United States
Environmental Protection
Agency
Off in of
Pesticide* and Toxic Substances
Washington DC 20460
April 1982
SEPA
Hexachlorohexahydromethano-
2,4,3-benzodioxathiepin 3-oxide
(Endosulfan)
Pesticide Registration
Standard
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Endosulfan
Pesticide Registration Standard
Bruce Kapner
Charlotte Blalock
Linda Garczynski
George Ghali
Hoyt Jamerson
Steve Hopkins
George LaRocca
Robert Lenahan
Patricia Ott
Thomas Parshley
Tim Stanceu
Project Manager (SPRD)
Chemist (BED)
Writer/Editor (SPRD)
Toxicologist (HED)
Entomologist (BFSD)
Plant Physiologist (HED)
Product Manager (RD)
Economist (BFSD)
Environmental Chemist (HED)
Product Manager (RD)
Attorney A3 visor (SPRD)
March .1982
Office of Pesticides and Toxic Substances
Environmental Protection Agency
401 M Street, S.W.
Washington, D.C. 20460
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- TABLE OF CONTENTS -
Page
Chapter I How to Register Under a Registration Standard 1
Chapter II Regulatory Position and Rationale 8
Chapter III Summary of Data Requirements and Data Gaps 14
Chapter IV Product Chemistry 32
Chapter V Environmental Fate 38
Chapter VI Toxicology 43
Chapter VII Residue Chemistry 54
Chapter VIII Ecological Effects 68
Chapter DC Bibliography 75
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I. HOW TO REGISTER UNDER A REGISTRATION STANDARD
A. Organization of the Standard
B. Purpose of the Standard
C. Requirement to Reregister Under the Standard
D. "Product Specific" Data and "Generic" Data
E. Data Compensation Requirements under FIFRA 3(c)(l)(D)
F. Obtaining Data to Fill "Data Gaps"; FIFRA 3(c)(2)(B)
G. Amendments to the Standard
A. ORGANIZATION OF THE STANDARD
This first chapter explains the purpose of a registration standard and
summarizes the legal principles involved in registering or reregistering under
a standard. The second chapter involves the regulatory position and the
rationale supporting this position. The third chapter sets forth the data
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.
B. 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)(5) that:
"(A) its composition is such as to warrant the proposed claims for it;
(B) its labeling and other material required to be submitted comply
with the requirements of this Act;
(C) it will perform its intended function without unreasonable adverse
effects on the environment; and
(D) when used in accordance with widespread and commonly recognized
practice it will not generally cause unreasonable adverse effects
on the environment."
In making these findings, the Agency reviews a wide range of data which
registrants are required to submit, and assesses the risks and benefits
associated with the use of the proposed pesticide. However, the established
approach to making these findings has been found to be defective on two counts.
First, EPA and its predecessor agency, the United States Department of
Agriculture (USDA), routinely reviewed registration applications on a "product
by product" basis, evaluating each product-specific application somewhat
independently. In the review of products containing similar components, there
was little opportunity for a retrospective review of the full range of
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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 22, 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 reregister 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 reregistration 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)(l)(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(c )]. A pesticide is
classified for "restricted use" when some special regulatory restriction is
needed to ensure against unreasonable adverse effects to man or the
environment. Many such risks of unreasonable adverse effects can be lessened
if expressly-designed label precautions are strictly followed, Thus the special
regulatory restriction for a "restricted use" pesticide is usually a
requirement that it be applied only by, or under the supervision of, an
applicator who has been certified by the State or Federal government as being
competent to use the pesticide safely, responsibly, and in accordance with
label directions. A restricted-use pesticide can have other regulatory
restrictions [40 CFR 162.11(c)(5)] instead of, or in addition to, the certified
applicator requirement. These other regulatory restrictions may include such
actions as seasonal or regional limitations on use, or a requirement for the
monitoring of residue levels after use. A pesticide classified for "general
use," or not classified at all, is available for use by any individual who is
in compliance with State or local regulations. The registration standard
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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.
Co REQUIREMENT TO REREGISTER UNDER THE STANDARD
FIFRA Section 3(g), as amended in 1978, directs EPA to reregister all currently
registered products as expeditiously as1 possible. Congress also agreed that
reregistration 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
ooatmerce, must apply for reregistration. 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 reregistration set forth in the Guidance Package
which accompanies this standard.
Do "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 43 FR
29696, July 10, 1978? 43 FR 37336, August 22, 1978; and 45 FR 72948,
reoverrfoer 3,, 1980, as applied to the use patterns of the products to which this
standard applies. Where it appeared that data from a normally applicable
Guidelines requirement was actually unnecessary to evaluate these products, the
standard indicates that the requirement has been waived. On the other hand, in
SO7E8 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 standarel explains the Agency's reasoning. Data guidelines have not yet
been proposed for the Residue Chemistry discipline, but the requirements for
such data have been in effect for some time and are, the Agency believes,
relatively familiar to registrants. Data which we have found are needed to
evaluate the registrability of some products covered by the standard may not be
needed for the evaluation of other products, depending upon the composition,
formulation type,, and intended uses of the product in question. The standard
states which data requirements apply to which product categories. (See the
third chaptero) The various kinds of data normally required for registration
of a pesticide product can be divided into two basic groups:
lo Data that are product specific , i.e. data that relate only
to the properties or effects of a product with a particular
composition (or a group of products with closely similar
composition)? and
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2. Generic data that pertains to the properties or effects of a
particular ingredient, and thus are 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 reregistration of any product, whether it is a manufacturing-
use or end-use product, and without 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 erri-use products are 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 concern 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 ID-50 of the active ingredient in its technical or purer grade; see
proposed guidelines, 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
guidelines,43 FR 37363, which requires subchronic oral testing of the
active ingredient with respect to certain use patterns only). Where a
particular data requirement is use-pattern dependent, it will apply to each end-
use product which is to be labeled for that use pattern (except where such end-
use product is formulated from a registered manufacturing-use product
permitting such formulations) and to each manufacturing-use product with
labeling that allows it to be used to make end-use products with that use
pattern. Thus, for example, a subchronic oral dosing study is needed to
evaluate the safety of any manufacturing-use product that legally could be used
to make an end-use, food-crop pesticide. But if an end-use product's label
specified it was for use only in ways that involved no food/feed exposure and
no repeated human exposure, the subchronic oral dosing study would not be
required to evaluate the product's safety; and if a manufacturing-use product's
label states that the product is for use only in making end-use products not
involving food/feed use or repeated human exposure, that subchronic oral study
would not be relevant to the evaluation of the manufacturing-use product either.
If a registrant of a currently registered manufacturing-use or end-use product
wishes to avoid the costs of data compensation [under FIFRA Section 3(c)(l)(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
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use patterns from his labeling at the time he reregisters his product. An
applicant for registration of a new product under this standard may similarly
request approval for only certain use patterns.
E. DATA COMPENSATION REQUIREMENTS UNDER FIFRA ^(c)(1) (D)
Under FIFRA Section 3(c)(l)(D), an applicant for registration, reregistration,
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 are all data which are described by all of
the following criteria:
1. The data were first submitted to EPA (or to its predecessor
agencies, USDA or FDA), on or after January 1, 1970;
2. The data were submitted to EPA (or USDA or FDA) by some other
applicant or registrant in support of an application for an
experimental use permit, an amendment adding a new use to a
registration, or for registration, or to support or maintain
an existing registration;
3. They are the kind of data which are .relevant to the Agency's
decision to register or reregister the applicant's product
under the Registration Standard, taking into account the
applicant's product's composition and intended use pattern(s);
4. The Agency has found the data to be valid and usable in reaching
regulatory conclusions; and
5. 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
concerning the safety of an active ingredient of the applicant's
product, not to "product specific" data. The exemption is
available only to applicants whose product is labeled for end-
uses for which the active ingredient in question is present in
the applicant's product because of his use of another registered
product containing that active ingredient which he purchases from
another producer.
An applicant for reregistration of an already registered product under this
standard, or for registration of a new product under this standard, accordingly
must determine which of the data used by EPA in developing the standard must be
the subject of an offer to pay compensation, and must submit with his
application the appropriate statements evidencing his compliance with FIFRA
Section 3(c)(l)(D).
An applicant would never be required to offer to pay for "product specific"
data submitted by another firm. In many, if not in most cases, data which are
specific to another firm's product will not suffice to allow EPA to evaluate
the applicant's product, that is, will not be useful to the Agency in
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
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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 reregistration of a manufacturing-use
product, and each applicant for registration or reregistration of an end-use •>
product, who is not exempted by FIFRA Section 3(c)(2)(D), must comply with the
Section 3(c)(l)(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 reregistration (or new registration) under this standard is found in the
Guidance Package for this standard.
Fo 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 to fill the data gaps
identified by a section 3(c)(2)(B) order, his product's registration may be
suspended until the data are submitted. A mechanism is provided whereby two or
more registrants may agree to share in the costs of producing data for which
they are both responsible.
The standard lists, in the third 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
possess sufficient "product specific" data on one currently registered product,
but may lack such data on another. Only those standards which apply to a very
small number of currently registered products will attempt to state
definitively the "product specific" data gaps on a "product by product"
basis. (Although the standard will in some cases note which data that EPA does
possess would suffice to satisfy certain "product specific" data requirements
for a category of products with closely similar composition characteristics.)
As part of the process of reregistering 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 are "product specific" or "generic" — in accordance with a schedule.
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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).
G. 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-off8' date is stated at the beginning of the second chapter. Any
subsequent data submissions and any approved amendments will be incorporated
into the Registration Standard by means of addenda, which are available for
inspection at EPA in Washington, D.C., or copies of which may be requested from
the Agency, When all the present "tfata gaps" have been filled and the
submitted data have been reviewed, the Agency will revise the Registration
Standardo Thereafter? when the Agency determines that the internally
nraintained addenda have significantly altered the conditions for registration
under the standard, the document will be updated and re-issued.
Mhile 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 any one standard, the Agency has initiated
the evaluation of some inert pesticide ingredients. Where the Agency has
identified 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 AND RATIONALE
A, Introduction
B. Description of Chemical
C. Regulatory Position
D. Regulatory Rationale
E. Criteria for Registration Under the Standard
F. Acceptable Ranges and Limits
G. Required Labeling
H. Tolerance Reassessment
I. New and Amended Registrations Under this Standard
A. INTRODUCTION
(This chapter/presents the Agency's regulatory position and rationale based on
an evaluation of all registered products containing endosulfan as the sole
active ingredient. The regulatory position contained in the standard reflects
a review of this chemical and not of other active ingredients in a mixturetl
After briefly describing endosulfan, this chapter presents the regulatory
position and rationale, and the criteria for registration of products
containing this chemical. Also included in this chapter are labeling
considerations and the tolerance reassessment. A summary of data requirements
is contained in Chapter III. Data supporting this regulatory position are
discussed in each of the disciplinary chapters, IV through VIII.
B. DESCRIPTION OF CHEMICAL
Endosulfan is the common name for hexachlorohexahydromethano-2,4,3-
benzodioxathiepin 3-oxide. It is registered with the U.S. Environmental
Protection Agency as a broad spectrum insecticide/acaricide.
Endosulfan formulated products are marketed under various trades names such as
Beosit, Chlorthiepin, Cyclodan, Insectophene, Kop-Thicdan, Malix, Thifor,
Thimul, Thicdan, Thionex, and Tiovel. These products represent a wide range of
end-use formulations including dusts, wettable powders, granulars, emulsifiable
concentrates, pressurized liquids, and impregnated materials.
C. REGULATORY POSITION
The Agency has reviewed the scientific data obtained from the open literature
as of September 30, 1981, and the data submitted by the registrants up through
the time of the publication of this standard. Based on this review, the Agency
has made the following determinations:
o Pesticide products containing endosulfan as the sole active ingredient may
be registered, subject to the terms and conditions specified in this
standard.
o The risk criteria for hazardous effects on aquatic species may be exceeded
for the use of this active ingredient on watercress (40 CFR
162.11(a)(3)(i)(B)(3) and 40 CFR 162.11(a)(3)(ii)(B); however, more
information is required for this determination.
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o The use on alfalfa, blueberries, citrus (all), corn, cotton, lettuce, logs
(felled),, pecans, pineapples, soybeans, sugarcane, sunflower, tobacco,, art
tomatoes may also exceed the criterion for risk to endangered species
(40 CFR 162oll(a)(3)(ii)(B).
o The registrant must develop or agree to develop additional data, specified
in Chapter III, to maintain the existing registration or to obtain new
registrations.
o The tolerances for the registered uses on agricultural crops are support-
ed by the residue data submitted, except where noted in Chapter III.
D. REGULATORY RATIONALE
A review of the available data regarding the manufacturing-use and end-use
products of endosulfan shows that much of the information on toxicology and
environmental fate is invalid and not useful for registration. Although these
data requirements are still outstanding, the Agency has concluded that it
should continue the registration for this chemical for the following reasons.
The Pesticide Incidence Monitoring System (PIMS) found 91 reports of human
poisoning and ecological effects incidents related to the use of endosulfan.
Only one third were reports of endosulfan as the sole active ingredient. Some
of the reports concerned accidental poisonings due to improper methods of
application,, or accidents during the manufacture of the material. Many of the
reports were unsubstantiated. No regulatory changes based on these data will
be required.
The Agency has concluded that information is insufficient to determine whether
the direct application to water during the treatment of watercress poses the
risk of unreasonable effects on the aquatic environment. Submitted studies
demonstrate that endosulfan has a high level of toxicitiy to a wide variety of
aquatic species and use on watercress will theoretically result in residues at
the application site exceeding the LC5Q values for all aquatic species
tested. However, before determining whether a Refouttable Presumption Against
Registration (RPAR) has arisen with respect to risk to aquatic organisms, the
Agency must consider the actual or potential exposure of non-target aquatic
organisms to the residues resulting from the application of endosulfan to
watercress. To determine these exposure levels, the Agency must have
additional monitoring information from which it can assess the potential for
contamination of freshwater and estuarine environments by various pathways.
Should the required monitoring information demonstrate actual or potential
exposure to aquatic non-target or endangered species, the Agency will attempt
to resolve any factual issues through consultation with the registrants before
issuing a Notice of Rebuttable Presumption Against Registration (RPAR) for the
use of endosulfan on watercress.
Regarding the protection of all aquatic species, monitoring data will be
required on the levels of endosulfan in the aquatic environment resulting from
terrestrial applications.
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Regarding the protection of endangered species from the use of endosulfan, the
Agency prepared a request for a formal consultation with the Office of
Endangered Species, U.S. Fish and Wildlife Service, U.S. Department of the
Interior on February 4, 1982 (as required by Section 7 of the Endangered
Species Act of 1973, as amended). The sites of concern are alfalfa,
blueberries, citrus (all), corn, cotton, lettuce, logs (felled), pecans,
pineapples, soybeans, sugarcane, sunflower, tobacco, tomatoes, and watercress.
In accordance with FIFRA, the Agency's policy is not to cancel or to withhold
registration merely for the lack of data. (See sections 3(c)(2)(B) and 3(c)(7)
of FIFRA). Rather, publication of the standard provides a mechanism for
identifying data needs, and registration under the standard allows for
upgrading of labels during the period in which the required data are being
generated. When these data are received, they will be reviewed by the Agency.
The Agency will then determine whether these data will warrant further
regulatory action.
Eo CRITERIA FOR REGISTRATION UNDER THE STANDARD
To be subject to this standard, products must meet the following conditions:
o contain endosulfan as the sole active ingredient; and
o bear required labeling; and
o conform to the acute toxicity limits, product composition and use
pattern requirements stated in Section F, below.
An applicant for registration or reregistration of products subject to this
standard must comply with all terms and conditions described in this standard
including a commitment to fill data gaps on a time schedule specified by the
Agency and, when applicable, offering to pay compensation to the extent
required by 3(c)(l)(D) of the Federal Insecticide, Fungicide and Rcdenticide
Act (FIFRA), as amended, 7 U.S.C. 136a(c)(l)(D).
