data
obt2ine~ by ~ethods supplied to the Agcncy.
Adequate analytical ~ethods for the identification and quantification
of Ethoxyquin in the technical and fornuJated end-use prodtlct have not heen
sub~itted. Acceptable ~etho~s for the analysis of inpurities also have not
been subnitted. The nanufacturer, i.c., ~!onsanto, did not report l.R. or
U.V. spectra \!nich coulc1 he used in the identific<1tion of Ethoxyquin.
Physical ~n(! Chenical Properties r1~1.~1-~1
For every pesticide product, the Proposed Guidelines require cata on
certain physical and chenica1 properties useful for identification ~urposes
or for evaluation of hazard potenti~l.
24
-------
A small amount of data are available on the physical and chemical
properties of ethoxyquin. Availahle data on purified ethoxyquin (Monsanto,
1975, MRID #004X; Rexolin Chemicals, 1971, MRID #006X) give these details:
Color: Varies from yellow to brown.
air.
o
Boiling Point: 125 C at 2 mm Hg. 0
Density or Specific Gravity: 1.03 at 25 C
Physical State: Technical ethoxyquin is a
o
Flammability: Flash point 285-290 F (CaC)
Darkens when exposed to light or
liquid when purified.
and >1750F (TCC)
C.
Product Chemistry - Emulsifiable Concentrate Ethoxyquin
See the Tables in Chapter 3 for a complete listing of the Data
Requirements and Data Gaps for EC ethoxyquin.
1.
Topical Discussions
The product chemistry of ethoxyquin has been dealt with in the
Manufacturing-Use Ethoxyquin section of this chapter. The following are
data required of all EC formulated products of ethoxyquin.
Active Ingredient Limits in Pesticide Products [163.61-5}
For all pesticide products, the Guidelines would require that upper
and lower limits be established for each active ingredient, impurity.
reaction product, and degradation product.
Current registrations of EC ethoxyquin contain 52.2, 59.0, 65.5, and
70% active ingredient.
Product Analytical Methods and Data [163.61-71
The Guidelines would require submission of, or reference to,
analytical methods measuring each active ingredient in a pesticide
product.
Section 163.61-7 of the Proposed Guidelines would require that
applications for registration of pesticide products contain analytical data
obtained by methods supplied to the Agency. Data obtained by the method
described above have not been submitted.
Section 163.61-7 of the Proposed GuideJines would also require that
registrants of formulated products produced by an integrated formulation
system (Proposed Guidelines, section 163.61-1) submit methods not only for
the active ingredient, but for each identifiable impurity associated with
manufacture of the technical chemical. Such cethods have not been
submitted for any ethoxyquin formulation.
25
-------
Physical and Chemical Properties (163.61-81
For every pesticide product, the Proposed Guidelines would require
data on certain physical and chemical properties useful for identification
purposes or for evaluation of hazard potential.
The following physical and chemical properties are required for all EC
products 0f ethoxyquin. No data have been submitted.
Required Physical/Chemical Properties: Color, odor, density or
specific gravity, pH, storage stability, flammability, oxidizing or
reducing action, explosiveness, and corrosion characteristics.
D.
Product Chemistry - Impregnated Product Ethoxyquin
See Tables in Chapter 3 for the Data Requirements and Data Gaps
corresponding to the impregnated formulation.
1. Topical Discussions
Registrants are advised that if some formulation other than the
technical or manufacturing-use product is used in the manufacture of
impregnated wraps, the aforementioned data requirements must be fulfilled
for that formulation.
The product chemistry of ethoxyquin ~~ has been dealt with in the
Manufacturing-use Ethoxyquin section of this chapter. The following are
data required of all impregnated formulated products of ethoxyquin.
Active Ingredient Limits in Pesticide Products [163.61-51
For all pesticide products, the Guidelines would require that upper
and lower limits be established for each active ingredient, impurity,
reaction product, and degradation product.
Current federal registrations of impregnated ethoxyquin products
contain 0.04 to 0.131% a.i.
An upper and lower limit for wraps impregnated with ethoxyquin has
not been established.
Product Analytical Methods and Data [163.61-71
The Guidelines would require submission of, or reference to,
analytical methods measuring each active ingredient in a pesticide
product.
Section 163.61-7 of the Proposed Guidelines would require that
applications for registration of pesticide products contain analytical data
obtained by methods supplied to the Agency.
Section 163.61-7 of the Proposed Guidelines would also require that
registrants of formulated products produced by an integrated formulation
system (Proposed Guidelines, section 163.61-1) submit methods not only for
26
-------
the active ingredient, but for each identifiahle impurity
manufacture of the technical chemical. Such methods have
submitted for any ethoxyquin formulation.
associated with
not been
Physical and Chemical Properties [163.61-81
For every pesticide product, the Proposed Guidelines would require
data on certain physical and chemical properties useful for identification
purposes or for evaluation of hazard potential. Data on the physical and
chemical properties of substances used to impregnate wraps are required if
the substance is not suhstantially similar to a product for which the
Agency has acceptable data.
Required Physical/Chemical Properties: Color, odor, density or
specific gravity, pH, storage stability, flammahility, oxidizing or
reducing action, explosiveness, and corrosion characteristics.
27
-------
v
ENVIRONMENTAL FATE
A.
Use Profile
Ethoxyquin formulations are applied to apples and pears by pre-
harvest spray and post-harvest dip or spray. Ethoxyquin is also
impregnated on paper wrappings to prevent scald, post-harvest.
There are two types of ethoxyquin products currently registered to
treat apple and pear scald. Five companies have labels for emulsifiable
concentrates containing from 52.2 to 70% active ingredient.
Current registrations for ethoxyquin include "No Scald Ethoxyquin"
(Chemley Products Co., EPA registration number 4543-9) and "Deccoquin 305
Concentrate" (Pennwalt Corp., EPA Registration number 4581-316), basically
dominating the market where drenches, sprays, dips, and waxes are used.
Both are available in 5 gal. cans ready to dilute ~ith water in treatment
tanks. Two companies have labels for paper wraps. Only one company
(Crown Zellerbach) still actively markets its wraps; "Crownoil Apple tJraps"
(EPA registration number 3222-9), "Green Crownoil Pear Wraps" (EPA
registration number 3222-6). The wraps are available as individual sheets
ranging in size from 9 x 9 to 14 x 12 inches. All of the above formulators
apparently obtain their ethoxyquin from the primary manufacturer, the
Monsanto Company.
State and Federal recommendations and other literature sources list
preharvest and postharvest sprays, postharvest drenches and dips, wax dips,
and paper wraps as means for treating fruit with ethoxyquin. In current
practice preharvest sprays are apparently not used. The most commonly used
treatment method is a fruit drench in an ethoxyquin aqueous solution at the
packinghouse. In this method bulk bins of recently harvested fruit are
flooded for several seconds with the treatment then allowed to drain for a
few minutes before removal (usually by forklift) to cold storage. Excess
solution is recovered and recycled for immediate re-use. Recommended
ethoxyquin concentrations are between 2000 to 2700 ppm active ingredient.
The solution often contains a surfactant and an antifoaming agent. It is
a1so normal practice to add one or more antirot fungicides to the mix snch
as captan (1 lb/l00 gal) and/or benlate (6-8 oz/100 gal).
A small number of packinghouses dip their harvested apples in similar
solutions. Typically a forklift places a bulk bin into a tank of
ethoxyquin for a period of 15 seconds to 2 minutes, depending on the
temperature of the solution. In all application ~ypes, fruit are only
treated once.
Accurate data on number of workers and fruit packinghouses using
ethoxyquin fruit treatment are not available. An estimate of apple
packing-houses in this country is between 500 to 1000. The nuober of
workers exposed to ethoxyquin per packinghouse varies with the treatment as
will be explained in the following treatment descriptions.
28
-------
Fruit Wrapping is principally done at some 40 packinghouses handling
'Anjou' pears. An estimated 20 to 90 Sorter/Wrappers (typically women) per
house handle wrappers. Wrapping continues 8 hr/rlay during a 1-2 month
harvest season. Workers usually wear gloves, but these are primarily to
protect the fruit from bruising, not as a protective device. All labels
contain the warnings, "Keep out of reach of children" and "Wash hands
before eating".
In ethoxyquin drench or dip operations only 2-3 workers per
packinghouse engage in treatment of apples. Typically these operations
are performed outdoors and involve maneuvering truckloads or bulk bins
through drench showers or into dipping tanks. Forklift operators, machine
operators, and truck drivers are all potentially exposed to some spray and
liquid. ~ost of these operations are at least partially automated. For
example, bins and truckloads of fruit are dragged through drenches by
motorized chains operated by a worker at a control board. Individual
apples in these methods are seldom handled until after storage when they
are sorted and packed for shipment. There are an estimated 500 to 1000
packinghouses using these methods. Except for gloves normally worn by
fruit handlers, protective clothing is not usually worn.