Fo ACCEPTABLE RANGES AND LIMITS
1. Manufacturing-Use Products
a» Product Composition Standard
To be eligible for registration/reregistration under this standard, technical
grade products must contain endosulfan as their sole active ingredient and such
products may contain endosulfan in the range of 94-96 percent active
ingredient. In addition, these products must not contain impurities other than
those in currently registered technical grade products and at no higher
concentration than those in currently registered products. Any technical
product not meeting these requirements will be considered to be a new product
ard will not be registerable under this standard.
For a manufacturing-use product other than a technical, a registered technical
must be used and it must be used to produce an acceptable end-use product. Any
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manufacturing-use product not meeting these requirements will be considered to
be a new product and will not be registerable under this standard.
Manufacturing-use products meeting these requirements may contain any
percentage active ingredientup to 96 percent.
b. Acute Toxicity Limits
The Agency will consider registration of manufacturing-use products containing
endosulfan regardless of the toxicity category, provided that the labeling of
such products bears appropriate precautionary statements.
c. Use Patterns and Application
To be registered under this standard, manufacturing-use products containing
endosulfan must be labeled to allow for formulation of insecticide/acaracide
products approved by the Agency in one or more of the following use categories:
-Domestic outdoor use
-Greenhouse use
-Tree fruit and nut crops
-Field and vegetable crops
-Aquatic food use (watercress)
-Forestry use
2. End-Use Products
a» Product Composition Standard
Erd-use formulations may contain up to the following percent active ingredient:
dust - 5 percent; granular - 3 percent; wettable powder - 50 percent;
emulsifiable concentrate - 34 percent; pressurized liquid - 10 percent; and
impregnated material - 15 percent. For formulations intended for food-use, all
the inerts must be cleared under 40 CFR 180.1001. The appropriate
certification of limits must be provided and the application rates per acre
basis must remain the same or less.
b.. Acute Toxicity Limits
The Agency will consider for registration end-use products in Toxicity Category
II„ III, and IV. This consideration, is predicated upon label incorporations
of appropriate hazard warnings, as well as precautionary and use restrictions
as required. There are no currently registered end-use products in Toxicity
Category I. Any products submitted for registration in this category would
require supporting data, and would not be registerable under this standard.
Co Use Patterns
To be considered under this standard, end-use products must bear directions for
uses as an insecticide/acaracide, which are intended for ground and/or aerial
applications to one or more of the following use categories:
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-Domestic outdoor use
-Greenhouse use
-Tree fruit and nut crops
-Field and vegetable crops
-Aquatic food use (watercress)
-Forestry use
G. REQUIRED LABELING
All manufacturing-use and end-use endosulfan products must bear appropriate
labeling as specified in 40 CFR 162.10. The guidance package which accompanies
this standard contains specific information regarding labeling requirements.
1. Manufacturing-Use Products
a. Use Pattern Statements
All manufacturing-use products containing endosulfan must list on the label a
statement which provides that the product may be used only in the formulation
of insecticide/acaracide products approved by the Agency for one or more of the
following use categories:
-Domestic outdoor use
-Greenhouse use
-Tree fruit and nut crops
-Field and vegetable crops
-Aquatic food use (watercress)
-Forestry use
b. Precautionary Statements
Because of the absence of data needed to assess the environmental and health
hazards of endosulfan, the Agency cannot evaJuate the adequacy of precautionary
statements on manufacturing-use product labels. Therefore, no changes to
current label statements are required at this time. The Agency may, after
review of all data to be submitted under this standard, require revisions to
current labels and may also impose additional label requirements.
2. End-Use Products
a. Use Pattern Statements
Additional labeling restrictions may be required to protect endangered
species. The possible necessity for this labeling can be determined only after
completion of the formal consultation with the Office of Endangered Species.
b. Precautionary Statements
Because of the absence of data needed to assess the environmental and health
hazards of endosulfan, the Agency cannot evaluate the adequacy of precautionary
statements on end-use product labels. Therefore, no changes to current label
12
-------
statements are required at this time. The Agency may, after review of all data
to be submitted under this standard, require revisions to current labels and
may also impose additional label requirements.
H. TOLERANCE REASSESSMENT
A listing of the tolerances for residues of endosulfan in or on raw
agricultural commodities in the United States as stated in 40 CFR 180.182 is
found in Chapter VII. A list of the CODEX tolerances is also found in Chapter
VII.
The toxicology tests on endosulfan demonstrate that the chemical may induce
adverse effects, especially liver and kidney effects, and testicular atrophy.
However, the no observable effect level (NOEL) has not yet been established,
nor has the reversibility of these effects been demonstrated adequately.
Sufficient information does exist to utilize 30 ppm as a provisional NOEL, and
because sufficient data exist to suggest the the NOEL, once firmly established,
will not be significantly below the 30 ppm level, a 100X safety factor can be
utilized.
A 30 ppm NOEL equates to a 0.75 ngAg/day NOEL for humans, yielding an
acceptable daily intake (ADI) of 0.0075 mg/kg/day (the maximum permissable
intake or MPI is 0.45 ing/day for a 60 kg person). The existing food tolerances
yield a theoretical maximum residue contribution (TMRC) of 0.6314 mgper day,
which is 140 percent of the MPI as calculated from the provisional NOEL.
Therefore, it is necessary to require the data to establish the NOEL and also,
to re-examine existing tolerance levels to determine if they are truly
representative of the actually occuring residues on foods.
A final reassessment of all endosulfan tolerances cannot be made at this time
since there are several registration/tolerance data requirements which have not
been satisfied. Until these gaps are filled, the Agency is unable to estimate
the contribution of the by-products apple pomace, grape pomace, tomatoe pomace,
and pineapple bran to residues in meat and milk.
13
-------
III. SUMMARY OF DATA REQUIREMENTS AND DATA GAPS
rvpoiieants for registration of manufacturing-use and end-use erdosulfan
products must cite or submit the information identified in the tables in this
chapter. The tables applicable to end-use products indicate whether the
product to be tested is the technical grade or formulation. Data generated on
one formulation may be used to satisfy the data requirement for a substantially
similar formulation,, Information on which product specific data requirements
are already met is available in the guidance package.
throve »?ach requirement is listed the section of the Proposed Guidelines which
ds-surabe.s the type of data and when the data are required to be submitted (43
Mi, 2'i-696 of July 10, 19781 43 FR, 37336 of August 22, 1978; and 45 FR, 72948
ot Nbvaitoer, 3, 1980),, Justification for the test requirement is provided in
the Guidelines,, A discussion of why data additional to those already submitted
are necessary, or why data normally required are not necessary for this
chemical, are explained in footnotes to the tables. Ttie data requirements
specified are the minimum that will be required. Areas where additional data
may be required as the result of tiered testing are ind icated.
14
-------
DflfTA REQUIREMENTS CHART A
ENDOSULFAN
Generic Data Requirements: ENVIRONMENTAL PATE
Guidelines
Citation
163.62-7(b)
163.62-7(c)
163.62-8(b)
163.62-8(c)
163.62-8(d)
163.62-8(e)
163.62-8(f)
Name of Test When Required!/
Hydrolysis A,
Photodegradation C,
Aerobic Soil Metabolism A,
Anaerobic Soil Metabolism
Anaerobic Aquatic Metabolism
Aerobic Aquatic Metabolism
Microbiological
B,C,D,E,F
D,E,F
B,C,D,F
D
E,F
E
Composition
y
y
y
y
y
y
Does EPA have data Bibliographic
to partially or Citation
totally satisfy
this requirement?
Partially
Partially
Partially
Partially
No
No
05012725, 05003007 .
05005315
05002841
05005047
05005047
05003471, 05005315 •
Must additional dat
be submitted under
FIFRA 3(c)(2)(B)?
If so, due when?
Yes/8 months!/
Yes/8 months!/
Yes/26 months5-/
Yes/26 months5-/
Yes/26 months6-/
Yes/26 months
ReservedZ/
163-62-8(g) Activated Sludge
163.62-9(b) Leaching C,D
163.62-9(c) Volatility B
163.62-9(d) Adsorption/Desorption A,B,C,D,E,F
y
No
Technical Grade of Partially
Active Ingredient
05003007, 05012725
05013674, 05017001
05004262, 05004617
05010061
05013707, 05019845
05002841
y
No
Reserved!/
Yes/14 months
Yes/14 months!/
Yes/14 months
These data requirenents are based on the draft registration guidelines published on July 10, 1978 (43 FR 29696). These testing requirements
are based on proposed guidelines. Registrants are advised to consult with the Agency prior to initiating these tests.
I/ This column specifies the use sites for which the data are required using the following codes: A= Domestic outdoor; B= Greenhouse; C= Tree
Truit and nut crop; D= Field and vegetable crop; E= Aquatic food use (watercress); F= Forestry use.
2/ Radiolateled analytical grade or nonradiolabeled technical grade material.
"?/ These studies were done primarily to study the microbial degradation of endosulfan. The hydrolysis properties were not fully
detailed.
4/ The analysis for photolysis products was only conducted once. Therefore, no conclusion can be drawn on the rate of endosulfan degradation.
V Data are insufficient to determine the rate of metabolism in soil. Data are needed using sampling intervals that are adequate
to determine the half-life of endosulfan and the rate of formation and decline of the endosulfan metabolites.
6/ This study may substitute for the anaerobic soil metabolism study (163.62-8(c)), but the reverse is not true.
7/ The requirement for the submission of these data is reserved, pending the review and modification of the testing protocols.
5/ Full analytical procedural details were missing, but the studies did provide information for estimating expected back-
ground levels of endosulfan in agricultural areas.
March 1982
-------
ENVIRONMENTAL FATE CONTINUED
Guidelines Nans of Test
Citation
163 o 62-9 «e) Water Dispersal
163.62-10 (b) Terrestrial Field
Dissipation
163. 62- 10 (c) Aquatic Field Disspiaticn
163. 62-10 (d) Dissipation-Forestry
163.62-10(e) Aquatic Impact Uses
163.6J2-10(g) Long Term Field
Dissipation
163.62-ll(c) Accuirulation in
Irrigated Crops
163. 62- 11 (d) Fish Accumulation
163.62-13 Disposal & Storage
When Required^
E
A8C,D,E,iF
E,F
P
E
A,C,D,E,F
E
C,D,E,F
Conpoaition Does EPA nave data Bibliographic
to partially or Citation
totally satisfy
this requirement?
A Representive
Formulation
A Representative
Formulation
A Representative
Formulation
A Representative
Formulation
A Representative
Formulation
1'
5/
No
Partially 00003800, 05003336
No
NO
No
-
No
Yes 05005824, 05003053
Must additional data
be submitted under
FIFRA 3{c)(2)(B)?
If so, due when?
Yes/14 months
Yes/14 months^
Yes/14 months
Yes/14 months
Yes/14 months
Reserved^
Yes/14 months
No
Reserved—
These data requirements are oa sea on the draft registration guidelines published on July 10, 1978 (43 FR 29696). These testing requirements
are based on proposed quidelines. Registrants are advised to consult with the Agency prior to initiating these' tests.
I/ This column specifies the use sites for which the data are required using the following codes: A=« Domestic outdoor; B= Greenhouse; O Tree
fruit and nut crop; D= Field and vegetable crop; E= Aquatic food use (watercress); F= Forestry use.
2/ Additional studies are needed to fulfill the requirements in this section in order to determine the terrestrial dissipation
rate. The Agency will need to see the proposed protocols for and results of specific runoff monitoring studies. Formulations
to ba tested must be specified and the ecological appropriateness of the study plots must be assessed by the Agency prior to
approval of the protocols.
3/ The requirement for this test depends on results of 163.62-8(b), 163.62-11, 163.62-10fb)(l), and 163.62-ll(d).
T/ Radiolabeled analytical grade, if residues are found, then a field test using a representative formulation product.
5/ Radiolabeled analytical grade or nonradiolabeled technical grade material.
?/ The requirement for the submission of these data is reserved, pending the review and modification of testing protocols.
March 1982
-------
DMA REQUIREMENTS CHART A
ENDOSULFAN
Generic Data Requirements: TOXICOLOGY
Guidelines Nane of Test When Required-'
Citation
163.81-1
163.81-2
163.81-3
163.81-4
163.81-5
163.81-6
163.81-7
163.82-1
163.82-2
Acute Oral Toxicity A,B,C,D,E,F
Acute Denial Toxicity A,B,C,D,E,F
Acute Inhalation Toxicity A,B,C,D,E,F
Primary Eye Irritation A,B,C,D,E,F
Primary Dermal Irritation A,B,C,D,E,F
Dermal Sensitization A,B,C,D,E,F
Acute Delayed Neurotoxicity A,B,C,D,E,F
Subchronic Oral Toxicity A,B,C,D,E,F
21-Day Subchronic Dermal A,B,C,D,E,F
Toxicity
Composition Does EPA have data Bibliographic
to partially or Citation
totally satisfy
this requirement?
Technical Grade of
Active Ingredient
Technical Grade of
Active Ingredient
Technical Grade of
Active Ingredient
Technical Grade of
Active Ingredient
Technical Grade of
• Active Ingredient
Technical Grade of
Active Ingredient
Technical Grade of
Active Ingredient
Technical Grade of
Active Ingredient
Technical Grade of
Active Ingredient
Yes 00003762, 00003693
GS014007, 05002183
GSO 14001, 05003703
Yes. 05003718
Yes 05007645, G5014005
Yes GSO 14004
Yes GS014003
No
Partially 05011227, 05007646
05004972
No
No
Must additional data
be submitted under
FIFRA 3(c)(2MB)7
If so, due when?
No
No
No
No
No
Yes/8 months
Yes/14 months^
Yes/14 months
Yes/14 months
These tables reflect the toxicological questions we have about enoosultan and, by reference to the guidelines, possible ways these
questions may be answered. The guidelines represent one way these questions may be answered but certainly not the only way. This
pesticide is unusual in that there is a mass of toxicological data available. While many of the individual toxicological studies
considered in this standard are not adequate to fill specific data gaps, in there entirety these studies do contain some toxicological
information. Some of the remaining toxicology questions may be resolved by more simple thus less expensive toxicology studies if used
in conjunction with the toxicology data discussed in this docunent.
I/ This column specifies the use sites for which the data are required using the following codes: A° Domestic outdoor; B= Greenhouse?
C= Tree fruit and nut crop? D= Field and vsgstable crop; E= Aquatic food use (watercress); F= Forestry usso
2/ Endosulfan does not relate to a kncsa
-------
TOXICOLOGY CONTINUED
CO
Guidelines
Citation
163.82-4
163.82-5
163.83-1
163.83-2
163.83-3
163.83-4
163.84-2
through -4
Mane of Test When Required^/ Conposition Does EPA have data Bibliographic Must additional data
to partially or Citation be submitted under
totally satisfy FIFRA 3(c)(2)(B)?
this requirement? If so, due when?
Subchronic Inhalation A,B,C,D,E,P
Toxicity
Subchronic Neuro-
toxicity
Chronic Feeding C,D,E
Oncogenicity C,D,E
Teratogenicity A,C,D,E
Reproduction A,C,D,E
Mutagenicity A,C,D,E
Technical Grade of No
Active Ingredient
— —
Technical Grade of Partially
Active Ingredient
Technical Grade of Partially
Active Ingredient
Technical Grade of Yes
Active Ingredient
Technical Gmde of No
Active Ingredient'
Technical Grade of Partially
Active Ingredient
Yea/14 months
2/
Reserved^
00003604, 00003741 ' Yes/50 months^
00003602
00004256, 05010016 Yes/50 months^
GS014008, GSO 14023 No
Yes/38 months
00003711, GSO 14009 Yes/26 months^
Thsse tables reflect the toxicological questions we have about endosulfan and, by reference to the guidelines, possible ways these
questions may be answered. The guidelines represent one way these questions may be answered but certainly not the only way. This
pesticide is unusual in that there is a mass of toxicological date available. While many of the individual toxicological studies
considered in this standard are not adequate to fill specific data gaps, in there entirety these studies do contain some toxicological
information. Some of the remaining toxicology questions may be resolved by more simple thus less expensive toxicology studies if used
in conjunction with the toxicology data discussed in this document.