Spray, brush, or wax operations are usually located inside the
packinghouse but are separated by walls from most of the workers. One or
two workers are potentially exposed to ethoxyquin in liquid or wax, as they
oversee the operation of the belt line. One of these workers usually is
responsible for adding and mixing of fresh ethoxyquin solution. Sprays are
stream-like rather than a fine mist. After the fruit is dried, it is
handled by sorter/packers. These workers usually wear gloves but no other
protective clothing. Wax treatment of the fruit may be somewhat tacky at
this stage. Approximately 40 to 80 packinghouses use these treatment
methods.
B.
Manufacturing-Use Ethoxyquin
1.
Environmental Fate Profile
There are no data currently available on the environmental fate of
Ethoxyquin.
2.
Exposure Profile
Because of the scarcity of data on the environmental fate of
Ethoxyquin, it is impossible to quantitatively assess exposure of
humans and wildlife to manufacturing-use Ethoxyquin.
3.
Data Requirements and Data Gaps
Since the outdoor spray (preharvest) use of ethoxyquin is
reportedly discontinued, and in light of the low market volume and
29
-------
use patterns of ethoxyquin 1~ich indicate ninimal exposure.
nental fate data requirements may be \l.
-------
The potential for human exposure (inhalation and dermal) during
loading, mixing and application operations is recognized. For drench and
dip operations, 2-3 workers are closely involved in the treatment of apples
in each of an estimated 500 to 1000 packinghouses using these methods.
Operations are typically performed outdoors with forklift operators.
machine operators and truck drivers all potentially exposed to some spray
and liquid. Individual apples are seldom handled until after storage when
they are sorted and packed for shipment. Except for ~loves normally worn
by fruit handlers, protective clothing is not usually worn. Spray. brush
or wax operations are usually performed inside the packinghouse where one
or two workers are potentially exposed to ethoxyquin in each of the
approximately 40 to 80 packinghouses which use these treatment methods.
These workers are usually responsible for adding and mixing fresh
ethoxyquin solution. Fruit is handled by sorter/packers who usually
wear gloves but not other protective clothing.
In summary. about 1000-3000 workers are involved in the application of
ethoxyquin to fruit using EC formulations. The presence of liquids and
sprays containing the active ingredient is a potential source of dermal
and inhalation exposure to all of them. An undetermined number of
sorter/packers who usually wear gloves are exposed to a lesser de~ree.
Residues on fruit surfaces would be a source of slight dermal exposure to
humans during marketing and consumption.
Impregnated material (Paper fruit wrap)
Fruit wrapping is presently performed in some 40 packin~houses
handling "AnjC\u" pears. An estimated 20 to 90 sorter/wrappers (typically
women) per house handle the wrappers. Wrapping continues 8 hr/day during
a 1-2 month harvest season. Workers usually wear gloves but not
other protective gear. Residues of ethoxyquin transferred to fruit from
treated paper wraps may be a source of slight dermal exposure during
marketing and consumption, but the dietary contribution is extremely low.
31
-------
VI
TOXICOLOGY
A.
Manufacturing-Use Ethoxyquin
1.
Toxicology Profile
The chronic no-observed effect level for ethoxyquin is 0.0062%.
Acute oral data, although insufficient in detail, indicates low acute
oral toxicity (LDSO in rats: 3150 mg/kg).
2.
Data Requirements and Data Gaps
The toxicology data requirements and data gaps are listed in
Chapter 3 of this Standard.
Since no manufacturing-use Ethoxyquin is currently registered, these
data requirements would automatically become data gaps in the event an
application for registration was filed for a manufacturing-use chemical.
Food Use (Requires a Tolerance or Exemption)
All applicants for registration of technical products which are
formulated into end-use products intended for use on food must submit or
cite the following:
Category of Test
Description
Data Requirement
Chronic Feeding
063.83-1)
A two year feeding study
in the rat.
Satisfied
Oncogenicity
(163.83-2)
An oncogenicity study in each
of two suitable mammalian species.
Satisfied
Teratogenicity
(163.83-3)
Teratogenicity testing in two
nammalian species.
Satisfied
Reproduction
(163.83-4)
A two-generation reproduction
study, preferably in the rat.
Satisfied
32
-------
Mutagenicity
(163.81-1
through
163.81-4)
A mammalian in vitro point ~uta-
tion test; a sensitive sub-ma~-
malian point Dutation test; a
primary DNA damage test; a mam-
malian in vitro cytogenetics test.
Satisfied
Metabolism
(163.85-1)
A general metabolism study in one
mammalian species.
Satisfied
Human and Domestic Animal Hazard Assessment
Since no manufacturing-use Ethoxyquin products are currently
registered, potential acute, sub-acute or chronic effects in humans and
animals cannot be assessed.
Required Labelin~
Precautionary labeling of each product must correspond to the toxicity
categories determined by five acute toxicity tests. Acceptable cate-
gories 9f acute toxicity and the corresponding required labeling appea~
in the Chapter 2 of this Standard.
3.
Topical Discussions
Corresponding to each of the Topical Discussions listed below is the
number of the section(s) in the 'Proposed Guidelines' of Au~ust 22, lq78
(43 FR, No. 163 37336) which explain(s) the mini~um data that the Agency
usually requires in order to adequately assess ethoxyquin's toxicology.
Where no section number is listed, a minimum requirement has not been set
for such information.
The topical discussions describe available toxicity data on
technical ethoxyquin and its formulations and state whether they are
adequate for Agency regulatory purposes should application be made for
registration for a manufacturing use Ethoxyquin.
Acute Oral Toxicity (163.81-1)
The minimum testing needed on acute oral toxicity is one test, in the
laboratory rat, on the technical chemical and on each manufacturing-use
product.
No adequate data were available for adequately assessing the acute
oral toxicity of technical Ethoxyquin; testing is required. However, the
available data do indicate a low oral toxicity. A Russian report which
has insufficient details gives oral LD50's of 3150 mg/kg for rats and
3000 mg/kg for mice (Kellman, G.Y., 1965, MRIDq 05000684). The acute
oral LD50 for chickens has been reported to be 8-10 gm/kg, suggesting a
low acute oral toxicity in chicks (Gassner, 1960; MRID# 05000517; and
Colorado Agricultural Research Foundation, 1951; MRID# 00001917).
33
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Acute Derma] Toxicity (163.~1-2)
The MiniMuM testing neeoed on acute oernal toxicity is
ferably in the albino rabbit, on the technical chemical and
facturing-use product.
one test, pre-
on eacl1 manu-
No tests on technical ethoxyquin are available.
Acute Inhalation Toxicity (163.~1-J)
The Minimum oata requireMent for acute inhalation toxicity is one
test, preferably in the albino rat, on the technical chemical ann on each
manufacturing-use pronuct. TPerc ~7as one study using technical ethoy.yquin
(Scientific Associates, 1f)60, HRID #()0002202). Seven Males ann eight
feI!lale rats \-'ere exposed 6 hours to 15.54 Mg./liter (ca. 1750pPM.), then
observed for 14 days. Droplet size "as 1 to 6.75 Micron (c)O-92~~ 2-4u'. 110
ill effects uere observed. necropsies revealed no t:\acroscopic systemic
damage. This study fulfills the data requireMent.
Primary Eye Irritation (163.81-4)
The t:\iniMum testing needen to evaluate eye irritation potential is one
test, in albino rabbits, on each Manufacturing use product. If thp test
substance has a pH of 1-J or 12-14, however, it ui]l be .;uos;ed corrosive,
and an eye irritation test is not neened. If the test substance has been
judgeo to be dernally corrosive, an eye irritation test is not needed.
No data were available for assessing the priMary eye irritation of
technical Ethoxyquin.
Primary Dermal Irritation (16J.31-5)
The miniMuM testing neene(! to evaluate dermal irritation potential is
one test, preferably on the albino rabbit, on each Manufacturing use
product. No data uere available for assessing priMary dermal irritation
of technical ethoxyquin.
Skin Sensitization (16J.~1-6)
The mininuM requireMent for assessing skin sensitizntion is an
interdermRl test in one Mm~nalian species, preferal-,ly the guinea pig, on
each Manufacturing-use product. Skin sensitization ~ms studied by the
Method of Draize, Woodward and Calvery (MRID 105(0474). Ethoxyquin was
mixed with an equal aMount of ~7een 30 anc suspended in saline for
injection. No sensitization developed. This is an acceptable laboratory
sensitization test. Nevertheless, note human experience discussed in
the supplementary information section at the end of this Chapter.
~4
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Subchronic Testing
Subchronic Oral Toxicity (1#;3.82-1)
The minimum data requirement for subchronic oral toxicity is one test
for the technical formulation in two mammalian species, preferably using the
rat and dog.
Twelve studies relating to the subacute oral toxicity of ethoxyquin
were reviewed. They are listed on the following table.