\J This column specifies the use sites for which the data are required using
the following codes: A= Domestic outdoors; B= Greenhouse;
C= Tree fruit and nut crop; D= Field and vegetable crop; E> Aquatic food use (watercress); F= Forestry use.
_2/ The decision of whether testing is required cannot be made until the results of the acute delayed neurotoxicity testing are
submitted and reviewed.
3/ Because of the inadequacies in the submitted rat study, an additional study will need to be conducted on the rat.
T/ The studies submitted were inconclusive due to improper testing protocols. Further oncogenic testing is required using both
the rat and mouse.
J>/ The Agency requires a battery of valid mutagenicity tests which demonstrate the potency of the chemical to induce point
and chrofTosomal mutations, either directly or indirectly. After the results of the testing have been considered, additional
testing may be required to further characterize or quantify the potential genetic risks. Although the Agency's mutagenic testing
requirements are not final, the standards for these tests should be based on the principles set forth in 43 FR 37388. Protocols
and choices of test systems should be accompanied by a scientific rationale. Substitutions of.test systems will be considered
after discussion with the Agency. As the submitted studies indicated a negative dominant lethal response and no mutagenic
potential in bacteria, the Agency will consider these requirements fulfilled.
March 1982
-------
TOCICDI£G? CONTINUED
Guidelines Hams of Test
Citation
When Requirecli Ccnpositicn
Doss EPA have data
to partially or
totally satisfy
this requirement?
Bibliographic
Citation
Must additional data
ba submitted under
FIFRA 3(c){2)(B)?
If so, due when?
163.85-1
Metabolism
(Identification
of Metabolites)
C,D,E
Radiolabeled
Analytically Pure
Grade of Active
Ingredient
163.86-1 Domestic Animal Safety A,B,C,D,E,F
Special Studies:•
Emergency Treatment
A,D,C,D,E,F
Yes
Yes
No
05003703, 00004257
00003761, 05007464
05003503
00003603
No
Yes/14 months
These tables reflect the toxicological questions we have about endosulfan and, by reference to the guidelines, possible ways these
questions may be answered. The guidelines represent one way these questions may be answered but certainly not the only way. This
pesticide is unusual in that there is a mass of toxicological data available. While many of the individual toxicological studies
considered in this standard are not adequate to fill specific data gaps, in there entirety these studies do contain some toxicological
information. Some of the remaining toxicology questions may be resolved by mare simple thus less expensive toxicology studies if used
in conjunction with the toxicology data discussed in this document.
I/ This colum specifies the use sites for which the data are required using the following codes: ff Domestic outdoors; B= Greenhouse;
C"« Tree fru^t and nut crop; D= Field and vegetable crop; E- ftquetic food use (watercress); F» Forestry use.
March 1982
-------
DATA REQUIRIMENTS CHART A
ENDOSULFAN
Generic Data Requirements: RESIDUE CHEMISTRY
Name ot Test
Metabolism in
Plants
Metabolism in
Animals
Analytical
Methods
Composition Does EPA nave data
to Partially or
Totally Satisfy
this Requirement?
Radiolabeled Yea
Active Ingredient
Radiolabeled Yes
Active Ingredient
Technical Grade Yes
of Active Ingredient
00003600,
05018169,
05002565,
05003336,
00003838,
05003222,
00003795,
00003840,
Bibliographic Must additional Data be
Citation Submitted under FIFRA
3(c)(2)(B)? If so, when?
00003642,
05004385,
05003004,
05003085
05003877,
00003742,
00003959,
05003395,
00003654
05004620
05003801
00003743
00003840
00003703
GS014024
NO
No
No
Residue Data: Crops
Alfalfa (fresh) Technical Grade of Yes
Active Ingredient
Alfalfa hay " Yes
Almonds
Alrrond hulls
Apples
Apricots
Artichokes
Beans
Blueberries
Brocolli
Brussels sprouts
Cabbage
Carrots
Cauliflower
Celery
Cherries
Col lards
Cottonseed
Cucuirbers
Eggplants
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
No
Filberts Yes
•00003834,
00003835,
00003834,
00003835,
00004254,
00004254,
00003789,
00003587,
00003725,
00003836, 00004258
00003841
00003836, 00004258
00003841
00003612
00003713, 00003612
00003787
00003784
-
00003796
00003788, 00003843
00003796
00003796
00003790
00003796
00003796
00003796
00003782
00003796
00003726, 00003777
-
00004254
Yes/26 months^
No
No
No -,
Yes/26 months^
No ,.
Yes/26 months^
No
N°4/
No-L'
No
No
No
No ,,
Yes/26 months^
Yes/26 months^'
No
No -,
Yes/26 months^
Yes/26 nonths-
No
2/ Residue data on apple potnace is necessary to determine if endosulfan concentrates in pomace used as animal feed.
7/ There are no available adequate residue data for total endosulfan on artichokes at the time of-harvest, i.e. 7 days
after last application. Residue data by an adequate analytical method capable of determining residues of endosulfan sulfate
are required.
4/ There is no available adequate residue data on brooolli, however, the estimation of residues may be based upon
data available for another similar crop, such as brussels sprouts and cauliflower.
5/ Residue data at four day treatment to harvest interval is required.
7[/ Residue data for the enulsifiable concentrate formulation is required.
_7/ There are no available adequate residue data using an. adequate analytical method capable of determining total endosulfan
residues. None of the methods submitted have been shown to be adequate for the analysis of endosulfan sulfate, and these
residue data are not adequate to support the established tolerance, therefore residue data by an analytical method capable
of determining residues of endosulfan sulfate are required.
March 1982
-------
RESIDUE CHEMISTRY CONTINUED
Name of Test Composition Does EPA have data
to Partially or
Totally Satisfy
this Requirement?
Grapes Technical Grade of
Active Ingredient
Kale °
Lettuce "
Macadamia Nuts "
Melons . °
Mustard greens *
Mustard seed "
Nectarines " .
Peaches . "
Pears •
Peas (succulent type) "
Pecans "
Peppers "
Pineapples "
Pluns
Potatoes "
Prunes "
PurpV.ins "
Rape ssod "
Safflownr seed •
Spinach "
Stravberries •
Grains of: barley, oats, "
rye and wheat
Straw of: barley, oats, "
rye and wheat
Sugarbects •
Sugarcane •
Simmer squash "
Sunflower seed "
Sweet corn "
Sweet potatoes •
Tea
Tomatoes • •
Turnip greens •
Walnuts "
Watercress "
Winter squash "
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
00003790,
00003789,
00003789,
00003949,
00003797,
00003786,
.00003786,
00003730,
00003901,
00003634,
00003642,
00003756,
Bibliographic Must additional Data be
Citation Submitted under FIFRA
3(c)(2)(B)7 If so, when?
00003788
00003796
00003722,
00004254
-
00003796
00003724
00003784
00003784
00003865
00003917
00004254
00003864
00003798, 00003799
00003791
00003709
00003791
-
00003724
00003727
00003796
00003785
00003710
00003710
00003728
00003676
-
00003796
00003760
00003569
00003744
00003783
00003796
00004254
00003796
Yes/26 months^
No 2/
Yes/26 months-'
No -.
Yes/25 iranths^
No
No
No
No
No
No
No
Yes/26 months^
No
No
No ,7
Yes/26 months^
No
No
No
No
No
No
No
No ,.
Yes/26 months^'
No
No
NO
Yes/26 months^'
No
No
No ,.
Yes/26 months^'
r/ Residue data tor grape pomace and raisin waste are necessary to determine the contribution of this animal teed item
to milk and meat.
2/ Residue data on untrimned heads of lettuce are needed,
5/ There are no available adequate residue data using an adequate analytical method capable of determining total endosulfan
residues* None of the methods submitted have been shown to be adequate for the analysis of endosu.lfar, sulfatep and thesa
residue data are not adequate to support the established tolerance hhe^fsre seesithie d?.ta by em ^nalytiss.", '"
' of determining residues of endosulfan sulfat^ are required
4/ Resifi:^ data s?. pineapple brars ere. rtsosMsuif ifj t.:\^X£K* "»a sKro'-.^titJ-; as i? ts ir-.-/; ;€'->- c. r.:. .••• *:•••.*!<<•
;* 'M'-.:-. ?r
-------
RESIDUE CHEMISTRY CONTINUED
to
to
Name of Test Composition Does EPA have data Bibliographic Must additional Data be
to Partially or Citation Submitted under FIFRA
Totally Satisfy 3(c)(2)(B)7 If so, when?
this Requirement?
Residue Data: Animal Foodstuffs
Alfalfa (fresh) Technical Grade of
Active Ingredient
Alfalfa (hay)
Almond hulls "
Apple pomace •
Beans (vines, forage, "
fodder)
Carrots ' "
Cottonseed (meal, " '
forage, fodder)
Grain of: barley, oats, • "
rye and wheat
Grape pomace (and "
raisin waste)
Nectarine pomace •
Peach pomace and waste "
Peas,, succulent (vine, "
forage and fodder)
Pineapple bran "
Straw of: barley, oats "
rye and wheat
Sugar beets (tops and •
dried pulp
Sugarcane (bagasse and "
dried pjlp)
Sunflower seed meal "
Sweet corn waste •
Tomato pomace "
Residue Data:
Meat "
Yes
Yes
Yes
No
No
No
No
No
No
No
No
No
No
No
Yes
Yes
Yes
Yes
No
Yes
00003834, 00004258, 00003835
00003841
(sane as for fresh alfalfa)
00004254, 00003612, 00003713
-
• -
-
-
^
-
-
-
'
-
0000 3728
00003901, 00003676, 00003796
00003796
00003760
00003838, 00003743, 00003742
No
NO
Yes/26 months^
No—
. .
NOy-/
Noi
Noi
Yes/26 months^
...
NOry
NOr-y
Noi
2/
Yes/26 months^'
ij-i/
No
...
No-
No,,
No^' ,,
Yes/26 months^'
No
Milk
Poultry
00003877, 05003222, 05013696
Yes 00003838, 00003743, 05003877
05003222, 05013696
Yes 00003840
No
NO
JL/ Label restrictions prohibit the use of this commodity as animal feed, therefore residue data are not being required. In
order to remove label restrictions, i.e., allow use of this commodity for animal feed or food, appropriate residue data
showing the nature and the amount of expected residues are necessary.
2/ The Agency has concluded that restrictions against feeding this commodity to animals is impractical, in that the
grower has no control over the disposition of this commodity's by-products. Residue data are required to determine
if there are endosulfan residues in this by-product and to determine if a food additive tolerance is needed.
3/ Husklage from processing or canning cannot be fed to livestock pc_* label restrictions.
March 1982
-------
NJ
U)
DSTA REQUIRBEOTS CHART A
ENDOSULPfiN
Generic Data Kequiraraentes E001OGICAL EFFECTS
Guidelines Kama ©f Test
Citation
t*en Requiredi'
Composition
Does EPA have data
to partially or
totally satisfy
this requirement?
Bibliographic
Citation
Must additional data
be submitted under
FIFRA 3(c)(2)(B)?
If so, due when?
163.71-1 Avian Single-Dose
163.71-2 Avian Dietary
163.71-4 Avian Reproduction
163.72-1 Fish Acute LC
A,C,D,E,F
A,C,D,E,F
A,C,D,E,F
A,C,D,E,F
153,72-2 Acute Toxicity to Aquatic A,C,D,E,F,
Invertebrates
163o72-3 Anite Toxicity to
Estuarine s Marine
- Organisms
163.72-4 Fish Early Life-Stage
Aquatic Invertebrate
Life Cycle
163.72-5 Fish Life-cycle
163.72-6 Aquatic Organism
C,D,E
Technical Grade of Partially
Active Ingredient
" Yes
Partially
Yes
Partially
Partially
—
05003452, GS014015 Yes/8 months^
Yes/14 months
00022923
GS014012, 05003107 Yes/14
GS014014, 05014941
05008271, 05017538 No
05009242
00001328, 05000819 Yes/8 months^
05005824, 05003062
05008271
Reserved—
Reserved-^
Reserved^
These data requirements are current as of March, 1982. Refer to the guidance package for updated requirements.
\f This column specifies the use sites for which the data are required using the following codes: A= Domestic outdoors; B= Greenhouses; O Tree
fruit and nut crops; D= Field and vegetable crops; E= Aquatic fotx3 use (watercress); F= Forestry use.
2/ The dose response data were not provided by the acute oral studies reviewed, therefore no statistical evaluation was possible.
?/ The submitted studies on coldwater fish did not provide dose response data nor the percentage of active ingredient tested,
therefore no statistical evaluation could be performed, nor could the generic status be confirmed. Since the available data on
formulation testing indicate coldwater fish are more sensitive to endosulfan's effects than warnwater fish or aquatic
invertebrates,, the eoldwater 96 hour LCegis essential to the hazard assessment.,
£/ The submitted teses partially fulfili this requirement because they provided information en the acute tosicity to fiah
and shrimp. However, additional studies rasst be submitted on the crab and mollusc.
J/ This requirement is reserved pending the evaluation of required environmental fate data°
March 1982
-------
DATA REQUIREMENTS CHART B
ENDOSULFAN
Product-Specific Manufacturing-Use Data Requirements: PRODUCT CHEMISTRY
to
Guidelines
Citation
163.61-3
163.61-4
163.61-5
163.61-6
163.61-7
163.64-2
163.64-3
163.64-4
163.64-5
163.64-7
163.64-8
163.64-9
Name of Test
Product Identity and
Disclosure of Ingredients
Description of
Manufacturing Process
Discussion on Formation
of Unintentional Ingredients
Declaration & Certification
of Ingredients Limits
Product Analytical Methods
and Data
Color
Physical State
Odor
Melting Point
Density or Specific Gravity
Solubility
'Vapor Pressure
Composition Does EPA have data Bibliographic Must additional data
to partially or Citation be submitted under
totally satisfy FIFRA 3(c)(2)(B)7
this requirement? - If so, due when?
Each Product
Each Product
Each Product
Each Product
Each Product
Each Product^
Each Product-/
Each Product^'
Each Product-/
Each Product-/
Each Product-/
Each Product-/
Partially
Partially
No
Partially
Yes 00003657, 00003794
'.'artially
Partially
Partially
Partially
Partially
Partially
Partially
Yes!/
Yes!/
Yes!/
Yes!/
No
Yes!/
Yes!/
Yes!/
Yes!/
Yes!/
Yes!/
Yes!/
These data requirements are current as ofMarch, 19827 Refer to the guidance package for updated requirements.
I/ These requirements must be fulfilled by each applicant. Data from other applicants may not be cited. Therefore, even if
the requirements have been partially or completely fulfilled for some products, no references are given. These requirements
roust be filled at the tine of registration or reregistration.
2/ If the manufacturing use product is a formulation intermediate, then data must be submitted on the technical used to
manufacture the intermediate.
3/ If the manufacturing use product is a formulation intermediate, then data must be submitted on the technical used to
manufacture the intermediate and on the intermediate itself.
March 1982
-------
PRODUCT CHEMISTRY CONTINUED
Guidelines
Citation
.163.64-11
163.64-12
163.64-13
163.64-14
163.64-15
163.64-16
163.64-17
162.64-18
163.64-19
163.64-20
Name of Test
Octanol/Vater partition
P«
Stability
. Oxidizing/Reducing Action
Flanrnability '
Explosiveness
Storage Stability
Viscosity
Miscibility
Corrosiveness
Composition Does EPA have data Bibliographic Must additional data
to partially or Citation be submitted under
totally satisfy FIFRA 3(c)(2)(B)?
this requirement? If so, due when?
Each Product^
Each Product-/
Each Product-/
Each Product
Each -Product
Each Product
Each Product
Each Product
Each Product
Each Product
No
No
Partially
No
Partially
Partially
Partially
Partially
No
Partially
Yesi/
Yesi/
Yesi/
Yesi/
Yesi/
Yesi/
Yesi
Yesi/
Yesi/
Yesi/
These data requirements are current as of March; 19B2,-Refer to the guidance package for updated requirements.
I/ These requirements must be fulfilled by each applicant. Data from other applicants may not be
the requirements have been partially or completely fulfilled for some products, no references are
must be filled at the time of registration or reregistration.
2/ If the manufacturing use product is a formulation intermediate, then data must be submitted on
manufacture the intermediate.
3/ If the manufacturing use product is a formulation intermediate, then data must be submitted on
manufacture the intermediate and on the intermediate itself.
cited. Therefore, even if
given. These requirements
the technical used to
i
the technical used to
March 1982
-------
DATA REQUIREMENTS CHART C
ENDOSULFAN
End-Use Product-Specific Data Requirements: PRODUCT CHEMISTRf
Guidelines
Citation
163.61-3
163.61-4
163.61-5
163.61-6
163.61-7
163.64-2
163.64-3
163.64-4
163.64-7
163.64-12
163.64-14
163.64-15
163.64-16
163.64-17
163.64-18
163.64-19
163.64-20
Name of Test
Product Identity &
Disclosure of Ingredients
Description of
Manufacturing Process
Discussion on Formulation
of Unintentional Ingredients
Declaration & Certification
of Ingredients Limits
Product Analytical Methods
& Data
Color
Physical State
Odor
Density or Specific Gravity
PH
Oxidizing/Reducing Action
Flamnability
Explosiveness
Storage Stability
Viscosity
Miscibility
Corrosive ness
Composition Does EPA have data Bibliographic Must additional data
to partially or Citation be submitted under
totally satisfy FIFRA 3(c)(2)(B)7
this requirement? If so, due when?
Each Product
Each Product
Each Product
Each Product
Each Product
Each Product
Each Product
Each Product
Each Product
Each Product <>
Each Product
Each Product
Each Product
Each Product
Each Product
Each Product
Each Product
Partially
No
No
Partially
Yes
No
Yes
No
Partially
No
NO
No
No
Partially
No
No
Partially
Yesi/
Yes!/
Yesi/
Yesi/
No
Yesi/
No
Yesi/
Yesi/
Yesi/
Yesi/
Yesi/
Yesi/
Yesi/
Yesi/
Yesi/
Yesi/
TTiese data requirements are current as of March, 1982.Refer to the guidance package for updated requirements.
I/ These requirements must be fulfilled by each applicant. Data from other applicants may not be used. Therefore, even if
the requirement has been partially or completely fulfilled for some products, no references are given. These requirements must
be filled at the time of registration or reregistraticn.
March 1982
-------
DATA REQUIREMENTS CHART C
ENDOSUI.FAN
Product-Specific End-Use Data Requirements: TOXIOOincJf
Guidelines
Citation
163.81-1
163.81-2
163.81-3
163.81-4
163.81-5
Name of Test
Acute Oral Toxicity
Acute Dermal Toxicity
Acute Inhalation To.xicity
Primary Eye irritation
Primary Skin Irritation
Composition
Each Product-
Each Product-i/
Each Product-
Each Product-
Each Product—
Does EPA have data Bibliographic
to partially or Citation
totally satisfy
this requirement?
, No
NO
No
No
No ' -
Must additional data
be submitted under
FIFRA 3(c)(2)(B)?
If so, duo when?
Yes/8 months.
Yes/8 months
Yes/8 months
Yes/8 months
Yes/8 months
These data requirer.ents are current as of March, 1982. Refer to the guidancepackage for updated requirements.
_!/ Testing is required for representatives of the following forrnulations: dust (5 and 25%), wettable powder (50%),
and emulsifiable concentrate (9, 22-24, and 50%).
2/ Testing is required for representatives of the following formulations: dust (5 and 25%), wettable powder (50%),
Impregnated material (15%) and pressurized liquid (aerosol 10%).
3/ Testing is required for representatives of the following formulations: dust (5 and 25%), grannular (3%), wettable
powder (50%), and emulsifiable concentrate (9, 22-24, and 50%).
£/ Testing is required for representatives of the following formulations: dust (5 and 25%), wettable powder (50%),
emulsifiable concentrate (9, 22-24, and 50%), and pressurized liquid (aerosol 10%).
March 1982
-------
oo
DATA REQUIREMENTS CHART C
ENDOSULFAN
Product-Specific End-Use Data Requirements: ECOLOGICAL EFFECTS
Guidelines Name of Test Composition
Citation
163.71-5 Simulated and Actual Field Testing
noes EPA have data
to partially or
totally satisfy
this requirement?
Bibliographic
Citation
Must additional data
be submitted under
FIFRA 3(c)(2)(B)?
If so, due when?
Reserved^
for Mammals and Birds
163.72-1 Fish Acute LC
50
163.72-2 Acute Toxicity to
Aquatic Invertebrates
163.72-3 Acute Toxicity to
Estuarine and Marine
Organisms
163.72-6 Simulated or Actual Field Testing
For Aquatic Organisms
Representative
Products of 35EC,
50WP, and 4D
Representat i ve
Products of 35EC,
50 WP, and 4D
Representative
Products of 35EC,
50WP and 4D
Partially
No
No
GSO14011, GS014010
05003103, 05004797
05003351
Yes/8 months^ -
Yes/8 months-
Yes/8 months^
Reserved—
These data requirements are current as of March, 1982. Refer to the guidance package for updated requirements.
V If adverse effects are demonstrated by testing under 163.71-4, expected field residue information will be evaluated to
determine whether data should be conditionally required under 163.71-5 to demonstrate effects of formulations on avian survival
and reproduction.
"if The data requirement is only partially satisfied for the 35FC formulation because no information was given in the studies
other than to indicate that the test material was a 35EC. This is not sufficient test material identification, as other inerts
or additives are presumed to be a part of this formulation. Ultimate identification of formulations for which this requirement
(163.72-1) is satisfied will be accomplished by comparing "Confidential Statements of Formula" received with registration
applications, to the Data Evaluation Records of the submitted formulated product studied in the Agency's files.
V This requirement is reserved pending the evaluation of required environmental fate data.
7/ This data requirement applies only to the watercress use pattern.
March 1982
-------
INDEX OF CITATIONS USED IN THE DATA REQUIREMENTS CHARTS
REFERENCES LISTED IN NUMERICAL ORDER
MRID
00001328
00003587
00003600
00003603
00003604
00003612
00003634
00003642
00003654
00003657
00003669
00003676
00003693
00003703
00003709
00003710
00003711
00003713
00003722
00003724
00003725
00003726
00003727
00003728
00003730
00003742
00003743
00003744
00003756
00003760
00003761
00003762
00003777
00003782
00003783
00003784
00003785
00003786
00003787
00003788
00003789
00003790
00003791
00003794
9f003795
00003796
00003797
00003798
CITATION
Earnest, R. (1970)
Shuttleworth, J.M. (1971)
FMC Corporation (1958)
Keller, J.G. (1959)
Keller, J.G. (1959)
FMC Corporation (19??)
Stanovick, R.P. (1967)
FMC Corporation (1964)
Ware, G.W. et al. (1961)
Hooker Chemical Corporation
Stanovick, R.P. (1965)
FMC Corporation (1964)
Elsea, J.R. (1957)
FMC Corporation (19??)
FMC Corporation (1969)
FMC Corporation (1970)
Arnold, D. (1972)
FMC Corporation (1971)
Hinstridge, P.A. (1966)
Winterlin, W. (1968)
FMC Corporation (1966)
FMC Corporation (1969)
FMC Corporation (1967)
Shuttleworth, J.M. (1971)
FMC Corporation (1970?
Maier-Bode, H. (1966)
Gorbach, S (1965)
Gorbach, S. (1973)
American Hoechst Corporation
Hinstridge, P.A. (1968)
Chin, W.T.; Stanovick, R.P.
Palazzolo, R.J. (1964)
R.P.
R.P.
R.P.
R.P.
P.A.
P.A.
P.A.
P.A.
P.A.
P.A.
P.A.
(1964)
(1968)
(1964)
Stanovick,
Stanovick,
Stanovick,
Stanovick,
Hinstridge,
Hinstridge,
Hinstridge,
Hinstridge,
Hinstridge,
Hinstridge,
Hinstridge,
(1964)
(1963)
(1964)
(1965)
(1963)
(1963)
(1963)
(1963)
(1963)
(1963)
(1964)
Velsicol Chemical Corporation (1974)
Cassil, C.C.; Drummond, P.E. (1965)
FMC Corporation (1965)
Hinstridge, P.A. (1966)
Thornburg, W. (1966)
29
-------
MRID
RTOAHO 3TW3M35ttUQ3H ATAH
CITATION
00003799
00003800
00003834
00003835
00003836
00003838
00003840
00003841
00003843
00003862
00003864
00003877
00003901
00003917
00003949
00003959
00004254
00004257
00004258
00022923
05000819
05002183
05002565
05002841
05003C04
05003007
05003U53
05003062
05003085
05003103
0500310'?
05003222
05003336
05003351
05003395
05003462
05003471
05003503
05003703
05003718
05003801
05003877
05004262
050^4385
ro004617
05004620
05004797
05005047
05005315
05005824
Thornburg, W. (1966)
Stanovick, R,P. (1966)
Hinstridge, P. A. (1964)
Hinstridge, P. A. (1965)
Stanovick, R.P. (1964)
Stanovick, R.P0 (1965)
Stanovick, R.P. (1967)
Ware, G.W. (1967)
FMC Corporation (1971)
Hinstridge, P»A. (1971)
Hinstridge, PoA. (1966)
Keller, JoC0 (1958?)
FMC Corporation (1964)
MC Corporation (1965)
FMC Corporation (1965)
FMC Corporation (19??)
. FMC Corporation (1967)
Deema, P» et alo (1966)
Stanovick, R,P0 (1964)
Hill, EoFo et al. (1975)
Xo""" 1 • PawvKsr;*' P. M974)
«-•*• •• (,* 'j, —•- ..V-._> i_ p 4VO \ .4. _* * T /
Eoyd, 2oMo et alo (1970)
Beard, JoE0? Ware, G.W0 (1969)
Archer, TcEo et alo (1972)
Chopra, N0Mo,° Mahfouz, A»M0 (1977)
Martens, Ro (1976)
Ernst, Wo U977
Rcberts, Do (1975)
Kavadia, V»S« et al, (1978)
Muinikutty, CoK0? Rege, MoS, (1977)
Ptecek-, KoJo et al. (1969)
Gorbach, SoG» et alo (1968)
Stewart, D0KoR0? Cairns, K0G. (1974)
Rsridy, ToG0,° Gomathy, S0 (1977)
Burke, Jo? Mills, PoA. (1963)
Hudson, RoHo et alo (1972)
El Zorgani, G0Ao,° Omer, M.E.H. (1974)
Gupta, PoKo? Ehrnebo, M. (1979)
Dorough, HoW0 et alo (1978)
Gupta, PoKo? Chandra, S»V. (1975)
Chopra, NoM,,° Mahfouz, A.M. (1977)
Frank, R. et alo (1975)
Peeters, J.F. et al. (1975)
Terranova, A.C.; Ware, G»W. (1963)
Rao, M.V.R.? Rana, R.S. (1977)
Harrison, RoB» et al, (1967)
Frick, KoEo (1959)
Martens, R. (1977)
Martens, R. (1972)
Schinmel, S.C. et al. (1977)
30
-------
MRID
CITATION
05007464
05007645
05008271
05009242
05010061
05012725
05013674
05013696
05013707
05014941
05017001
05017538
05018169
05019845
GS014001
GS014003
GS014004
GS014005
GS014007
GS014008
GS014009
GS014010
GS014011
GS014012
GS014014
GS014015
GS014023
GS014024
Schuphan, I. et al. (1968)
Ely, T.S. et al. (1967)
Macek, K.J. et al. (1976)
Sanders, H.O. (1969)
Pay, P. et al. (1975)
Miles, J.R.W.; Moy, P. (1979)
Bardyopadhyay, S. et alo (1979)
Oeser, H. (1970
Spiro, S.; Trevisani, G.R. (1974)
Pickering, Q.H.? Henderson, C. (1966)
Gaikawad, S.T. et'al. (1973)
Sanders, H.O. (1972)
Terranova, A.C. (1962)
W.M.J.; Huneault,'H. (1979)
. (1975)
(1975)
(1975)
(1976)
(1969)
Raltech Scientific Services (1981)
Fahrig, R. (1974)
Ludeman, J.A. (1972)
U.S.E.P.A. (1976)
U.S.E.P.A. (1976)
Buccafusco, R.J.; Sleight, B.H. (1976)
Schafer, E.W. (1972)
Raltech Scientific Services (1981)
Gunther, F.A. (1951)
Strachan,
Reno, F.E
Reno,
Reno,
Reno,
Gains,
F.E.
F.E.
F.E.
T.B.
31
-------
IV. PRODUCT CHEMISTRY
A. Chemical Identity
B. Manufacturing Process
C. Formation of Unintentional Ingredients
D. Ingredient Limits in Endosulfan Products
E. Product Analytical Methods and Data
F. Physical and Chemical Properties
G. Summary of Data Gaps
A. CHEMICAL IDENTITY
In the United States, the American National Standards Institute (ANSI) approved
common name for hexachlorohexahydromethano-2,4,3-benzodioxathiepin 3-oxide is
"endosulfan". The Chemical Abstracts Service Collective Indexes list the names
as 6,7,8,9,10,10-hexachloro-l,5,5a,6,9,9a-hexahydro-6,9-methano-2,4,3-benzo-
dioxathiepin 3-oxide (9CI) and 1,4,5,6,7,7-hexachloro-5-norbornene-2,3-di-
methanol cyclic sulfite (SCI). Endosulfan is also commonly known by the trade
name "Thiodan" and by numerous other names. The Chemical Abstracts Registry
number (CAS) is 115-29-7, and the EPA Shaughnessy number is 079401. Endosulfan
is a mixture of two geometric isomers (endosulfan I and II), a synthetic
cyclediene, that was introduced in 1956 as an experimental broad spectrum
pesticide.
The structural formula is:
Cl
I
^C /CH2-0
Cl-C \^C Z \
II I \
|| CClJ S=O
cl~C\'xcx /
C CH2-0
Cl
B. MANUFACTURING PROCESS
The synthesis process for endosulfan can be found in U.S. Patent No. 2,799,685
which is held by Farbwerke Hoechst, AG (1957). The Pesticide Manufacturing and
Toxic Materials control Encyclopedia (Sittig, 1980) outlines the following
manufacturing process.
32
-------
The first step consists of a Diels-Alder condensation of hexachlorocyclopenta-
diene (hex) with 2-butene-l,4-diol to form the corresponding adduct.
Cl
CH^H |
CH Cl-C |XC-ai0OH
« . II cci2| 2
h CH ;> Cl-C *C-CH0OH
I N. 1^ £.
CH-£>H Cl
Cl Cl
In the second step this adduct is reacted with thionyl chloride to form the
erdosulfan product.
Cl Cl
I I
/^X _. _'Cl
Cl-C I C-CH2OH Cl-C
|| CC12| -l- SOC12 > || CC12| * ^S=0 + 2HC1
Cl-C \^ C-CH2OH C1~Cx' s G-QA-pr
\ I
Cl CL
Hooker Chemical (19??, MRID 00003658) and Velsicol (1975, MRID 00003793)
describe similar processes. Further manufacturing details are considered to be
trade secret information, and cannot be elucidated in this standard.