Subacute Oral Dosin~ Studies Reviewed
Studies Authors Species ~ID Number
1. Panner and Packer rat 05000529
2. Ke lIman mouse & rat 05000684
3. Parke, Rahim and rat 05000411
Walker
4. Walker, Rahim and rat 05000440
Parke
5. Pa I' ke, Rahim and rat 05000450
Walker
6. Skaare, Nafstad and rat 05001835
Dahle
7. Takahashi and Hirago rat 05012507
8. Gordon and Machlin dog 00001932
9. Whanger, Wesig,
Old field, Cheeke and lamb 05000420
Schmitz
10. Colorado A & M Uni ver- chicken 00001919
sity
11. Poultry Producers of
Central California chicken 00001920
12. Gassner, Buss, Hopwood
and Thompson chicken 05000517
Seven studies assessed the effects of ethoxyquin on rats; one study
each tested the effects of ethoxyquin on dogs and lambs and three studies
assessed the effects of ethoxyquin on chickens. None of these reviewed
studies met the standards of the subacute oral toxicity testing. The
first study (Panner and Packer, MRID #05000529) examined the effect of
Flector H on hepatic alterations in both male and female rats fed 1.5 or
3.0% of the compounds for up to one month. The study showed that Flector
H is capable of causing gross as well as microscopic alterations in the
35
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li"ers of r:\ts. In3c1equ;1te informi1tion about the prepnration used O
-------
kidney, thyroid and testes were also normal. The eleventh report (Poultry
Producers of Central California MRID #00001920) also investigated the
toxicological effects of ethoxyquin (0.0075, 0.075 and 0.15% Santoflex in
diet) on leghorn cockerels starting from one day old. At the end of the
eight week period, there were no significant differences among the various
groups as to weight gain and feed consumption. Further, no gross patho-
logy of birds on eight week Santoflex treatment was noted. The last study
(Gassner, Buss, Hopwood and Thompson, MRID #05000517) reported that there
were no significant effects on growth and feed consumption of chicken fed
different amounts of ethoxyquin (0.00075, 0.0015, 0.003, 0.0075 and
0.075:) in diet for 12 weeks. Tissues of chicken showed neither gross nor
micropathologic changes. Because of ethoxyquin's low toxicity as indicated
by chronic oral toxicity data, and by years of experimental use experience,
additional testing is not required.
Subchronic Dermal Toxicity (163.R2-2)
The minimum data requirement for subchronic 21-day dermal toxicity is
one study for the technical chemical, preferably using the Albino rabbit.
One study (Wilson and DeEds, MRID #0500474) reviewed related
to subacute dermal toxicity testing. In this study both rabbits and
guinea pigs were used for the study of skin irritation. A single drop of
the oily undiluted ethoxyquin was rubbed over an area of skin 2 em. in
diameter, daily 5 days per week for 2 weeks. This treatn~nt produced a
slight erythema followed by a papular eruption and occasional scab forna-
tion. The study also revealed that when tre~tment was stopped, the
lesions disappeared, leaving a normal appearing skin after a few ~leeks.
This study lacks details of techniques used, no sexes or n~ber of animals
were mentioned and no control animals were compared.' The experiment did
not follow the requirement of 21-day (163.82-2) or 90-day (163.32-3)
periods.
Subacute dermal toxicity data conducted using experimental
protocols acceptable by the guidelines are not available for ethoxyquin.
The above study is only considered to be a preliminary study. However,
because of ethoxyquin's low toxicity as indicated by acute and chronic
oral testing in rats, further dermal testing is not required.
Chronic Testing
Chronic Feeding (163.83)
A chronic feeding study is normally required for all food uses in one
mammalian species (laboratory rat) using the technical product. The
study would normally be required for all food uses of ethoxyquin.
Data on a chronic feeding study would be required for the registra-
tion of each manufacturing-use product. Testing is usually required in at
least one mammalian species (the species is normally the laboratory rat).
37
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Equal numbers of males and females of each species and strain tested
must be used. Dosing of rats begins as soon as possible after weaning and
in any case before the animals are 6 weeks old.
Eight studies relating to chronic feeding testing of ethoxyquin
were reviewed. Four of these studies met the species requirement of
the Agency's Guidelines. Three studies which dealt with the chronic feed-
ing of ethoxyquin in dogs and chickens could be regarded as supportive
studies. The other article was a review of some of the individual
studies. They are summarized in the following table.
Studies
1
2
3.
4.
5.
6.
7.
8.
Authors
u.S. Agricultural
Research Service,
Western Utilization
Research Branch
Wilson and De Eds
Panner and Packer
Rudra, Dickerson and
Walker
Hanzal
Colorado A ~ M Uni.
Gassner, Buss,
Hopwood and Thompson
Pascal (review article)
Species
Duration
MRID Number
rats
715 days
00001923
rats 715 days
rats 2 years
rats 500 days
dogs 50-60 weeks
chicken 70 weeks
05000474
05000529
05000419
00001925
00001919
chicken
70 weeks
05000517
rats &
chicken
715 days
050001.12
The first study (U.S. Agricultural Research Service, Western
Utilization Research Branch, MRID #00001923) reported that 5 to 10 rats of
both sexes were fed different dose levels (0,0.0062, 0.0125, 0.025, 0.05,
0.1 and 0.2%) of ethoxyquin for 715 days. The study revealed that the
animals on all dose levels appeared comparable to control rats of the same
age. Mortality ~~as not extreme until after the 700th day when an infection
spread through the entire colony causing termination of the experiment.
The main histopathological findings were in the kidney at the 0.2% level
in females and 0.1-0.2% in male rats. The lesions ~Jere not more severe
than those seen in comparable animals autopsied after shorter feeding
periods (200 or 430 days). Proximal renal tube atrophy, renal tube
dilation, widening of collecting tubules, and patchy lymphocytic and
fibrous tissue infiltration were found. The main drawback of this study
was the small number of animals used for the testing.
38
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Wilson and De Eds (MRID #05000474) examined the chronic toxicity of
ethoxyquin (0.0062-0.2% in the diet) in 270 weanling albino rats for up to
715 days. This study indicated that ethoxyquin incorporated into the diet
exhibited a transient depression of growth rate of rats. Hemoglobin levels
remained normal. There was no altered urinary excretion of hemoglobin or
protein. Because of ethoxyquin metabolites, experimental urines were
darker, blackened with time. The life span of animals was not altered.
At autopsy. there appeared shallow pitting of the renal cortex in male
rats receiving the higher dose levels for 200 or more days.
Ambiguous increases in liver weights were observed in females. Increases
in kidney weights in females and liver and kidney weights in males were
observed. Microscopic examination revealed no lesions in females, but
lesions in kidneys, livers, and thyroids of males. The kidneys of males
showed irregular zones of fibrosis, tubular atrophy, focal tubular dila-
tion and lymphocytic infiltration characteristic of chronic pyeloneph-
ritis. There was a dose response in the occurrence of these lesions.
Groups of male hepatic cells showed rounded eosinophilic hyaline inclu-
sions of different sizes up to the diameter of the cell nuclei. The
thyroids of treated males showed decreases in stored colloid, vith diffuse
increase in height of the follicular epithelium, indicating mild hyper-
plasia. The no observable effect level (NOEL) was found to be 0.0062%.
Panner and Packer, MRID #05000529) reported the test of 35 male
and 35 female rats which were maintained for 2 years on the following
diets: control, 0.01% and 1.5% Flectol H. Only 3 males and 5 females
given the 1.5% diet in the 2 year study survived to sacrifice. The study
showed that ethoxyquin caused gross as well as microscopic alterations in
the livers of both male and female Wistar rats. The specific signs were
live~ enlargement, fatty infiltration, necrosis and atypical biliary duct
hyperplasia. These effects were most pronounced at a dietary level of
1.5%. The study lacks in the number of animals, dose selection and many
points of the guidelines. The Fourth study (Rudra, Dickerson and Walker,
MRID #05000419) reported the effect of ethoxyquin at 0.5% level on body
weight and kidney in weanling male Wistar rats for 500 days. The study
showed that ethoxyquin reduced weight increment and caused severe kidney
damage. This study is of limited value since many areas of guidelines
e.g. duration of testing, number of dose levels, both sexes of rats,
observations of animals, etc. are lacking. The fifth study (Hanzal, MRID
#00001925) reported that ethoxyquin produced substantial toxic effects in
the liver and kidney at dose rates of 10 to 100 mg/kg/day. The associated
stress of histoplasmosis (in one dog) appeared to enhance similar signs
of toxicity at the lower dose rate of 3 mg/kg/day. These data provide a
fair basis for speculating that the minimum effective dose of Ethoxyquin
lies in a range below the 3-10 mg/kg/day oral dose given over a period
of 50-60 weeks. However, a no-observed-effect-level was not found.
The sixth study (Colorado A & M University, MRID #00001919) reported the
effects of ethoxyquin (0,0.00075 and 0.075%) on chickens. No effect on
growth of the breeding flock was found during the 70 weeks study. The
seventh study (Gassner, Buss, Hopwood and Thompson, MRID #05000517) also
reported the effect of feeding ethoxyquin on chickens. In this study,
39
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O.O()075, 0.0075 anti O.075~: ethoxyquin uere used in the feeti for 70 ueeks.