C. FORMATION OF UNINTENTIONAL INGREDIENTS
No theoretical discussions have been submitted, nor couM be found, on possible
contaminants in the technical materials (other than those listed in the
Confidential Statements of Formula) nor in any of the end-use products. Little
information is available on the formulating processes of end-use products.
D. INGREDIENT LIMITS JN ENDOSULFAN PRODUCTS
There are four manufacturers of technical endosulfan. They are Food, Machinery
and Chemical Corporation (FMC), Hooker Chemical Corporation, Makhteshim
Chemical Vforks (Israel), and Velsicol Chemical Corporation. The technical
product ranges from 94-96% active ingredient.
Three companies produce formulation intermediate endosulfan'(manufacturing use
products) and they are Chevron Chemical Company, FMC, and Makhteshim (Israel).
A commitment (certification) is required from each registrant that the
ingredients and impurities in the products will be maintained within specified
limits for as long as the product is offered for sale. Upper and lower limits
are required for the active and intentionally added inert ingredients. Upper
limits are required for the impurities. This information is to be submitted
with the Confidential Statement of Formula.
33
-------
E. PRODUCT ANALYTICAL METHODS AND DATA
The EPA Manual of Chemical Methods for Pesticides and Devices (1976) describes
the following methods suitable for the analysis of all endosulfan products.
1. Alkaline Hydrolysis
This determination is based on the alkaline hydrolysis of endosulfan, yielding
sodium sulfite. This is reacted with an excess of acidified standard iodine
solution. The amount of endosulfan is calculated from the amount of iodine
used by the sodium sulfite.
2. Infrared Spectroscopy (tentative)
Samples are dissolved in carbon disulfide which contains a small amount of
sodium sulfate.
3. GLC-TCD or GLC-FID (tentative)
Gas-liquid chromatography (GLC) with thermal conductivity (TCD) or flame
ionization detectors (FID) are used as the internal standard. A further GLC-
FID method (also tentative) determines the two isomers of endosulfan. The
ratio of I (alpha) to II (beta) ranges in samples from about 4:1 to 2:1.
Velsicol (1974, MRID 00003794) submitted similar GLC methods (with FID or TCD
detectors as above) for detection of endosulfan and the individual isomers in
formulated products.
F. PHYSICAL AND CHEMICAL PROPERTIES
1. Color
Pure endosulfan is colorless to white (FMC, 19??, MRID 00003729; Makhteshim,
1969, MRID 00003821; and American Hoechst, 1965, MRID 00003746).
Technical endosulfan ranges in color from light brown or tan to dark brown
(FMC, 19??, MRID 00003729; Makhteshim, 1969, MRID 00003821; American Hoechst,
1965, MRID 00003746; Velsicol, 19??, MRID 00003772; and Hooker Chemical, 19??,
MRID 00003658).
Two of the formulation intermediates (manufacturing use products) were light
brown to brown (Makhteshim, 19??, MRID 00003821).
2. Q3or
There is no cdor for the pure compound (FMC, 19??, MRID 00003729 and
Makhteshim, 1969, MRID 00003821).
The technical compound has a slight odor of sulfur dioxide (FMC, 19??, MRID
00003729; Makhteshim, 1969, MRID 00003821; American Hoechst, 1965, MRID
00003746; arri Velsicol, 19??, MRID 00003772).
34
-------
The manufacturing use products will have the specific odor of the solvent used
(Makhteshim, 1969, MRID 00002821).
3. Melting Ftoint
There are two isomers of. the pure compound, I (alpha) and II (beta). For
isomer I, the melting range is 106-110°C; for isomer II the range is 208-
210°C; and the melting range for the technical product is 70-100°C (FMC,
19??, MRID 00003729; Makhteshim, 1969,'MRID 00003821; American Hoechst, 1965,
MRID 00003746; Velsicol, 19??, MRID 00003772; and Hooker Chemical, 19??, MRID
00003658).
4. Solubility
The following results were reported for the technical product at 20°C, except
where noted.
Solvent
xylene
Solubility
45 g/100 g
45-55 g/100 g
soluble
Reference
FMC, 19??, MRID 00003729
American Hoechst, 1965, MRID 00003746
Makhteshim, 1969, MRID 00003821
water
0.6 ppm
insoluble
insoluble
0.0
530 ug/1 (isomerl)*
FMC, 19??, MRID 00003729
Makhteshim, 1969, MRID 00003821
Velsicol, 19??, MRID 00003772
Hooker Chemical, 19??, MRID 00003658
Weil et al., 1974, MRID 05012895
280 ug/1 (isomer II)* Weil et al., 1974, MRID 05012895
*done at 25°C
kerosene 20 g/100 g FMC, 19??, MRID 00003729
25 g/100 g American Hoechst, 1965, MRID 00003746
chloroform 50 g/100 g FMC, 19??, MRID 00003729
100 g/100 g American Hoechst, 1965, MRID 00003746
soluble Makhteshim, 1969, MRID 00003821
>150 g/100 g Hooker Chemical, 19??, MRID 00003658
ethanol 5 g/100 g FMC, 19??, MRID 00003729
American Hoechst, 1965, MRID 00003746
soluble Makhtshim, 1969, MRID 00003821
>7.2 g/100 g Hooker Chemical, 19??, MRID 00003658
methyl chloride 45 g/100 g FMC, 19??, MRID 00003729
acetone 35 g/100 g - FMC, 19??, MRID 00003729
50 g/100 g American Hoechst, 1965, MRID 00003746
soluble Makhteshim, 1969, MRID 00003821
benzene 37 g/100 g FMC, 19??, MRID 00003729
59 g/100 g American Hoechst, 1965, MRID 00003746
35
-------
Solvent
(continued)
Solubility
Reference
carbon tetra- 29 g/100 g FMC, 19??, MRID 00003729
chloride 29 g/100 g American Hoechst, 1965, MRID 00003746
81.8 g/100 g Hooker Chemical, 19??, MRID 00003658
alkylbenzenes 25 g/100 g FMC, 19??, MRID 00003729
(Solvesso 100) 25 g/100 g American Hoechst, 1965, MRID 00003746
methanol 11 g/100 g FMC, 19??, MRID 00003729
11.9 g/100 g Hooker Chemical, 19??, MRID 00003658
11 g/100 g American Hoechst, 1965, MRID 00003746
toluene 57 g/100 g American Hoechst, 1965, MRID 00003746
>150 g/100 g Hooker Chemical, 19??, MRID 00003658
amyl acetate 53 g/100 g American Hoechst, 1965, MRID 00003764
fuel oil 14 g/100 g American Hoechst, 1965, MRID 00003746
methylene chloride 45 g/100 g . American Hoechst, 1965, MRID 00003746
acetic acid 18 g/100 g Hooker Chemical, 19??, MRID 00003658
dioxane >150 g/100 g Hooker Chemical, 19??, MRID 00003658
chlorcbenzene >150 g/100 g Hooker Chemical, 19??, MRID 00003658
heptane 16.5 g/100 g Hooker Chemical, 19??, MRID 00003658
5. Stability
In the presence of acids, alkalis, and moisture, pure and technical endosulfan
will decompose to sulfur dioxide and endosulfan alcohol (FMC, 19??, MRID
00003729; Makhteshim, 1969, MRID 00003821; American Hoechst, 1965, MRID
00003746; and Velsicol, 19??, MRID 00003772).
6. Physical State
The technical and pure forms are crystalline solids (FMC, 19??, MRID 00003729;
Makhteshim, 1969, MRID 00003821; American Hoechst, 1965, MRID 00003746;
Velsicol, 19??, MRID 00003772; and Hooker Chemical, 19??, MRID 00003658).
7. Density or Specific Gravity
The apparent density in xylene at 20°C is 1.745 (FMC, 19??, MRID 00003729;
American Hoechst, 1965, MRID 00003746; and Velsicol, 19??, MRID 00003772).
The density of the emulsifiable concentrate formulation intermediate (35%) is
1.10-1.11 at 20°C (Makhteshim, 1969, MRID 00003821).
36
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8. Vapor Pressure
There is no measurable vapor pressure at 20-75°C (FMC, 19??, MRID 00003729;
American Hoechst, 1965, MRID 00003746; and Makhteshim, 1969, MRID 00003821).
At 80°C, me (19??, MRID 00003729) reports that the vapor pressure of the
technical material is .009mm Hg.
9. Storage Stability
Makhteshim, 1969, MRID 00003821) reports that the 35% emulsifiable concentrate
and the 50% wettable powder formulation intermediates are stable when kept;in
intact containers.
10. Flammability
Makhteshim (1969, MRID 00003821) reports that the pure compound and the 50%
wettable powder formulation intermediate are nonflammable.
11. Explosiveness
Velsicol (19??, MRID 00003772) reports that there is no explosive hazard for
the technical material.
12. Viscosity
Hooker Chemical (19??, MRID 00003658) reports that at 210°C, the technical
has a viscosity of 231.3 centistrokes=49.47.
13. Corrosion Characteristics
Makhteshim, 1969, MRID 00003821) reports that the pure and technical compounds
and the 35% emulsifiable concentrate formulation intermediate is corrosive to
iron.
G. SUMMARY OF DATA GAPS
Data requirements for product identity, description of manufacturing process,
certification of ingredient limits, and physical/chemical properties may have
been partially satisfied for technical and manufacturing use endosulfan. The
registrants have not discussed the formation of unintentional ingredients. The
Agency requires submission of this information.
37
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V. ENVIRONMENTAL FATE
A. Use Summary
B. Environmental Fate Profile
C. Exposure Profile
D. Summary of Data Gaps
A. USE SUMMARY
Endosulfan is a nonsystemic insecticide with contact and stomach action which
is federally registered for use on a large number of agricultural and
ornamental crops. Approximately 60-80 percent of the pesticide is used on
fruit trees (apples, peaches, pears and cherries) and vegetables (potatoes,
tomatoes, green beans, lettuce and sweet corn); Other use sites consist
primarily of cotton, alfalfa, tobacco, sugar beets, artichokes, grapes, plums,
prunes and pecans. Use of endosulfan on cotton, which occurs primarily in the
southwestern United States, varies from year to year.
Endosulfan is used on potatoes in the northeastern and north central states for
the control of aphids, flea beetles and Colorado potato beetles; apples in the
north central states for the control of aphids and white apple leafhoppers;
tomatoes in California and the southeastern states for control of aphids, flea
beetles and lepidopteran larvae; lettuce in the southwestern states for control
of stink bugs and occasionally lepidopteran larvae. Endosulfan is also
registered for use on watercress to control Cyclamen mites.
Endosulfan is manufactured into 96, 95 and 94% technical products. The
formulation intermediates include 50 and 35% wettable powders, 35% emulsifiable
concentrate, and 25% dust concentrate formulations. Endosulfan is formulated
for end use into 2, 4, and 5% dusts; 3% gr.mules; 50% wettable powders; 9, 22-
24, and 33-34% emulsifiable concentrates; 10% pressurized liquids (aerosol);
and a 15% impregnated material (pressure fumigant). The emulsifiable
concentrate and wettable powder end use formulations are diluted with water and
applied predominately as foliar applications by aircraft and ground equipment.
Endosulfan is compatible with most other pesticides except lime sulfur and
other strong alkaline chemicals.
It is estimated that the domestic use of endosulfan totals 1.5 to 2 million
pounds of the active ingredient annually.
B. ENVIRCM1ENTAL FATE PROFILE
The available data are insufficient to completely assess the environmental fate
of endosulfan.
Sterile controls of metabolism studies (Miles and May, 1979, MRID 05012725;
Martens, 1976, MRID 05003007; and Martens, 1972, MRID 05005315) clearly
demonstrate that physico-chemical hydrolysis of the ester linkage of endosulfan
occurs. Endosulfan was hydrolyzed after six week's incubation at 27°C to
endosulfan diol with a strong dependence on the pH (the values ranged from 1
percent hydrolysis occurring at pH 4.3 to 90 percent at pH 8 or above).
However, additional data will be required on the hydrolysis properties of
endosulfan, since these properties were not fully detailed.
. 38
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Preliminary data (Archer et al.., 1972, MRID 05002841) show that undiluted
endosulfan (endosulfan I and II isomers) has a photolytic half-life of
approximately seven days. The primary photolysis product is endosulfan diol,
which is further photodegraded to endosulfan alpha-hydroxyether and an
unidentified metabolite with a half-life of approximately seven days.
Endosulfan alpha-hydroxyether and endosulfan ether were photodegraded (11-30
percent) to endosulfan lactone. Endosulfan lactone and endosulfan sulfate are
stable to light. Since the analysis for photolysis products was conducted only
once, additional data are required on the rate of endosulfan degradation.
In general, endosulfan and its metabolites appear to persist in soil. When
applied to aerobic or anaerobic soil, 21-59 percent and 55-69 percent,
respectively, of the endosulfan remained 15 weeks after treatment (Martens,
1977, MRID 05005047). Endosulfan is oxidized to its major transformation
product, endosulfan sulfate.
In flooded soil (Martens, 1977, MRID 05005047), the rate of endosulfan
degradation was slower than under aerobic conditions but faster than under
anaerobic conditions. Hydrolysis to endosulfan diol was the major
transformation, however, some oxidation to endosulfan sulfate did occur. The
data from this anaerobic soil study are insufficient to determine the rate of
formation and decline of endosulfan metabolites.
When added to cultures of 59 soil bacteria species (including actinomyces) and
28 species of soil fungi, endosulfan was transformed by approximately one-
fourth of the bacteria and over half of the fungi (Martens, 1976, MRID
05003007; and Martens, 1972, MRID 05005315). The degradative pathway appeared
to be pH dependent. At pH 6.5 or above,.hydrolysis of endosulfan to endosulfan
diol appears to be the predominant reaction. The process is probably physico-
chemical but appeared to be accelerated by microbes, either by the enzymatic
reactions or by induced changes in pH. Endosulfan diol oxidized to endosulfan
alpha-hydroxyether, which oxidized to endosulfan lactone. These processes
occur under sterile as well as nonsterile conditions but at a slower rate under
sterile conditions. Endosulfan lactone transformed to unspecified products at
equal rates under sterile and nonsterile conditions, thus indicating that its
breakdown is a physico-chemical process. At pH's below 6.5, endosulfan
primarily oxidized to endosulfan sulfate. This occurred only under nonsterile
conditions. Some endosulfan sulfate hydrolyzed to endosulfan diol (Miles and
Moy, 1979, MRID 05012725; Martens, 1976, MRID 05003007; and Martens, 1972, MRID
05005315).
Endosulfan had no effect on ammonification and stimulates nitrification
(Gaikawad et al., 1973, MRID 05017001). The effect on nitrogen fixation is
unclear because endosulfan stimulated the growth of Azobacter vinelandii by 100
percent but reduced it nitrogenase activity by 77 percent (Peeters et al.,
1975, MRID 05004262). Thus the inhibition of nitrogen-fixing capacity of A.
vinelandii by endosulfan might be offset by increases in its growth. Seven
symbiotic Rhizcbium species were not inhibited in vitro by 0.2% endosulfan;
however, R. leguminosarum was slightly inhibited~(Bandyopadhyay et<;al., 1979,
MRID 05013674). Endosulfan applied at 20-38 kg/ha (18-24 lb/A) to soil
initially inhibited the soil microbial population. The micrcbial population
39
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was able to recover within 20 days. The application rate was in excess of the
application rates recommended in the use patterns, therefore, it is possible
that there would be no initial inhibition of the micrcbial populations (Roy et
al., 1975, MRID 05010061).
Data from a photolysis study (Archer et al., 1972, MRID 05002841) demonstrated
that endosulfan and its metabolites volatilized when directly exposed to
sunlight. More than DD percent of the applied endosulfan or individual
metabolites may be lost by volatilization after severe exposure for seven
days. Monitoring studies also show that endosulfan volatilizes. Spiro and
Trevisani (1974, MRID 05013707) found endosulfan background levels of up to
25 ng/m3 in Italy in 1973. Strachan and Huneault (1979, MRID 05019845) found
endosulfan I and II residues in some rain and snow samples collected in the
Great Lakes region in Ontario in 1976. Although the data presented partially
fulfill the requirements for determining volatility, no attempts were made to
identify the volatized compounds and full analytical procedures were not
detailed.