The results concluded that ~lith ~raden levels up to 0.075~~ of ethoxyquin
in the ~iet showe~ no significant effects on mortality, growth, feed con-
sumption, livability, egg production, fertil ity of e~gs and 1'1atchability
of e~gs. Tissues of chickens sho~~d neither gross nor micro-patholo~y
which could he ascribeo to the treatment. The study revie~"ed in the
eighth article (Pascal, r'ffiID #050n.0412) has heen discussed in the pre-
vious studies n.,rilson Lind De £o.s, HRID if 0501)047/1 and Gassner, TIuss, Hop-
~lOOO and Thompson, HRID #0500(517). The no observable effect! evel of
0.0062% found in the DeEds eta ala study for the rat is accepted, and
satisfies this oata requireMent.
Oncogenicity (1~J.3J-2)
Only one stuny (Hilson anc De Eds, ;-.!RID 110500047/1) mentioneo the
presence of tumors in n report on chronic toxicity of ethoxyquin
(O.OOo2-0.2~~ in the diet) in rats fed up to 715 days. The study
stated that occasional tumors ,.,ere present in the 700-day animals.
The study does not indicate that ethoxyquin has oncogenic potential,
since tU!:1ors, particularily in this age group, <'Ire not unusual, and the
incidence of occurrence was without relationship to dose level.
Further testing is not required.
Reproduction Test~ng
Terato]ogy (163.~J-3)
No individual reports of tests satisfying the teratogenic guidelines
t7ere founn. He no have infornation relating to teratogenic potential,
t~ich includes reproc!uctive studies tn rats and the use for nany years of
ethoxyquin as an additive in animal feeds.
Because rats tend to resorh rather than ahort imperfect conceptus,
the resorption in rats fed ethoxyquin was stucHed (Te1forti, LR. et al ,
lQ62, ~RID# 0500042~). A single dose of 0.25 r,rams (ca. 50 mg/kg:) ~J;S
given after positive mating. ~~nty days aftpr positive mating, pregnant
rnts ""ere killed and young oel ivered by caes:"\rian section. There Here no
greater percent of absorption for the treated group than for the control
group. ~io gross malfornations uere reported.
~thoxyquin tlClS fed to rC1hhits (Isenstein, R.S.. 1 970, rrRID;~ ()SOOOJ~6)
in ~mounts up to four times the amount used as ~ feed additive (O.Ol~; c~.
J og/k1/day). Treatment started 10 days hefore hree~in~ ~nn continued
until 2 "eeks after pArturition. Therp Here no ahortions or gross
deformities noted.
40
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In addition, feed containing ethoxyquin added under FDA regulation
has been fed to livestock for many years. No reports of harmful effects
of any kind from such feeding have been found. Further testing for
teratogenicity is not required.
Reproduction (163.83-4)
The minimum data requirement for reproduction is testing in one mammal-
ian species, preferably the laboratory rat, using the technical formulation
and lasting for two generations.
Nine studies relating to reproductive testing of ethoxyquin were
available for review. Of the nine studies, one was a review article,
five were reports submitted to Monsanto, and three were articles from the
original literature. None of these studies met the requirements
individually for reproduction testing.
MRID n 00001919 is a study of the reproductive effects of ethoxyquin
on chickens. No effects on growth of the breeding flock were noted during
the study. No effects could be attributed to ethoxyquin treatment on any
of the parameters measured in this study (body weight, hatchability, etc.).
MRID # 0001915 is a review article w~ich considers work on the toxi-
city of ethoxyquin from 1951 to 1q54.
Another study (MRID Q0001933) was carried out with albino Sprague-
Dawley rats. Animals were fed diets slightly deficient in vitamin E in
which ethoxyquin was mixed to give the following dietary levels: 0,0.025
and 0.05%. Animal treatment groups consisted of from 8-19 animals each.
Feeding the experimental diet was begun at 60 days of age and feeding of
the ethoxyquin-mixture was continuous. Female rats were mated at 100 days
of age (Fa). After weaning, the females were bred two more times. In
addition, progeny from the first mating were placed on the ethoxyquin diet
for 100 days and mated at 100 days of age (F1). The number of litters and
average litter size was recorded for all matings. The results indicated
that diets containing ethoxyquin did not interfere with reproduction in
rats. Instead, the ethoxyquin increased reproductive efficiency. This
increase may have resulted because the diets were marginal in Vitamin E.
Initial treatment was at day 60 instead of day 40 and only two doses
(instead of three) were used. This study does not meet the guideline
requirements for a reproductive study.
A diet supplement study (MRID #00001934) in which ethoxyquin was fed
to Sprague-Dawley rats from 60 days of age onward at a dietary level of
0.1%. Two matings were monitored. The animals receiving the experimental
diets produced young and raised them successfully as did the controls. Off-
spring of animals receiving 0, 0.025 and 0.5% ethoxyquin in their diets
were studied. Insufficient details are given to make this a meaningful
report.
A study was carried out by the Wisconsin Alumni Research Foundation
(MRID #0001924) with white albino Sprague-Dawley rats. Females believed to
be pregnant from 1-10 days were grouped into 4-9 animals each and placed on
test diets containing 125, 375 and 1125 ppm ethoxyquin. The number of
young produced, the number of live young born, the number of animals liv-
41
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ing at 3 days, the number of animals weRned and the weanling weights ~~ere
recorded. In a second study young adult vir~in female rats were mated and
placed into six experimental groups of 4-9 animals per group. The same
diet regime as in experiment 1 was used. In addition to the parameters
recorded in experiment 1, gestation time also was recorded. There
appeared to be a reduction in the average number of young per litter in
the ethoxyquin treated group; however, it was not dose-related and in fact
the 125 and 325 ppm ethoxyquin-treated groups showed a greater reduction
in litter size than did the higher dose level. There was a reduction in
the number of live animals in experiment 2 at 1125 ppm ethoxyquin but this
did not agree ~~ith the comparable group in experiment 1. Furthermore the
high doses in experiments 1 and 2 did not agree. A possible explanation
may be related to the lack of control mating and marking of pregnancy in
the females in group 1. The numbers of animals that survived to weanling
were not different in any of the groups with the exception of the 1125 ppm
ethoxyquin treatment. The experimental protocol employed in this study
did not conform to established EPA guidelines.
A study published in the American Journal of Anatomy (110:29-36) (MRID
#05000428) dealt with fetal absorption in the rat as influenced by ethoxy-
quin. The data presented suggested that ethoxyquin offered some bene-
ficial effects on the resorption rate; however, alpha and gamma tocop-
herol as well as other antioxidants ~lere more effective. In this study
Walter Reed-Carworth Farm strain rats in their first generation were used.
They weighed approximately 200 g at the time of breeding. After positive
mating, the females were randomly distributed into experimental and con-
trol groups and the experimental groups were given Ethoxyquin orally or
it was placed into their diets. Twenty-two days after mating, the females
were killed and the young delivered by Caesarian section. A careful micro-
scopic survey was made for resorption sites and resorptions were charted
as to location in the respective regions of the horns and classified as to
degree of resorption. There were no adverse effects. This is not an
acceptable reproductive study as now required by EPA guidelines.
A study published in the American Journal of Vet. Research (31: 907-
909) (MRID #05000366) involved feeding ethoxyquin at levels up to four times
normal to rabbits during pregnancy. Male and female New Zealand white
rabbits were used, age unknown. Not all animals were virgins. Some of
the animals used in the first experiment were re-used in the second experi-
ment. The prior exposure of the animals to ethoxyquin if any, was not
indicated. Female rabbits received experimental feed from at least 10
days before breeding to at least two weeks after parturition. Male
rabbits received experimental feed for at least 10 days prior to breed-
ing. There were 11-20 rabbits per group. There were no absorptions or
physical defects noted. In the first experiment there were no differences
in average litter size, gestation period and percentage of mortality at or
following birth between experimental and controls. In the second experi-
ment there was greater neonatal mortalilty in the groups which had not
received ethoxyquin.
42
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Finally a reproductive study which was published in the Journal of
Agricultural and Food Chemistry (7:203-206) (MRID #05000474) deals with
Sprague-Dawley rats which were on a diet containing 0, 0.025, 0.05 and 0.1%
ethoxyquin. The animals were placed on their respective diets when 60 days
old and received the diets continuously thereafter. The rats were mated
when 100 days old, with four females and one male to a cage and rotation of
the males once a week. After this mating, the rats receiving 0.1%
ethoxyquin were discarded because this concentration seemed "unnecessarily
high". After all litters were weaned, the rats were re-mated and following
weaning of these litters, a third mating was initiated. In addition to the
above, offspring of animals receiving 0, 0.25 and 0.05% ethoxyquin diets
were saved from the first mating, continued on their respective diets and
mated when 100 days old for a second generation study. There were no
effects that could be related to ethoxyquin treatment.
Although the available studies do not individually meet current
guidelines for reproductive toxicity testing, collectively they
no harm to reproductive ability should be expected.
indicate
Mutagenicity
The Agency's mutagenicity testing requirements are being revised.
Only a single study relating to the mutagenic potential of ethoxyquin
was reviewed (Joner, P.E., 1977; MRID #05000385). TA 1535, 1537, 1538, 98
and 100 of Salmonella typhimurium were used. The tests were performed with
and without the addition of a PCB-induced microsomal mixed function
oxidase system (S-9) obtained from rat liver. The test system utilizing
the five strains of Salmonella, was run at 10, 100 and 1000 ug ethoxyquin
per plate. The compound was not mutagenic in the tests. One hundred and
1000 ug of ethoxyquin per plate were toxic especially to trains TA 1535 and
TA 100. Thus at high concentrations, ethoxyquin was toxic to the growth of
Salmonella but was not mutagenic. In addition to the above test (Ames),
other mutagenic testing may be required when guidelines have been
revised. No testing is requested at this time.
Metabolism (163.85-1)
The minimum data requirement for metabolism is a single dose using the
analytical pure grade of the active ingredient in the radioactively labeled
form.
A sn:dy was conducted in the rat and CO'" (Hilson, 1959; MRID #05(00475)
using C ethoxyquin. Although this study does not meet data
re~llirements for metabolism due to improper testin~ methocloJogy (animals
were exposed to diets containing ethoxyquin prior to the start of the
metabolism study and metabolite investigation was incomplete), it did show
that ethoxyquin tffiS excreted in the urine and feces (rats received a single
1.5 mg dose; cows received a single 155 mg dose). In addition, metabolites
43
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found in the urine were water soluble (althou~h individual metabolites
were not isolated) and there was some indication of transfer and excretion
in the milk of the cow.
Another study (Monsanto, 19??; MRID #00001935) was conducted using the
dog. This study did show that labelled ethoxyquin was excreted in the
urine (after collection for 24 hours) and 85% of the labeled ethoxyquin was
excreted as a metabolite, suspected to be sulfate or glucuronide conjugates
(the identification of the metabolites was incomplete). In addition,
another dog was given labeled ethoxyquin and sacrificed at 4 hours. The
liver and kidney were examined and labeled ethoxyquin was detected in these
tissues. Chromatography demonstrated that the primary metabolites were
glucuronides and sulfates.
Another study (TerMeu1in and Walker, 1977; MRID #050024Ql) was
conducted usin~ the laboratory rat. Chromatography showed that metabolites
(not identified) were present in the bile within 12 hours after the
administration of labeled ethoxyquin.
Skaare, J.U., and Nafstad , I. (1979, MRID #05012506) studied the
distribution of S,7-(14C) Ethoxyquin in male rats. Two rats were
sacrificed after oral intubation (104 mg./kg.-25Ou cu./kg.)at 0.5, 1, 2, 4,
8, 10, 12, 10, 20, 24, 48, and 144 hour intervals. Whole-body
autoradiographs were made, and radioactivity in livers was measured.
Radioactivity peaked in the liver between the first and fourth day(2-3~ of
dose). After 6 days, 0.2% remained. High radioactivity was reported to
have remained in the renal cortex after 6 days.
No attempt to identify the compounds retaining the radioactivity was
reported.
The above data is not sufficient to satisfy the data requirement as set
forth in the guidelines for metabolism. However the data do indicate
that ethoxyquin is metabolized to more polar compounds (conju~ates with
glucuronic acid or sulfate are the most likely metabolites) in the dog.
Such metabolites have been identified in both tissue and urine in the dog.
In addition, the rat also metabolizes ethoxyquin to more polar compounds,
but the identification of the metabolites has not been made.
Additional metabolism testing is not required at this time.
B. Toxicology - Emulsifiable Concentrate Ethoxyquin
1. Toxicology Profile
The acute oral toxicity of 70% EC ethoxyquin is low based upon
research by Younger, 1960, (?1RID #00001880). Acute dermal toxicity is
described as very low, according to a report by Scientific Associates,
1960, (MRID # 00001884). Acute inhalation testing showed no ill effects
in rats (MRID #GS-0003-3). Primary eye irr.itation is described as mild by
Younger, 1960, (MRID #000018flO). Ethoxyquin is described as a mild primal
dermal irritant by Younger, 1960, (MRID #00001880). Tests on dermal
sensitization of ethoxyquin from manufacturing exposures indicate mild, non-
persistant and unpredictable allergic dermatitis.
44
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Chapter 3 contains data tables for emulsifiable concentrate showing
which categories of test within the proposed guidelines are required for EC
ethoxyquin, along with the guideline citation, composition characteristic,
use pattern, whether or not the Agency has sufficient data to satisfy these
requirements, and, if so, the bibliographic citation containing this
information. The requirement for submission under FIFRA 3(c)2(B) and the
amount of time allowed for submission is also listed in these data charts.
2. Topical Discussions
For information concerning subchronic and chronic studies using E.C.
formulations refer to the Manufacturing-use Ethoxyquin section of this
chapter, as data on the Manufacturing-use product may be extrapolated
to end-use formulations for these data categories.
Topics
Acute Oral Toxicity
Acute Dermal Toxicity
Acute Inhalation Toxicity
Primary Eye Irritation
Primary Dermal Irritation
Skin Sensitization
Subchronic Dermal (21-Day)
Toxicity
Acute Testing
Acute Oral Toxicity (163.81-1)
The minimum testing needed on acute oral toxicity 1s one test in the
laboratory rat on each formulated E.C. product.
The acute oral toxicity of 70% E.C. Ethoxyquin (6 lb/gal.) in the
laboratory rat is 3.3 g/kg (C.I. 3.0 - 3.6 g/kg) using Santoquin
(61b./gal.) (Younger, 1960; MRID #00001880). Toxic symptoms included
diarrhea, lethargy, weight loss and collapse. No paralysis was noted.
Principal autopsy findings were inflammation of the gastric mucosa and
renal congestion upon microscopic examination. This information is
sufficient to satify the data requirements for acute oral toxicity for the
EC ethoxyquin and assign labelling Toxicity Category III, which corresponds
to a low acute oral toxicity.
Acute Dermal Toxicity (163.81-2)
The acute dermal ~D50 in rabbits is greater than 8 g/kg using EC
Santoquin (A. I. 70%) (Younger 1960; ~mID #00001884). Toxic symptoms were
45
-------
lethargy and temporary loss of appetite. This inforoation satisfies the
data requirement to assign labeling Cate~ory IV; very low Acute dermal
toxicity.
Acute Inhalation Toxicity (163.81-3)
A study using the emusifiab1e concentrate (Scientific Associates, 1960,
MRID #GS-0003-4) was reviewed. Seven male and eight female rats were
exposed for 6 hours to 0.120 mg./liter (ca. 24ppm) solutions. Droplet size
was less than 1 to 7 microns(90-95%-1.75-3.5u). All rats survived the
dosing and were observed for 14 days. There were no signs of ill effect.
Although the study had only one dose level, it is acceptable for current use
patterns.
Primary Eye Irritation (163.81-4)
A primary eye irritation study was conducted on rabbits (Younger 1960;
MRID #00001884). In the study 100 mg of EC Santoquin (A.I. 70%) was
applied to the rabbit eye resultin~ in mild eye irritation.
The above information is sufficient to satisfy the data requirement for
primary eye irritation and assign labeling Toxicity Category III,
corresponding to a mild eye irritation potential.
Primary Dermal Irritation (163.81-5)
A primary dermal irritation study was conducted on rabbits (Younger
1960; MRID #00001884). In the study an unspecified amount of EC Santoquin
(A.I. 70%) was applied to rabbit skin resulting in mild dermal irritation
at 24 hours and no irritation at 72 hours.
The above study is not sufficient to satisfy the rlata requirement for
primary dermal irritation due to lack of reportin~ of the amount of
substance applied. However, the data suggests that EC Santoquin (A.I. 70%)
is a mild skin irritant. Additional testing is not required.
Dermal Sensitization (163.81-6)
The minimum data requirement for rlermal sensitization is an intradermal
test for the manufacturing-use product and each registered product,
preferably using the guinea pig.
No laboratory data were availtb1e for assessing dermal sensitization of
EC Ethoxyquin, ho~~ever epidemiological information from manufacturing
exposure indicated mild, non-persistent and unpredictable allergic
dermatitis. Therefore, further testing is not required.
46
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3ubchronic TestinR
Subchronic 21-Day DernaJ Toxicity (lo1.~2-2)
The minimum requirement to assess subchronic 21-day de~al toxicity is
One study, prefe!"C\bly in the andling
"Anjou" pears. An estimated 20 to 90 sorter/wrappers (typically
"omen) per house handle the ~.JI"appers. t7rapping continues ~ hr./day rluring
an 1-2 nonth harvest season. Horkers llsually wcnr gloves but not otner
protective gear. Residues of ethoxyquin transferred to fruit from treated
paper wraps may be a source of slight dermal exposure during marketin~ nnd
consumption. If registrants can rlemonstrate that the n.:lterial lisen to
impregn.:lte ~~aps is substantially siMilar to the technical or m
-------
The fourth study in this series (Parke, 1974; MRID# 05000449) examined
the possibility that ethoxyquin inhibits mixed function oxidase enzymes.
These investigators using either a single administration of ethoxyquin or
repeated dietary exposure to ethoxyquin demonstrate that ethoxyquin
interferes with certain mixed function oxidase enzymes when administered
continuously in the diet.