Field studies (Stewart and Cairns, 1974, MRID 05003336 and Stanovick, 1966,
MRID 00003800) show that endosulfan is degraded to endosulfan sulfate in soil.
Residues of endosulfan sulfate and both isomers of endosulfan were present 469-
800 days after treatment. Numerous soil monitoring studies (Harris and Sans,
1971, MRID 05002908; Harris et al., 1977, MRID 05005136; Miles and Harris,
1978, MRID 05003003; Mullins et al., 1971, MRID 05003035; Wiersma et al., 1972,
MRID 05004938; Carey et al., 1979, MRID 05004976; Carey et al., 1979, MRID
05004978; Frank et al., 1977, MRID 05004013; Frank et al., 1976, MRID 05003049;
Miles et al., 1978, MRID 05005044; Harris et al., 1966, MRID 05002907; Carey et
al. 1979, MRID 05020171; Wiersma et al., 1972, MRID 05020663; and Carey et al.,
1978, MRID 05005978) conducted in North America in the 1960's and 1970's report
endosulfan and endosulfan sulfate residues in soil, providing further evidence
that endosulfan is persistent in soil. Therefore, annual applications or
several applications during a single growing season (which is allowed under the
current use patterns) would be expected to result in the accumulation of
endosulfan and endosulfan sulfate residues in the soil. The data from these
studies are insufficient to determine the dissipation rate of endosulfan.
Numerous aquatic monitoring studies (Frank et al., 1979, MRID 05017234; Frank
et al., 1979, MRID 05018066; Frank et al., 1977, MRID 05003337; Glooschenko and
Sampson, 1978, MRID 05005248; Greve, 1972, MRID 05004513; Greve and Wit, 1971,
MRID 05003342; Herzel, 1972, MRID 05003109; Miles, 1976, MRID 05002902; Miles
and Harris, 1971, MRID 05002903; Miles and Harris, 1973, MRID 05003001; Olney,
1972, MRID 05007651; Saleh et al., 1978, MRID 05004418; Gorbach et al., 1971,
MRID 05003017 and Wall et al., 1978, MRID 05003366) conducted in North America
and Europe report finding endosulfan in water, sediment, and fish samples
collected from areas where aquatic crops (watercress) treated with endosulfan
are not grown commercially. None of the samples were analyzed for the
endosulfan hydrolysis product endosulfan diol.
It cannot be concluded that endosulfan or its degradation products are
currently present in the aquatic environment because insufficient data are
available.
Data from Ernst (1977, MRID 05003053) indicated a low to moderate endosulfan
accumulation potential in the mussel Mytilus edulis. At equilibrium, mussels
40
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had an endosulfan bioconcentration factor of 600, with soft tissue containing
endosulfan at 84 ppb and the water containing endosulfan at 0.14 ppb. A
depuration half-life of 34 hours was calculated. However, it must be noted
that endosulfan was applied with six other pesticides, and thus interactions
among them may have influenced the results.
In experiments conducted by Schimmel (1979, MRID 05005824), bioaccumulation
factors of 2755X were found for the whole body of striped mullet, and 2249X for
the edible tissue of striped mullet after exposure to 0.08 ppb of endosulfan
for 28 days. After 48 hours in endosulfan-free seawater, no insecticide was
detected in either the edible or whole body tissues. These two studies
collectively satisfy the Guideline requirements for fish accumulation.
In summary, based on the available data, endosulfan will accummulate in the
terrestrial environment for several years when applied annually or several
times during a single growing season. When applied to soil, endosulfan'will be
gradually oxidized by microorganisms to endosulfan sulfate. Both endosulfan
and endosulfan sulfate are persistent in the.environment.
At pH values above 6.5, endosulfan undergoes hydrolysis to endosulfan diol.
This process is probably chemical but appears to be accelerated by microbes.
Endosulfan diol is degraded to endosulfan alpha-hydroxyether, which is degraded
to endosulfan lactone. Endosulfan lactone has been shown to be degraded in
aqueous soil culture media, but no data are available on degradation products
of endosulfan lactone. In addition, there are no data showing the breakdown of'
endosulfan's chlorinated ring, which implies that the ring will be stable in
the environment. Endosulfan severely inhibits soil microorganisms for
approximately 20 days, therefore, repeated applications of endosulfan within
this period (which is allowed under the current use patterns) may prolong these
inhibitory effects.
In the aquatic environment endosulfan is present in sediment, water, and fish
samples. Since it does not appear that these residues are the result of the
use of endosulfan in the aquatic environment, endosulfan must be considered as
a potential pollutant of the aquatic environment. It is likely that endosulfan
diol is also present in the aquatic environment as a result of endosulfan
hydrolysis; however, no data are available on the fate of endosulfan diol in
the aquatic environment.
C. EXPOSURE PROFILE
The use of airblast machines (which direct the spray upwards) and aircraft
sprayers increases the potential for exposure, via spray drift, of humans,
livestock, or wildlife outside the application site. Human exposure potential
via groundwater contamination cannot be assessed because soil mdbility data are
lacking. However, the potential for contamination of surface waters was
demonstrated by the presence of endosulfan and endosulfan sulfate residues in
surface waters sampled in the United States and Canada from 1968-1973. Levels
of contamination were generally less than 1 ppb, and the majority of all
samples collected did not contain the compounds at detectable levels.
Endosulfan residues indicated a potential to accumulate in aquatic organisms.
A maximum bioaccumulation factor of 600 was reported in the mussel Mytilus
edulis, with a depuration half-life of 34 hours. Data were also presented that
the bioaccumulation factors in striped mullet ranged from 2249 to 2755X.
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The mixers and' applicators of endosulfan formulations have the highest
potential for direct exposure. Sprayers applying endosulfan with tractor-drawn
airblast equipment in Washington State fruit orchards were exposed dermally at
an estimated 0.6-95.3 mg/hour (mean 24.7 rag/hour), and respiratory exposure was
an estimated 0.02 mg/hour during application (Wolf et al., 1972, MRID
05003239). Another study investigated the duration of pesticide residues on
the hands of farmers. Hexane rinsings of the hands of eight farmers revealed
endosulfan residue levels from 33.2 down to <0.2 ug, 1-32 days after the last
endosulfan application, respectively (Kazen et al., 1974, MRID 05003086).
Although the formulations of endosulfan were not specified in the above
studies, the exposures during field applications to fruit trees would be
similar for all formulations. Quantitative data are not available to estimate
the exposure potential during other kinds of field operations. However, an
additional potential for respiratory exposure would occur during opening and
mixing of the wettable powder, when "puff back" may contaminate the air.
Emulsifiable concentrate formulations increase the potential for dermal
exposure during the mixing operations due to splashing of the concentrate.
No data were found to quantify the potential exposure during the use of
pressurized liquid or impregnated material formulations on ornamental crops and
in greenhouses. Aerial dusting operations may expose flaggers, but again, no
data are available to quantify such exposure.
California has set a reentry interval of 48 hours following endosulfan
application for all crops.
D. SUMMARY OF DATA GAPS
A nunber of the guideline requirements have been partially fulfilled by the
data submitted. However, data are still needed to adequately assess the
environmental fate of endosulfan. The specific deficiencies can be found in
the Data Requirement Charts in Chapter III. The data gaps include: hydrolysis,
photcdegradation, aerobic and anaerobic soil metabolism, leaching, volatility,
adsorption/aesorption, and terrestrial field dissipation. Data on the
following requirements are reserved pending the review and modification of the
testing protocols: microbial metabolism, activated sludge metabolism, reentry,
and disposal and storage.
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VI. TOXICOLOGY
A. Toxicology Profile
B. Human and Domestic Animal Hazard Assessment
C. Summary of Data Gaps
A. TOXICOLOGY PROFILE
No data are available on the acute effects of end-use endosulfan products.
Testing will be required to assess the acute oral, dermal, inhalation, and
primary eye and dermal irritation effects of representative formulations. The
specific data requirements can be found in Chapter III.
1. Acute Effects
Sufficient data are available to show that technical endosulfan has a high
acute oral toxicity to mammals and is assigned to Toxicity Category I (see
Table 1). Acute intoxication signs are manifested as depression, salivation,
lacrimation, labored respiration, tremors and tonic-clonic convulsions. The
chemical was also shown to be more toxic to female than to male rats.
There are sufficient data to demonstrate that technical endosulfan is highly
toxic to mammals dermally, and can be placed in Toxicity Category I. The seven
day dermal LD^Q values for female rabbits were found to be 167-182 mgAg for
the technical product (Gupta and Chandra, 1975, MRID 05003718).
A combination of two supplementary studies indicated that technical endosulfan
is highly toxic to manroals by inhalation. Ely et al. (1967, MRID 05007645)
determined that the four hour LC^Q values for technical endosulfan were 0.35
and 0.08 mg/1 for male and female rats, respectively. In another study (Reno,
1975, MRID GS014005), ten male albino rats were exposed to endosulfan technical
dust at concentrations of 1.16 and 5.66 mg/1 for one hour. The LCcn value
was not determined. However, it may be estimated to be between 1.16 and
5.66 mg/1. On the basis of the inhalation toxicity data, technical endosulfan
is assigned to Category I.
In a study to evaluate the primary eye irritation potential of endosulfan
(Reno, 1975, MRID GS014004), six New Zealand rabbits received 83 mg of
technical endosulfan in one eye. No corneal opacity was observed but all
animals showed slight conjunctivae which cleared in four of the animals by 72
hours. Based on this study, the material can conservatively be assigned to
Toxicity Category III for eye irritation.
A primary dermal irritation study was conducted (Reno, 1975, MRID GS014003) in
which six New Zealand rabbits were dermally treated with 0.5 gram of endosulfan
on abraded and nonabraded skin areas. At 24 hours, all animals exhibited minor
erythema; by the end-of 72 hours it had cleared in four animals. The primary
dermal irritation score was 0.9. This material is therefore assigned to
Toxicity Category IV for dermal irritation.
Although endosulfan does not relate to a known group of cholinesterase
inhibitors, it was reported by Truhaut et al. (1974, MRID 05011227) to cause
the inhibition of hamster serum and rat hepatic cholinesterase. It was also
43
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TABLE 1
Acute Oral LD5Q Values for Technical Endosulfan
Animal
Sprague Dawley Rats
Unspecified Rats
Sherman Rats
Albino Wistar Rats
Sprague Dawley Rats
Unspecified Rats
Mice
Sex
LD,
'50
Male
Female
Male
Male
Female
Male
142 mgAg
53 mgAg
110 mgAg
43
18 mgAg
102 mgAg
Male
Female
Male
Female
40 mgAg
9 mgAg
82 mgAg
21 mgAg-
11
36
8 mgAg
120
270 mgAgf,
>2,000 2
Reference
Palazzolo, 1964, MRID 00003762
Elsea, 1957, MRID 00003693
Gains, 1969, MRID GS014007
Boyd et al., 1970,
MRID 05002183
Reno, 1975, MRID GS014001
Palazzolo, 1964,
MRID 00003762
Dorough et al., 1978,
MRID 05003703
I/ The LD5Q value is for the endosulfan sulfate metabolite.
2/ The LDgQ value is for the endosulfan I isomer.
3/ The LDgQ value is for the endosulfan II isomer.
4/ The ID,JQ value is for the -hydroxy ether and lac tone metabolites.
5/ The LD50 value is for the ether metabolite.
6/ The LD value is for the diol metabolite.
44
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reported by Gupta (1976, MRID 05007646) that acetylcholinestcrase activity in
the rat brain was decreased by 23-33 percent after intraperitoneal injection of
30 to 60 mgAg of endosulfan. Furthermore, the chief signs of acute
intoxication were mainly manifested as tremors and clonic convulsions that
could be centrally mediated. The intensity of these symptoms correlated well
with the concentration of endosulfan in all areas of the central nervous system
(Khanna et al., 1979, MRID 05004972). Since the compound causes esterase
depression, testing is required to assess the delayed neurotoxic potential of
endosulfan. The neurological effects may be included as an additional
parameter in the subchronic and/or chronic studies.
2. Subchronic Effects
In a rat subchronic feeding study endosulfan was orally administered to rats
daily for 15 days at the rate of 0, 5, or 10 mgAg. The liver and kidneys
appeared to be the organs most affected (Gupta and Chandra, 1977, MRID
05003078). Histopathological examination of the liver and kidney revealed
dilation of sinusoid around central veins, areas of focal necrosis and
degeneration of hepatocytes and mononuclear monolucocytes, proliferation in the
bile duct, and degenerative alterations in the epithelial lining of kidney
tubules. Other effects were kupffer cell hyperplasia, inflammatory areas in
the subpleural of the lungs and dilation of the alveoli, and severe
degeneration of the seminiferous epithelium. A "no observed effect level"
(NOEL) could not be established under the conditions of this experiment. This
study cannot be used to satisfy the subchronic feeding requirements.
3. Chronic Feeding
In a chronic feeding study (Keller, 1959, MRID 00003602), groups of 50 (25 male
and 25 female) Wistar strain rats were fed 0, 10, 30, or 100 ppm of technical
endosulfan incorporated in their diets for two years. Gross appearance,
behavior, body weight, food consumption, and hematological values were found to
be within normal ranges for all groups. A significant decrease in the number
of surviving females in the 100 ppm group was reported. Males received 100 ppm
showed a slight to moderate growth suppression throughout the study. No
increase in the tumor incidence was reported in the treated groups.
Significant increase in the absolute and relative weights of kidney were
observed in males in the 100 ppm group.
Microscopic examination revealed that the liver and kidneys were the organs
most affected by the exposure to the high level of endosulfan. The major
kidney lesion manifested as renal tubule dilation, formation of albuminus
casts, focal intersitital nephritis, and degeneration of tubule epithilium.
Histopathological examination of the livers of males in the 100 ppm group
revealed hydrophopic hepatic cells with pale eosinophilic cytoplasmic
inclusions.
These liver and kidney changes were not seen in the females that survived the
100 ppm treatment for the duration of the study. The NOEL was considered to be
30 ppm.
However, in addition to the small number of animals that were initially
assigned to each test group, the number of animals that survived the two year
45
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feeding were also limited. Furthermore, hematological and pathological
examinations and the nunber of animals examined were also limited. In
addition, no blood chemistry or urinanalysis were performed. For these
reasons, this study was classified as invalid and cannot be used for an
adequate assessment of toxic reactions resulting from the chronic ingestion of
endosulfan.
In a study by Baran (1967, MRID 00003741) four groups of eight beagle dogs
(four males and four females) were administered 0, 3, 10, or 30 ppm of
endosulfan in the diet for two years. One male and one female of each group
were sacrificed after one year. The rest of the animals were sacrificed at the
end of the study. Gross and histopathological examinations were performed on
all animals. No abnormal behavioral reactions were noted. Hematological arrl
clinical chemical testing and urinalysis did not reveal significant treatment
related effects. Gross and histopathological examinations did not reveal any
treatment related effects. The NOEL was considered to be 30 ppm.
Validation of this study was inconclusive. The study had major deficiencies
that could render it invalid, e.g. the lack of raw body weight data that
prevents complete validation as whether the same animals were used throughout,
the presence of differential leukocyte counts record at 18 and 21 months for a
male that died at 15 months although these were not included in the final
report, histopathological reports were not dated and contained no gross
pathology or organ weights, no raw data for food consumption, in addition two
females were suspected as being from a previous study. Although providing some
information of toxicological value, this study cannot be used to satisfy the
chronic feeding requirements.