The above information indicates that ethoxyquin is capable of
modulating hepatic mixed func.tion oxidase enzymes. In addition, there is
preliminary evidence that suggests prolongation of the life-span of "aging"
rats upon exposure to small levels of dietary ethoxyquin and continuous
administration results in enhancement of drug metabolizing enzymes in the
liver.
Topic 2: Potentiation
One study (Skaare, 1977; MRID#05001835) was reviewed. This study
examined the potentiation of dimethylnitrosamine toxicity after
administration of ethoxyquin in the laboratory rat. Principal findings
indicate that prior exposure to ethoxyquin either in the diet (500 ppm) or
as a very high acute dose (500 mg/kg, p.o.) increases hepatic necrosis and
accompanying sequelae due to subsequently administered dimethylnitrosamine.
Topic 3: Human Epidemiology (Demal Toxicity)
There ~re no requirements in the federal pesticide guidelines for
human epidemiological studies. Nonetheless, there are several reports in
the literature of various dermatological disorders probably related to
exposure to ethoxyquin. These h~an exposures and reactions have been
reported superficially. but should be noted. There are 10 reports of
human exposures to ethoxyquin in the workplace (mostly animal feeds)
which have resulted in skin disorders. They are:
Authors
File No.
Mehlhorn and Beetz
Koziak and Sesevicak
Schubert et al.
Zachariae - -
Burroughs
Jung
Garasek and Kolensky
Scott and Dawson
Ke 11 y
Fisher
05000401
05000394
05000543
05000444
05000669
05000186
05000384
05000421
GS-0003-3
05000618
All of these "studies" are essentially clinical reports of individuals
who developed dermatitis while working in a situation that would expose
them to ethoxyquin and perhaps other compounds. In some cases skin testing
(patch test) was done to document the allergic response (contact
48
-------
dermatitis) to ethoxyquin. In one study (File No. 421) ethoxyquin ~as used
as a "positive control" in a photo patch test study. All of the ethoxyquin
responses were negative. except for these photo patch tests.
In summary. these reports constitute a sizeable body of evidence ~hich
suggests that ethoxyquin can be responsible for a dermatitis. Transfer
of a worker to a site free from ethoxyquin "cured" some of these difficul-
ties.
All
studies and
Evidence of
of the data presented above represent an augnentation to other
supply additional data which may be valuable in the future.
h~an dermal reactions (probably allergic) should be noted.
49
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VII
RESIDUE CHEMISTRY
A. Residue Chemistry - Manufacturing-Use Ethoxyquin
1. Residue Chemistry Profile
Ethoxyquin is used to prevent scald in apples and pears during
storage. As an anti-oxidant it is also a food additive in animal-feeds (21
eFR 573.380), and in certain dehydrated forage crops (21 CFR 573.00), but
these uses are not being considered in this standard.
Ethoxyquin formulations are applied to apples and pears by spray pre-
harvest or as a dipping solution, post-harvest. Ethoxyquin is also
impregnated on paper wrappings to prevent scald, post-harvest.
Residues found in pears and apples are principally Ethoxyquin. There
are no data on the degradation of Ethoxyquin in treated apples and pears.
In feeds fortified with ethoxyquin, degradation products have been
reported but not identified.
International (Codex) tolerances of 3 ppm have been recommended for
residues of ethoxyquin in or on apples and pears. The United States has
indicated its acceptance of these Maximum Residue Limits (MRL) , which
are the same as the U.S. tolerances.
Whenever a pesticide is used on apples the Agency normally requires
data on whether residues in apple pomace, a feed item, are transferred
to meat, milk, poultry, and eggs; however, the Agency is not requiring
such data to support the use of ethoxyquin on apples.
Ethoxyquin is used (up to 150 ppm) in animal feeds (21 CFR 573.230)
and dehydrated forages (21 CFR 574.400). Tolerances for residues in eggs,
meat, milk and meat by products have been established to provide for such
feed additive uses (21 CFR 172.140). Assuming that the 3 ppm tolerance
in whole apples is not exceeded, the feeding of apple waste will not result
in over-tolerance residues in milk, eggs, meat, and meat by-products.
In addition, apples treated with ethoxyquin are likely destined for
the fresh market, and little or no production of p~wace is expected.
In studies with chickens using Ethoxyquin-2,4- C, 97% of the
radioactivity is recovered in fecal material. Degradation products in
feces, with similar Rf values as Ethoxyquin, were concluded to be
conjugates of Ethoxyquin.
The regulatory method for ethoxyquin in/on apples and pears
(PAM, Volume II) is a fluorometric method, modified from the original
method of Bickoff, et a1., (Anal. Chern. 23, 376 (1956), and is
adequate for enforc~e;t purposes, assuming that Ethoxyquin ~~
is the predominant residue. Residues in apples dipped in 3000 ppm
Ethoxyquin averaged 2.90 ppm. The pre-harvest spray at 3000 ppm of
Ethoxyquin resulted in no residues (method sensitivity not reported).
50
-------
Residues in pears dipped in 3000 ppt:! of Ethoxyquin showed 0.03 ppm 53
days after application.
Ethoxyquin residues were found in milk of cows fed 150 ppm Ethoxyquin
for 13 consecutive days. Ethoxyquin residues were found in calf, pig, and
lamb livers fed as little as 30 ppm Ethoxyquin for 10 days. The residues
consist mainly of Ethoxyquin, with less than 3% comprising the degradation
products and possible conjugates of Ethoxyquin.
2. Data Gaps (See Chapter 3)
The followin~ data are required to support a re~istration standard for
Ethoxyquin:
(1)
Data on the degradation of ethoxyquin in or on apples and pears
subjected to typical conmercial storage conditions are required.
No data are available.
If the required data identify degradation products considered
toxicologically significant, analytical methods for their deter-
mination will be required.
(2)
Additional residue data on the level of residues in or on ethoxyquin
treated apples and pears are required. Only a fraction of the
available data reflect maximum a1lo~Jab1e application rates.
3.
Topical Discussions
Use Patterns and Restrictions
Ethoxyquin is formulated as an emulsifiable concentrate (EC) containing
from 52.2h to 70% of the active ingredient. Formulations containing the
active ingredient Ethoxyquin, may be used as a spray pre-harvest on apples
and pears or as a dipping solution, post-harvest, with concentrations of
active ingredient Ethoxyquin, varying from 1.5 lb-2.25 lb/l00 gals. water.
The active ingredient is also used to impregnate fruit wrapping paper
at concentrations of 0.04% to 0.131%.
Use restrictions specify that:
(a)
Applications to specific varieties of apples and pears specified
on the labels are intended to prevent fruit injury to susceptible
species.
(b)
Spray treatment application should be made only when the daily maximum
o
temperature remains below 85 F, with one application within two days
before harvest.
(c)
fruit wrapped ~dth impregnated material should not have neen
previously treated with Ethoxyquin.
51
-------
Ethoxyquin is to he kept out of drinking \later or \Jatcr used for
domestic purposes, and not applied directly to lakes, streams, and ponds.
1. Metaholis~ in Plants
The data on ~etabolism and breakdo~m of Ethoxyquin is lioited. ;10
metabolites have been reportee. 14
Alfal fa meal ~las fortified \7ith C-Ethoxyquin and stored at roon
temperature for nine days. The l'Jeal was extracted Hith ether, and the
extract analyze~ by radiochroMatographic and fluoro~etric nethods.
Two oxidation products of Ethoxyquin were detected but \lCre not
othenlise identified (HRID ifOfiOOI90S).
A co~parison IR and UV spectra of "aged" Ethoxyquin, extracted from
feeds with "freshly distilled Ethoxyquin" indicated that there were no
Major degradative chanp,es. The degradative products were not identified
(~RID 1000019(6).
The liMited anount of information presentee gives no indication of
identity of "reaction protiucts" re!':\ainin~ follo\Jing "Dging" of Ethoxyquin.
There are no radiotracer studies of plant metabolisn with respect to uptake
and translocation of Ethoxyquin.
He conclude that r.1.etabolisr.1. of Ethoxyquin in plants is not adequately
defined.
2. Analytical ~1ethods
Until clarification of netabolic pathways and/or ~egracation of
Et~oxyquin residues in plants and anir.1.als has been presented, Ethoxyquin
remains the residue of concern.
The regulatory r.1.eth00 for ethoxyquin per se in PAM Volur.1.e II
and the method used to obtain data on residues of ethoxyquin in Dpples
and pears is a fluoror.1.etric r.1.et~od based on that of nickoff et al
(Anal. Chen. 2~, J71i (11)5/)). !1RIDff 0000I8~9).
J. P~sidues in Apples and Pears
The data of H~ID J!00001377 is pertinent to the registration standard
of Ethoxyquin but is an estir.1.ate and cannot be verified.
Five varieties of Rpples anc one variety of pears were treated as
follows with up to 3000 ppm of Ethoxyquin. Apples were sprayed 0-7 days
before harvest, sprayed 0-1 day post harvest, or ~ipped for 15 seconds into
a solution of Ethoxyquin. Pears were sprayed 5-7 days hefore harvest.
Fornulation used \JRS Stop-Scald-EC \lith 70~~ Ethoxyquin. Pre-harvest
treated apples and pears \lere analyzed 19-27 days after treatment, post-
harvest apples \rore analyzed 20-23 days after treat~ent; an~ dipped apples
4 days after treat~ent. Storage conditions for apples are unkno\m.
~axinur.1. residues resulted in apples dipped in lOOO ppn Etnoxyquin, in Hhicn
peels averaged 2.75 ppn; in the fruit 0.15 pp~. All otner sa~ples hRei
52
-------
corresponding residues. The pre-harvest spray (3000 ppm of
Ethoxyquin)resulted in no residues (method sensitivity not reported). The
possibility of volatilization or degradation to non-fluorescent products i5
suggested (MRID HOOOOI889).
Pears were treated with Ethoxyquin either by pre-harvest spray or post-
harvest dip. They were analyzed by the fluorometric method (MRID
#00001889), 2S to 63 days after treatment. Formulation used was Stop
Scald-EC with 70% active ingredient. The pears were treated with up to
2000 ppm of Ethoxyquin. Following post-harvest dip, the pears were
analyzed 53 days later, with maximum residues of 0.03 ppm in whole fruit
including peel. Following spray, samples analyzed 25-27 days after
treatment had maximum residues of 0.04 ppm; no residues Here detected 61-63
days after treatment. Data for blank samples or sensitivity of method were
not given. No information was given as to storage or storage stability of
Ethoxyquin (MRID #00001890).
Hartman and Crownoil paper wraps were impregnated with from 1 mg to
2.5 mg of Ethoxyquin. Anjou pears were wrapped with the impregnated paper
and stored for 8 months. Analysis showed that the Hartman wrap left no
Ethoxyquin residue on pears. Crownoil wraps left an average of 1.5 ppm on
pears. Data for blanks samples and sensitivity of method not given (MRID
#00002198). The data requirements are not satisfied by this study.
B. Residue Chemistry - Formulated Ethoxyquin
1. Registration Requirements
For future registration of a pesticide. product for use on a food or
feed crop not covered by this Standard, the A~ency must be provided with
data on metabolism of the pesticide in plants, and when appropriate, in
animals; a validated method for analysis of pesticide residues in or on raw
agricultural commodities, and residue data reflecting the proposed use of
the pesticide on the crop.
2. Required Labeling - Emulsifiable Concentrate
Labels on Emulsifiable Concentrate Ethoxyquin used for direct
application to fruit must contain a restriction against the use of
impregnated wraps at a later date.
Impre~nated Wraps
Wraps impregnated with Ethoxyquin intended for use on apples and pears
must bear a label restriction against application to fruit which has been
pre- or post-harvest dipped or sprayed with liquid formulations.
S3
-------
VIII
ECOLOGICAL EFFECTS
A. Ecological Effects Profile
Although no data are available on ethoxyquin toxicity to non-target
organisms, an assessment of potential hazard can be made by examining
information on use patterns. The use pattern profile indicates that
ethoxyquin is used as a post-harvest dip or spray on apples and pears,
and as a fruit wrap for use on apples and pears.
The use of wraps appears to present mimimal exposure to aquatic or
terrestrial habitat, therefore, wraps should not present an adverse
impact. The other uses, as well as the treatment of wraps, may expose
targets either directly from application or through dissipation from
treatment sites. Due to the absence of data on Ethoxyquin, a hazard
assessment on these uses cannot be made at this time.
The preharvest spray use is reportedly no longer practiced in the
orchard industry, but this use still appears on the label. If this use
is dropped from the label, the major route of exposure to non-target
organisms will be substantially reduced.
Based upon the status of ethoxyquin as a
Chapter 2) and the elimination of this major
the data requirements for Ecological Effects
non-
minor use pesticide (see
route of non-target exposure,
may be t.laived.
54
-------
GJide to Use of 'lhis BibliQ3raphy
1.
Content of BibliograF-hy. 'lhis bibliography contains citations of all
the stUdies revie\~d by lPA in arriving at the positions and conclusions
stated else\.here in this stanaard. 'lhe bibliography is divided into 3
sections: (1) citations that contributed infor.mation useful to the re-
view of the chemIcal and considered to be part of the data base supporting
registrat10ns 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
li terature.
2.
Units of Entry. The unit of entry in this bibliQ3raphy is called d
"stwy". In the case of published materials, this corresponds close.i.y to
an article. In the case of unpublished materials submItted to the Pgency,
the Pgency has sought to identify docunents at a level parallel to a
publlshed article fran within the typically larger volunE;;s in \Jhich they
were subnitted. 'lhe resulting "studies" generally have a distinct title
(or at least a single subject), can stand alone for pur~ses of review, and
can be described with a conventional bibliographic citation. '!he j.~ency
has attempted also to unite basic documents and commentaries upon them,
treating then as a single study.
3.
IdEntification of Entries. 'lhe entries in this bibliography are sorted
by authori date of the docunent, and title. EOch entry bears, to the left
of the citation proper, an eight-digit numeric identifier. '111is number 1S
unIque to the citations, and should be used at any time specitic reference
IS required. '1111S number is called the "r-k2ster lecord Identifiet:", or
1t-1RID". It is not related to the six-dig it II Pccession NUilber" \vhich has
I:x:en used to identify volunes 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 b8 preceded by a nine-character
temporary identifier. 'lhis is also to be used whenever a specific
reference is needed.
4. Form of the Entry. In addition to the Master I€cord Identifier (r-!RID),
each entry consIsts of a bibliographic citation containing standard elements
follo\~d, in the case of materials submitted to EPA, by a aescription of
the earliest krDwn subnission. '!he bibliographic conventions used reflect:
the standards of the imerican National Standards Institute (ANSI), expand.:d
to provIde for certaIn special needs. Same explanatory notes of specif1C
elements £0110\(:
a.
Author. hnenever the Agency could confidently identify one, the
~E:ncy has dlosen to show d personal author. ~hen no ind1vIdual was
identified, the Agency has sho\m an identifiable laboratory or
testing facility as author. As a last resort, the ~ency has shO\.n
the first Known submitter as author.
55
-------
b.
Document Date. W1en the date appears as four digits \vith no
questlOn marks, the Pgency took it directly iran the docunent. wnen a
tour-digit date is tollo\~ by a question mark, the bibliographer
deduced the date fran ~idence in the docunent. When the date appears
CIS (19??), the 1gency was unable to determine or estimate the date of
the docunent.
1'i tIe. 'Ihis is the third
it has been necessary for
docunent title. MY such
square brackets.
c.
d.
element in the citation. In sane cases
Pgency bibliographers to create or enhance a
editorial insertions are contained bet\.een
Trailing Parentheses. For studies submitted to us ln the past,
the tralllng parentheses include (in addition to any self-explanatory
text) the following elements describing the earliest knm.n submlSsion:
(1 )
Submission Date. Immediately following the \..ord 'received'
appears the date of the earliest krown subnission.
(2)
Administrative Number. 'Ihe next el~ment, mediately
follm~ing the word' under', is the registration nunber,
experimental permit number, petition nunber, or other
administrative number associated \iith the earliest known
submlssion.
(3 )
Submitter. 'lhe third element is the submit.ter, following the
the phrase 'subnitted by'. When authorship is defaulted to the
submitter, this element is anitted.
(4 )
Volume Identification. '!he final element in the traillng
parenthesis identifies the EPA accession number of the volune in
which the or ig inal submission of the study appears. '!he six-
digit accession number follows the symbol 'CDL', standing for
"COmpany r:ata Library". '1bis accession number is ln turn
followed by an alphabetic suffix wihich shows the relative
pJsition ot the study vJithin the vo1une. For example, \iithin
accession number 123456, the first stu:iy \..ould be 123456-A; th~
second, 123456-8; the 26th, l23456-Z; and the 27th, 123456-AA.
56
-------
HRID
005000423
005000368
005000461
005000669
000001917
000001919
005000368
005000474
005000497
005012189
Section I
OFFICE OF PESTICIDE PROGRAHS
REGISTRATION STAtIDARD BIBLIOGRAPHY
Citations Considered to be part of the Data Base
Supporting Registrations Under the Standard
CITATION
American Journal of Anatomy 110; 29-36.
American Journal of Veterinary Research 31; Q07-909.
Bickoff. E.H.; Guggolz, J.; Livingston, A.L.; Thompson, C.R.(l956)
Determination of 6-ethoxy-1.2-dihydro-2,2,4-trimethylquinoline
in biological materials.. Analytical Che~istry 28(3):376-37~.
Burroughs, D.; (1975) Contact dermatitis in animal feed mill
workers. British Journal of Dermatology 92:167-170.
Colorado Agriculture Research Foundation (1951) Project Pro~ress
Report: Investigations on the Toxicity of Carotene Stabilizing
Agents. (Unpublished study received Oct. 13, 11)58 unrler PP0315
prepared in cooperation with Colorado Agriculture Experi~ent
Station, Poultry and Chenistry Sections. submitted by Monsanto
Chemical Co.. St. Louis. }~.,: CDL:095541-9-S).