In another study (Keller, 1959, MRID 00003604) endosulfan was orally
administered at the rate of 0.075, 0.25, or 0.75 mgAg/day in gelatin capsules,
six days a week for one year to mongrel dogs. There did not seem to be any
treatment related adverse effects with respect to the rate of growth, internal
organs weight, biochemical and hematological testing, and urinalysis. Gross
and histopathological examinations also did not reveal any significant
difference between treated animals and controls. A NOEL is considered to be
0.75 mg/kg or 30 ppm. This study satisfies the Agency requirement for a
chronic feeding study in dogs.
4. Oncogenicity
In an oncogenic study in mice, endosulfan was administered in diets at the time
weighed average concentrations of 3.5 or 6.9 ppm and 2.0 or 3.9 ppm to males
and females respectively (U.S. National Cancer Institute, 1978, MRID 00004256).
No treatment related increase in tumors or compound related effects on body
weight changes, appearance, or general behavior were observed. However, the
high incidence of death among the males precludes the conclusion that
endosulfan does not have oncogenic potential and the negative results in this
sex should be regarded" as inconclusive.
In another study in the same report, endosulfan was administered in the diet to
male and female rats at the time weighed average concentrations of 408 and 952
ppm and 223 and 445 ppm respectively. The males in this study showed a
significant dose related depression in the rates of growth and survival. The
incidence of toxic nephropathy was significantly elevated in both sexes at all
.46
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dosage levels,, A significant increase in parathyroid hyperplasia associated
with these renal lesions and testicular atrophy were noted in male rats at both
dosage levels. Also associated with the parathyroid lesion was medial
calcification of the blood vessels „ No evidence of carcinogenicity was found,
however, the early death of the male rats preclude the usefulness of any
analysis of late developing tumors. As with the mouse study previously
discussed, such negative results for the males should be viewed with a great
deal of cautiono Furthermore „ several serious non-neoplastic lesions due to
endosulfan treatment were noted at both dose levels. Therefore, it is
concluded that any future regulatory actions for endosulfan should await the
establishment of no-cbservable-ef feet- levels for these lesions.
In another onccgenic study (Bionetics Research Laboratories, 1968, MRID
05010016),, endosulfan was tested in two different strains of mice by
incorporation in the diet at 3.0 or 6«0 ppm for 18 months or by a single
subcutaneous injection. In the feeding study, survival was very poor for both
strains at the high dosage level. There were four pulmonary adenomas found in
the males at the low dose level against two observed in the controls, and three
animals showed hepatomaSo A significant increase of pulmonary adenoma in
treated mice were also reported with no distinctions between animals of
different sex or strain. In the subcutaneous study, there were no significant
treatment-related differences in the number of mice surviving for the duration
of the experiment o There ware no increases in the tumor incidence in the
treated groups „
Although providing some information of toxicolcgical value, these onccgenic
studies do not meet the current Agency's requirements for onccgenic evaluation,
therefore additional studies in both the rat and the mouse are still required.
5. Teratogenicity
A study fesas conducted by Haley (1972, MRID 00003712) to assess the teratogenic
potential of enciosulfan. Twenty female Charles River rats were treated orally
with 0.5 mgAg/day, and another 23 females were treated with 1.5 mgAg/day,
from the sixth day through day 15 of gestation. No significant differences
were noted between the treated and control animals with respect to mortality
and body weight of dams, number of implantations, resorption sites, viable
fetuses, fetal skeletal development, and fetal external and internal
abnormalities.
Formation of terata was not evident in this study. The higher incidence of
changed atria size in the treatment groups perhaps represent a fetotoxic
effect o The significance of this finding is dubious, considering the
development state of the fetuses and the lack of clear dose response regarding
small atria o Kence it must be concluded that further investigation is required
to more clearly define the fetotoxic/teratogenic potential of endosulfan.
This study has recently undergone an audit which indicated that the raw data do
not support the conclusions in the final report. In addition, the fetuses in
all groups ware underdeveloped possibly due to the fact that the animals were
sacrificed prior to the scheduled 20th day of gestation. There was an
unreported increase of the small atria of 59.5 percent in one group and 42.9
47
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percent in the other group. There was also a ten-fold increase in large atria
in one group not reported .
As a result of these discrepancies and problems, this study is considered
invalid and cannot be used to support the safety of endosulfan with respect to
the teratogenic potential.
Gupta et al. (1978, MRID 05003227) investigated the teratogenic and enbryotoxic
effects of endosulfan in rats. One female rat died in the 5 mg/kg dose group
and five females died in the 10 mgAg group. At the high dose (10 mgAg)r
there was a significant increase in the number of litters with resorptions and
in litters with skeletal abnormalities. Since no raw data were presented in
this study, it cannot be considered a reliable assessment for the teratogenic
potential of endosulfan.
In a teratogenic study in the rat, a number of skeletal, visceral, and external
anomalies as well as significant reductions in size and weight were reported in
fetuses of the high (6 mgAg) treatment group (Raltech Scientific Service,
1981, MRID GS014008). However, at this dose level, maternal toxicity was
evident as manifested by decreased body weight and decreased body weight gain,
and clinical observations indicating central nervous system stimulation. The
NOEL for fetotoxicity is considered by the authors to be 2
In another study (Raltech Scientific Services, 1981, MRID GS014023) endosulfan
was orally administered to groups of pregnant rabbits at the rate of 0.3, 0.7,
or 1.8 mgAg/day on days 6 to 28 of gestation. Animals were sacrificed on day
29 of gestation. Maternal toxicity was evident in the 1.8 mgAg group as
manifested by noisy and rapid breathing, hyperactivity, convulsions and death.
There were no significant differences in the mean number of corbora lutea,
implantation efficiency, litter size, sex ratio, mean fetal length and weight
or in the number and percent of live and resorbed fetuses.
Gross and histopathological examinations of the fetuses did not reveal any
treatment related effects. However, common skeletal variations and anomalies
were present in all groups. The NOEL for maternal toxicity is considered to be
0.7 mgAg/day.
The above studies satisfy the Agency's requirements for teratology data.
6. Mutagenicity
A dominant lethal study in the mouse indicates that the number of
implantations, resorptions, and embryos were not affected by endosulfan
treatment (Arnold, 1972, MRID 00003711). The results did not indicate a
dominant lethal response at 5 and 10 mgAg.
In another study by Dikshith and Datta (1978, MRID 05003502), endosulfan was
administered orally to rats at 0, 11.0, 22.0, 36.0, and 55 mgAg daily for five
days. The rats were injected with 4 mgAg of colchicine four hours before they
were killed by decapitation.
Seminiferous tubules and bone marrows from the femurs were examined . There
were no major chromosomal aberrations either in the bone marrow cells or
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sperroatogonial cells. An unspecified nuitber of chromatid breaks with one or
two exchange figures were found in the bone marrow cells but not in the
spermatogonial cells. There was no chromosomal deletion nor formation of large
numbers of fragments. No significant mitotic inhibition were reported in any
of the treated groups. No details or quantitative effects data were reported,
therefore, no reliable conclusions can be drawn from this study.
In a recent study by Dorough et al. (1978, MRID 05003703), endosulfan and its
major metabolites were tested in Salmonella typhimurium mutagenicity test using
tester strains TA98, TA100, TA1535, and TA1978^The chemicals were tested at
concentrations of 10, 100, 500, and 1000 ug/plate in duplicates in the presence
and absence of an activating system. Acetoaminoflourine was included as a
positive control. Neither endosulfan I or II, nor any of the metabolites
tested showed any increase in the reversion rates beyond the controls, both in
the presence or absence of the activating systems. The diol, alpha hyroxy
ether, and the lactone metabolites severely inhibited bacterial growth even at
the lowest concentration used.
In this experiment it was obvious that only one S-9 concentration and
insufficient duplication were used. Furthermore, no raw data were provided.
For these reasons this study cannot provide reliable assessment for the
mutagenic potenial of endosulfan.
In a supplementary study (Fahrig, 1974, MRID GS014009), endosulfan did not
exhibit any positive response when tested for mutagenic potential in
Saccharomyces cervisia (mitiotic gene conversion), Escherichia coli (forward
mutation), and Serratia marcescens (reverse mutation).
The Agency requires a battery of valid mutagenicity tests which determine the
potency of the chemical to induce point mutations and chromosomal mutations
either directly or indirectly. The submitted studies do not adequately define
the mutagenic potential of endosulfan, and therefore additional testing will be
required.
7. Metabolism
The metabolism of endosulfan has been adequately delineated in a number of
different mammalian species. In some studies conducted on rats (Dorough et
al., 1978, MRID 05003703) it was found that endosulfan metabolites accumulated
in tissues, especially in the kidney and liver. Metabolites of endosulfan in
the rat include endosulfan sulfate, endosulfan diol, endosulfan ether,
endosulfan alpha-hydroxy ether, and endosulfan lactone. The sulfate and alpha-
hydroxy ether are the principal metabolites accumulated in tissues. Animals
administered endosulfan I eliminated 74.8 percent and 13.2 percent in the feces
and urine respectively, while those administered endosulfan II eliminated 68.3
percent and 18.5 percent in the feces and urine respectively .in a period of 120
hours. Up to 47 percent of the administered dose was eliminated via the bile.
Enterhaptic circulation was not apparent.
In another study (Deema et al., 1966, MRID 00004257) when mice were fed
endosulfan, large amount.', of endosulfan sulfate were recovered in the liver,
small intestine and visceral fat with a trace of this metabolite in the muscle
49
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and kidney after 24 hours. Endosulfan was found in the stomach, small
intestine and the feces. Endosulfan alcohol was detected in the urine. The
principal metabolic products were found to be endosulfan sulfate and
alcohol.Schuphan et al. (1968, MRID 05007464) studied the metabolism of
radiolabeled endosulfan I and II in rats and mice orally, intraperitoneally and
duodenally. The metabolites detected in the feces after the oral and
intraperitoneal administration were identified as lactone, alpha-hydroxy ether,
and sulfate derivatives of endosulfan in addition to the parent compound.
Urine metabolites were identified as the lactone and sulfate derivatives in
addition to an unknown metabolite and the parent compounds. Substances
detected in the bile after duodenal administration of either isomers were the
lactone and the unknown metabolite in addition to traces of the parent
compounds. In general, both isomers produced the same type of metabolites, but
in different proportions. When both endosulfan I and II were administered in
equal amounts, the ratio of the I and II isomers excreted in the urine after 24
hours was 5:1.
Chin and Stanovick (1964, MRID 00003761) found that most of the test material
(endosulfan I and II) was excreted in the feces and only traces were detected
in the urine of dogs. Endosulfan sulfate was the only metabolite found.
Gupta and Ehrnebo (1979, MRID 05003503) found that after interveneous
administration of endosulfan to rabbits, plasma clearance was 2.70+ 1.33
ml/hour/kg for the alpha isomer and 70.1-f 18.6 ml/hour/kg for the beta isomer.
8. Donestic Animal Safety
In a report by Schmidlin and Romann (1971, MRID 05013366), eight cows were
accidently fed hay contaminated with 750 to 900 ppm of endosulfan. Three of
the animals became severely ill. The symptoms were manifested as tonic-clonic
cramps, wobbly gait, dyspnea, muscle twitching, and salivation. One of the
three animals had to be sacrificed, the other two recovered after the
contaminated feed was removed.
Another case of domestic animal poisoning with endosulfan was reported by
Utflev and Westbye (1971, MRID 05012611) when a group of female sheep grazed in
a strawberry field that had been sprayed four days earlier with endosulfan.
Two of the lambs became ill with initial symptoms of unsteady walk and
uncontrolled leg movements, followed by an inability to stand. One animal
recovered after 24 hours, while it took one month for the recovery of the
second animal. The maximum dose that the animals ingested was estimated to be
5 rag/kg.
Nicholson and Cooper (1977, MRID 05003772) reported accidental poisoning in
five calves when they were dusted with 4% endosulfan dust for lice control.
About 12 hours later one calf was dead and the remaining four exhibited
poisoning symptoms manifested as muscle tremors, twitching of the ears,
snapping of the eyelids, violent body jerks, inability to stand, and occasional
convulsions. Frenzied activity and aimless jumping were also observed.
In a study conducted by Keller (1959, MRID 00003603) to evaluate the safety of
endosulfan to domestic animals, mature lactating Holstein dairy cows were fed
radiolabeled endosulfan at levels of 0.0, 0.3, 3.0 and 30 ppm for a period of
30 days. During this period and a subsequent 14 day recovery period, all of
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the animals exhibited normal appearance and behavior. Food consumption and
milk production were within normal limits. At the 3.0 and 30 ppm dietary
levels, concentration of labeled endosulfan in the blood gradually increased
for the first 21 days, and the level remained essentially the same for the
remainder of the period. During the 14-day recovery period there was a 60 and
52 percent reduction in blood endosulfan levels for the 3.0 and 30 ppm doses,
respectively. A sharp increase in the amount of labeled endosulfan in milk was
observed in the first week. The level remained essentially the same after that
and the residue entirely disappeared at the end of the recovery period.
9. Human Ibxicity and Epidemiology
Ely et al. (1967, MRID 05007645) reported nine cases of worker exposure to
endosulfan dust. All of these cases showed clonic convulsive episodes as the
chief symptom of acute intoxication. In all cases the route of exposure was
thought to be dermal or inhalational.
Six cases of human exposure to endosulfan were reported by Terziev et al.
(1974, MRID 05007645). In all cases, ingestion was the major route of
exposure, and five of the six cases were fatal. The signs of acute poisoning
were manifested as gagging, vomiting, agitation, tonal writherings, dyspnea,
and cyanosis. The deaths occurred within 1.5 to 3 hours. Autopsies in three
cases revealed circulatory abnormalities, including edema of the brain and
lungs, acute emphysema, and protein dystrophia in the parenchymal organs.
Staining showed almost complete chromatolysis at the neurons with karyolysis
and vascuolization in some of these cases.
Wolf et al. (1972, MRID 05003239) found that the dermal and respiratory
exposure of sprayers to a 0.06% spray of endosulfan was 24.7 mg/hr and 0.02
mg/hr, respectively. The stated exposure equaled 0.27 percent of a toxic dose
per hour.
Oiribier et al. (1974, MRID 05001387) measured the exposure to endosulfan using
respirator pad analysis and found that exposure was greater during the mixing
operation than during spraying. With a five minute exposure time, 182,800 ng
were detected on the respirator pad during the mixing while only 4,664 ng were
detected during the 30 minute spraying operation.
The potential vulnerability of the central nervous system of humans to
endosulfan was demonstrated in epileptic convulsions and altered EEC patterns
in three subjects exposed to the pesticide (Tiberia et al., 1970, MRID
00003077). In one of the subjects, occasional EEC alterations were observed a
year after the exposure.
10. Pharmacology
Endosulfan was shown to exert a slight contraction action in the rectus muscle
of a frog in an experiment using endosulfan at concentrations of 5 X 10 M or
greater. Acetylcholinesterase effects were observed at 6.5 X 10 M (FMC,
1956, MRID GS014006).
In the same study, a lowering of the blood pressure occurred in cats at a dose
51
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_
level of 0.1 mgAg or higher. At a molar concentration of 3 X 10 M or
higher, endosulfan apparently dampened the frequency and strength of the cat
heart beat.
After repeated oral administration of 5 or 10 mgAg of endosulfan to rats, the
compound was detected in the plasma and different parts of the brain (Gupta,
1978, MRID 05003361). The amount of endosulfan I in the brain was in
proportion to the blood level of the isomer. This was not the case for
endosulfan II whose concentration in the brain was much less than expected from
the plasma levels. This indicates the difference in the blood /brain barrier
permeability to each of these isomers art} may partially explain the difference
in their acute toxicities. Other factors that may contribute to the difference
in toxicity is the difference in the rate of metabolism and elimination of the
two isomers.