Colorado A&M University (1953?) Pro~ect 144: Experiment II and III
Chronic Toxicity of the antioxidant 6-ethoxy-2.2,4-trimethyl-
1.2-rlihydroquinoline (Santoquin. Monsanto). (Unpublished
study received Oct. 13. 1958 under PPO 315; prepared by
Agricultural Experinent Station, Poultry and Endocrine Sections,
submitted by }~nsanto Co.. St. Louis. Mo.; CDL:095541-Q-U).
Cielens, E.; Stroza. I.; Utno, L.; Vevere, L. (1974) Vliyanie
alpha-Tokoferola i antioksidantov na alimentarnyi stress u
tsypliat. [Effect of alpha-tocopherol and antioxidants on
alimentary stress in chickens.) Latvijas PSR Zinatnu
Akademijas Vestis. [Proceedings of the Academy of Sciences of
the Latvian SSR.J (11):54-60.
Draize. Hoodward and Calvery--See Hilson. R.H., DeEds. F. (1959)
below.
Dunkley, W.L.; Franke. A.A.; Low. E. (1968) Compounds in milk
accompa~ying feeding of ethoxyquin. Journal of Dairy Science
51(3):1215-1218.
Ernst, G.F.; Verveld-Roeder, 5.Y. (1979) High-performance liquid
chromatographic analysis of ethoxyquin in apples. Journal of
Chromatography 174(1):269-271.
-------
005000613
005000674
005000517
000011)32
000002198
000001920
nf)00019~5
05000366
00500385
05000474
005000386
Fisher, A.A. (1975) Allergic der~atitjs in animal feed handlers.
CUTIS 16(2):201-202.
FU.l iHara, K.; Hatanuki, S.; Arai, H., inventors; Seiko Chemical
Co., assignee (1973) (Production ~ethod for
6-ethoxy-2,2,4-trimethyl-1,2-rlihydroquinoline.] Japanese kokai
73 49774. Jul 13. 2 p.
Gassner, F.X.; Buss, E.G.; Hopwood, N.L.; Thompson, C.R. (1960)
Effect of Feeding 1,2-dihydro-6-ethoxy-2,2,4-tri~ethylquinoline
to chickens. Poultry Science 39: 524-533.
Gordon, R.S.; Hachlin, L.J. (l952?) Determination of Minimul'.1
Dietary Level of Santoquin which produces no more than 0.1 ppm
residue in dog and monkey liver: Ratio to Greatest Possible
Human Consumption of Santoquin and Calculation of Safety
Factors. (Unpublished study received Oct. 13., ]953 under
PP0315; subnitted by Monsanto Co., St. Louis, Mo.; CDL:095541-9-
AJ)'
Hadley, K.G. (19??) SumrnClry of Tests on Residues from Ethoxyquin
Treated Pear \Irap. (Unpublished study received Aug 2, 1965 un-
der 3222-6; submitted by Crown Zellerbach Corp., San Francisco,
Calif.; CDL:01074B-2-E)
Halloran, H.R. (1952) Chick Toxicity Test on Santo flex AW: Project
No.2-52. (Unpublished study including letter dated JulIO,
1952 from H.H. Armstrong to H.R. Halloran and letter dated Sep
10, 1952 from A.A. Klose to O. ~~y Thompson, received Oct 13,
1958 under P?0115; prepared by Poultry Producers of Central Cal-
ifornia, submitted by Monsanto Co., St. Louis, Mo.; CDL:
095541-9-V)
Hanza1, R.F. (1955) Final Report: Chronic Oral Administration
in Dogs: t-!etabo1ic Studies. (Unpublished study received Oct. 13,
1953 under PP0315; prepared by Hazeltol Laboratories, subMitted
by Monsanto Co., St. Louis, Ho.; CDL095541-9-AC).
Isenstein, R.S. (1970) Ethoxyquin in rabbit feed: study of
relationship to ~bortion and early neonatal death. AmericCln
Journal of Veterinary Research 31(5): ~07-909.
Joner, P.E. (1977) Hutylhydroxylanisol (BHA), hutylhydroxytoluene
(BHT) and ethoxyquin (EMQ) tested for nutagenicity. Acta
Veterinaria Scandinavica 18(2):1R7-93.
Journal of Food and Agricultural Chemistry-See Hilson, R.H., DeEds,
F., {J959) be1oH.
Jung, H.D. (1975) Berufsdermatosen in der Landwirtschaft des Agrar-
Industriebetriebezirkes Neubrandenburg. Professional dernatoses
in agriculture of the agricultural and industrial district of
Neuhrancenburg, East Ger~any. Deutsch Gesundheitswesen 10(11):
1540-1541.
-------
005000670
005000684
GS-0001-3
0500394
000001915
05000401
005000403
00000004X
00000I~S9
00001919
00001920
0000019~6
Kahl, R.; Netter, K.J. (IC)77) Ethoxyqllin as an inducer and
inhibitor of phenobarbital-type cytochrome P-450 in rat liver
microsomes. Toxicology and Applied Pharmacology 40(3):473-483.
Kellman, G.Y. (1965) Comparative Toxicity of Santoflex AW and
acetoaniline. Kauchuk i Rezina. Crude and Vulcanized Rubber
I: 24 n) : 40-41.
Kelly, R.E. (1965) Letter sent to Jack Early dated Oct. 1~, 1965.
(Relative to the dermatitis causing potential of Santoquin).
(In unpublished submission received Oct. 25, lC)65 under
524-Q; submitted by Monsanto Co., St. Louis, Mo.; CDL:I09275-A).
Koziak, B.; Sesevick, L. (1971) Kontaktny ekzem po krrnnvch
zmesiach pre hydinu. Eczema produced by contact uith poultry
feed mixtures. Praco"ni Lekarstvi. Occupational medicine.
23 (7) 240-244.
Maclay, ~".D., conp. (1954) Toxicity Data in Support of the Use of
0.015 Percent of 6-ethoxy-2,2,4-trimethyl-l,2-dihydroquinoline
on Alfalfa Heal for Carotene Preservation. Sunmary of studies
095541-C)-R through 095541-9-X. (Unpublished study received Oct
13, 1953 under PP0315; prepared by U.S. Agricultural Research
Service, Western Utilization Research Branch, Field Crop
Utilization Section, submitted by Monsanto Co., St. Louis, Mo.;
CDL:095541-9-Q)
~1elhorn, H.C.; Beetz, D. (1971) Das Antioxydans Aethothyquin als
berufliches Ekzematogen beim einen Futtermitteldosierer.
Antioxidant ethoxqyuin as an occupational eczematogenous agent
in a fodder-dosage distribution. Berufsdernatosen 19(2):84-91.
Honroy, H., inventor; (1973) nouvelles dihydro-l,2 quinoleines,
procede et appareil pour leur preparation. rApparatus and
nethod for manufacturing 1,2-dihydroquinolines.] French
demande de Brevet d'Invention 2,1~1,194. May 3. 20 p. Int.
CI.-2 C 07D 33/12; BOlD 1/06//A 01N.
~onsanto Co. (1975?) Product Specifications (Santoquin).
Unpublished submission by the PenntJal t Corporation received
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~onsanto Company (19??) Ethoxyquin on Apples and Pears. Undated
method. (Unpublished study recejved Feb 10, 1960 under PP0245;
CDL:092522-2-D)
~10nsanto Conpany-See Colorado AM! ITniversity (1953)
above.
Monsanto Company-See P~lloran, H. R., (1952) above.
Monsanto Company (19??) Lack of Residue il1 Pigs, Lambs, and Calves
Eating Santoquin Treated Forages. (Unpublished study received
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-------
000001935
000001905
000001906
000001377
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on5001765
05000529
050n0411
05000450
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05000412
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05000419
Monsanto Company (19??) The Metabolism of Santoquin C-14 by the
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-------
05000543
GS-0003-4
05000421
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000001930
00001933
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05000444
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Contact Dernatitis
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-------
MRID
005000458
005000565
005004172
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005000518
005000332
005013483
005000333
005012583
Section II
Examined
OFFICE OF PESTICIDE PROGRAMS
REGISTRATION STANDARD BIBLIOGRAPHY
and Judged to be Citations Inappropriate
in Developing t~e Standard
For Use
CITATION
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on the
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Crown Zellerbach Corporation (1966) Scald Control Data for Anjou
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Section III
Farm O1anical Handbook. (1979) l-Eister publishing.
~-il10l.grby .
Q1io.
The Federal Insecticide, Fungicide, and Rodenticide Act, as amended in 1978,
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5th ed., British Corp. Protection Council, oorcestershire, Ehg1and.
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tering Pesticides in the Lhited States; Hazard Evaluation: Humans and
Damestic Animals. Federal Register, 43(163) 37336.
u.s. Envirorrnental Protection !genc}' (1980); Eegulations for the EhtorCE::ffient ot
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u.S. Environmental Protection /genc}' (In press) PropJsed G..1idel1nes for Iegis-
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H (Label D:velopnent).
*1.1.8. GOVERNMENT PRINTING OFFICE: 1981 341-082/243 1-3
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Environmental Protection
Agency
Washington DC 20460
Official Business
Penalty for Private Use S300
Postage and
* Fees paid
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Protection
Agency
EPA 335
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