Khanna et al. (1979, MRID 05004972) studied the effects of endosulfan on the
cat brain. Endosulfan in propylene glycol was administered interveneously at a
concentration of 23 mgAg. The concentration in the lipids of the cat brain 15
minutes and up to six hours after administration was three times greater in the
cerebral cortex and cerebellum than in the brain stem and spinal cord. The
intensity of the convulsions and tremors correlated well with the concentration
of endosulfan in all areas of the central nervous system.
Oral administration of endosulfan to male and female rats at seven or 15 days
before an injection of pentobarbital increased liver weights, shortened sleep
time, increased induction time and rapidly decreased pentobarbital levels in
the blood and brain after 30 minutes (Gupta, 1977, MRID 05003362 and Gupta et
al., 1977, MRID 05003363).
Agarwal et al. (1978, MRID 05005443) found that oral administration of
endosulfan to rats at 2.5 or 5.0 mgAg daily for 14 days, induced hepatic lipid
peroxidase, aminopyrine-N-d erne thy lase, aniline hydroxylase, and tyrosine
aminotransferase.
Erdosulfan at 30 and 300 ug/ml did not inhibit liver microsomal-O-demethylase,
and at 50 and 500 ug/ml did not inhibit rat or mouse liver UDP-glucuronyl
transferase in vitro (Fonberg-Broczek, 1974, MRID 05007036).
11. Emergency Treatment
Supplementary information available (Kretchman, 1971, MRID 00003886) indicates
that atropine sulfate was a more effective antidote than pentobarbital, which
had only a slight therapeutic effect. Further studies are deemed necessary to
elucidate the mode of action of the convulsions and tremors which may be
centrally mediated, and to develop a more efficacious antidote for emergency
treatment of the acute poisoning cases.
B. HUMAN AND DOMESTIC ANIMAL HAZARD ASSESSMENT
Endosulfan has a very high acute toxicity to mammals via oral, dermal, and
inhalational routes. The major symptoms of acute intoxication are manifested
as tremors and convulsions indicating the involvement of the central nervous
system as a possible target site.
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A complete assessment of hazards associated with the long term exposure to
endosulfan cannot be made because only one valid chronic study is available.
However, there is an indication that the organs most effected by long term
exposure are the liver and kidneys. Furthermore, there are indications that
the chemical causes parathyroid hyperplasia, testicular atrophy, seminiferous
tubular epithelial degeneration, and calcium deposition in blood vessels as a
result of chronic exposure. Some of these adverse effects may be attributable
to calcium metabolism alteration. Endosulfan did not appear to alter the tumor
profiles of female mice and rats, however, no conclusion can be made with
respect to the tunorigenesis in males of either species. These aspects will
have to be carefully examined in future investigations.
No acute toxicity data have been submitted to evaluate the toxicity of end-use
endosulfan products. The endosulfan exposure profile (refer to Chapter V)
provides that maximum exposure will occur to those involved in direct mixing,
loading, and application of the end-use products. The principal routes of
exposure are anticipated to be dermal and inhalational, the latter coming from
applicator exposure to spray mist. Until such data are submitted and reviewed,
the Agency cannot make an evaluation of the hazards of the various end-use
products to humans and domestic animals.
C. SUMMARY OF DATA GAPS
Data gaps for dermal sensitization, acute delayed neurotoxicity, subchronic
oral toxicity, subchronic 21 day dermal toxicity, subchronic inhalation
toxicity, chronic feeding (rat only), oncogenicity (rat and mouse),
reproduction, and mutagenicity must be filled for technical endosulfan. No
data were available to assess the acute toxicity (oral, dermal, inhalational,
eye and skin irritation) of endosulfan formulations. See Chapter III for the
specific requirements for each type of formulation.
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VII. RESIDUE CHEMISTRY
A. Residue Chemistry Profile
B. Labeling Requirements
C. Summary of Data Gaps
A. RESIDUE CHEMISTRY PROFILE
1. Uptake, Distribution, and Metabolism in Plants
The absorption, distribution, and metabolic fate of endosulfan have been
extensively studied. Endosulfan is not generally translocated in plant
tissue. The residue remains where the pesticide application happened to
bemade. For example, FMC Corporation (1958, MRID 00003600) compared residues
in strawberries by two extraction procedures: macerate extraction of unstripped
strawberries versus surface stripping. There was no obvious difference in
residue values between the two procedures, leading to the conclusion that
endosulfan residues were not absorbed by the strawberries.
In a second study, FMC Corporation (1964, MRID 00003642) showed that total
residues of 0.11 to 0.15 ppm in the pulp of sweet potatoes from preplanting
soil treatment, while surface residues were from nondetectable to 0.11 ppm.
One sample of whole macerated sweet potato showed 0.37 ppm total endosulfan,
while other samples had nondetectable residues. In another experiment by FMC
(1969, MRID 00003709), there was no detectable residues of endosulfan or
endosulfan sulfate in macerate extraction of potatoes, while surface stripping
showed low but detectable residues.
Ware et al. (1961, MRID 00003654, and Ware, 1967, MRID 05011420) applied
radiolabeled endosulfan to alfalfa. The studies showed a decline in endosulfan
residues on the alfalfa, and also showed that endosulfan could be converted to
another product whose half-life is greater than endosulfan per se, and shown to
be endosulfan sulfate. In addition, traces of the impurity, encfosulfan ether,
occurred seven days after application.
Harvested alfalfa was treated with endosulfan and subsequently stored under
ultraviolet light, sunlight, and dark conditions (Archer, 1973, MRID
05002843). The maximum loss of total endosulfan occurred seven days after
application and exposure in the dark, five days on ultraviolet exposure, and
six days of sunlight exposure. In all exposure situations endosulfan sulfate
as a percentage of total residues increased most dramatically in the dark.
Endosulfan I hydroxyether increased in sunlight up to seven days. No
endosulfan lactone was detected in any of the exposure situations.
The metabolism of endosulfan in bean plants was studied by Terranova (1962,
MRID 05018169) and Terranova and Ware (1963, MRID 05004385). These studies
showed that endosulfan I and II, endosulfan alcohol, and endosulfan ether are
each absorbed via roots and translocated -to aerial plant portions. Foliar
application of endosulfan showed some metabolism to endosulfan ether but not to
the alcohol metabolite.
Harrison et al. (1967, MRID 05004620) researched the persistence of endosulfan
I and II on apple leaves and found the formation of an unidentified material
54
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that later was shown to be endosulfan sulfate. Endosulfan sulfate was found to
be more persistent than either of the isomers. It composed 75 percent of the
total residue on apple leaves at three weeks and 90 percent at eleven weeks.
The metabolism and translocation of endosulfan I and II, endosulfan ether,
endosulfan diol, and endosulfan sulfate in bean and sugar beet plants was
studied by Beard and Ware (1969, MRID 05002565). Endosulfan sulfate and
endosulfan II translocate to roots in both sugar beets and beans, with greater
amounts in sugar beet roots. Endosulfan sulfate as a metabolite is
translocated, but not when the leaf is treated with endosulfan sulfate per se.
Endosulfan ether was also found as a plant metabolite.
Chopra and Mahfouz (1977, MRID 05003004 and Chopra and Mahfouz, 1977, MRID
05003801) investigated the metabolism of endosulfan I and II, and endosulfan
sulfate in tobacco. The metabolites found were endosulfan sulfate, endosulfan
diol (trace), endosulfan ether, and endosulfan lactone. Also endosulfan I was
found on endosulfan sulfate treated tobacco but not endosulfan II, indicating
the conversion of endosulfan sulfate to endosulfan I. Further, the study found
the intraconversion between between endosulfan I and II, and proposed a
metabolic pathway for the direct hydrolysis of endosulfan I and II and
endosulfan sulfate to endosulfan diol. Another metabolic pathway was
endosulfan hydroxyether converting to endosulfan ether and endosulfan lactone.
Stewart and Cairns (1974, MRID 05003336) found that foliar application of
endosulfan resulted in endosulfan sulfate in potato peel and pulp at 0.01 ppm,
indicating possible translocation of the residue. Absorption of endosulfan I
and II and endosulfan sulfate by potato tubers from granular application was
much higher than from foliar application. Endosulfan sulfate was found in the
pulp while endosulfan I and II and endosulfan sulfate were found in the peel.
The movement of endosulfan into untreated portons of maize plants is reported
by Kavadia et al. (1978, MRID 05003085). After foliar application, endosulfan
was found in the husks 43 to 63 days later. However, there are no reported
results for endosulfan sulfate or other possible endosulfan metabolites.
The metabolism of endosulfan in plants is adequately understood and the
residues in plants are endosulfan I and II, and endosulfan sulfate. Endosulfan
sulfate is found most frequently on leafy surface crops where there is a large
surface to volume ratio. It is less frequently found on root crops such as
sugar beets, potatoes, sweet potatoes, or carrots.
2. Metabolism ir± Food-Producing Animals
The metabolism of endosulfan in animals has been extensively studied in the
cow, sheep, swine and chicken.
Stanovick (1965, MRID 00003838) showed that when lactating cows were fed a
mixture of endosulfan-I and II (5 ppm) plus endosulfan sulfate (5 ppm) in their
daily diet for 30 days, no detectable endosulfan I or II was found in the milk,
liver, kidney, fat or muscle. Endosulfan sulfate was detected in the milk,
fat, liver, kidney, and muscle sampled 30 days after feeding. When the cows
were allowed 30 days of feeding without endosulfan, residues in milk declined
and residues were found in the fat, but not in the liver, kidney, and muscle.
55
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This indicates some storage in the fat. Since this study did not employ
radiolabeled endosulfan, and excreta (other than milk) were not analyzed, a
material balance showing the metabolic distribution of endosulfan in the cow
cannot be estimated.
Erdosulfan and endosulfan sulfate have been reported by Beck et al. (1966, MRID
05003877) in milk and tissues of cattle fed on endosulfan treated silage or
grazed in endosulfan treated pastures of Coastal Bermuda grass. Their results
showed that although endosulfan sulfate was present in the silage, no
detectable residues of endosulfan sulfate were found in the butter fat or
omental fat samples. Endosulfan diol was not detected in any silage sample.
In sheep fed commercial grade endosulfan, metabolism and excretion resulted in
no endosulfan in the kidney, liver, muscle, brain tissue, kidney fat, or
intestinal fat (Gorbach, 1965, MRID 00003743). Up to 20 percent of the
administered compound was excreted in the feces. No endosulfan sulfate was
found in the feces or urine, but was identified in the milk; In the urine,
endosulfan alcohol accounted for 10 percent of the applied endosulfan, and an
unidentified endosulfan derivative accounted for another 20 percent.
The metabolism of radiolabeled methylene endosulfan in milk sheep was studied
by Gorbach et al. (1966, MRID 05003222). With a material balance of 95
percent, almost half of the radioactivity was excreted in the feces and almost
half in the urine. Maximum residues in the tissues were 0.03 mg/g in the
liver, less in the large intestine and fat, and less than 0.02 mg/g in other
organs and tissues. In the feces, the major component was found to be .
endosulfan, while the lactone, diol, and hydroxyether metabolites were not
detectable (less than 0.5 ppm). In the urine, the two metabolites were
endosulfan alcohol and endosulfan I hydroxyether, and two unidentified
metabolites. Endosulfan sulfate was the major metabolite in milk (mainly in
the cream), but the total amount of compound found in the milk was less than
two percent of the applied amount.
The distribution of endosulfan in various tissues of pigs fed technical
endosulfan showed endosulfan I and endosulfan sulfate in several bacon samples
only (Maier-Bode, 1966, MRID 00003742). No detectable endosulfan I and II, or
endosulfan sulfate were found in the liver, gall, spleen, kidney, lungs, heart,
brain, spinal cord, pancreas, blood, neck muscle, tongue, or ovary. Erdosulfan
metabolism is implied by the presence of the sulfate metabolite in the bacon
samples.
Chickens fed technical endosulfan at 0.3 and 3.0 ppm in the diet for seven
weeks showed no detectable endosulfan I or II, or endosulfan sulfate in the
eggs, muscle, heart, liver, gizzards, or intestines (Stanovick, 1967, MRID
00003840). Residues of the I and II isomers were found in the cavity fat at
the higher dosage only.
3. Analytical Methods
There are many methods for analysis of endosulfan in a variety of plant and
animal tissues. Analytical methods include total chlorine analysis,
colorimetric procedures, and gas chromatographic procedures using
microcoulometric, electron capture and sulfur detectors.
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While original tolerances for endosulfan were based on the two isomers of
endosulfan, the residue situation has been complicated by addition of the
metabolite endosulfan sulfate to the established tolerances. When endosulfan
was first registered, available information was that endosulfan was a mixture
of the two isomers, and several manufacturing by-products. In 1963 FMC
reported residues of an additional endosulfan related material, which later
became known as endosulfan sulfate. The first literature publication dealing
with this metabolite was by Cassil and Drummond (1965, MRID 00003795). They
found in some instances, up to 70 percent of the endosulfan residue could be.
endosulfan sulfate. Based on toxicological considerations, it was determined
that endosulfan sulfate would be included in the established tolerances.
Thereupon, an analytical method for quantitative detection of endosulfan
sulfate was required. Since several tolerances for endosulfan had already been
established, it was necessary that a certain amount of additional residue data
for endosulfan sulfate be required.
A nunber of residue studies submitted to the Agency were performed prior to the
initial finding of endosulfan sulfate, and therefore do not have adequate
information regarding the possible presence of endosulfan sulfate. Originally
acceptable procedures for total chloride and sulfur dioxide evolution methods
have not been shown to be adequate to determine endosulfan sulfate.
Microcoulometric gas chromatography had largely supplanted these two methods,
and was found to be adequate for the analysis of the sulfate metabolite.
However, residue data by the microcoulometric gas chromatography method prior
to 1963 are considered adequate for endosulfan per se only, but not adequate
for endosulfan sulfate. Only those residue studies which specifically report^
endosulfan sulfate residues by microcoulemstric gas chromatography procedures
are considered adequate to support currently registered uses of endosulfan.
Analytical methods have been submitted for the analysis of endosulfan and
endosulfan sulfate residues on plant and animal tissues. Most of the methods
are variations on the same basic procedure: endosulfan residues are extracted
from the animal or plant tissues by solvents or mixed solvent systems.
Extracted residues are further refined by several techniques, including solvent
partition or distribution techniques, and adsorption/desorption techniques.
When extracted residues are sufficiently purified, gas chromatography is
employed for quantitative and qualitative analysis. The nature of the sample
dictates the extraction or purification step. Some commodities are high in oil
content (cottonseed, rapeseod, nut crops, etc.), while others are low in
moisture content. Therefore there is a degree of variability in the exact
procedure. The following method descriptions were submitted and deemed
adequate for detecting the two endosulfan isomers and endosulfan sulfate on
commodities: FMC (19??, MRID 00003959)- carrots, sugar cane, sweet corn,
collards, kale, mustard greens, turnip greens, spinach, celery, brussels1
sprouts, cauliflower, sweet potatoes, peas, snap beans, lima beans, sunflower,
and pineapple; FMC (19??, MRID 00003703)- milk and meat; FMC (19??, MRID
00003612)- nut crops; and Stanovick (1967, MRID 00003840)- eggs and poultry
tissues.
The Pesticide Analytical Manual, Vol. II, has three methods for the analysis of
endosulfan per se. The first method is a microcoulometric gas chroma tog raphic
procedure. This method is adequate for enforcement purposes for analysis of
57
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both endosulfan and endosulfan sulfate in a variety of nonfatty foods. It is
Official First Action for the analysis of endosulfan and endosulfan sulfate in
apples and cucumbers. The method is described in Burke and Mills (1963, MRID
05003395).
Method II is a sulfur dioxide evolution nethod. The sensitivity is estimated
at 0.1 to 0.3 ppm of endosulfan per se, and the adequacy for analysis of
endosulfan sulfate has not been shown. As far as it is known, only two common
pesticides, sulfur aryj aramite, interfere with this procedure. A procedure for
removing sulfur from 'the spray residue samples has been developed and has been
adapted''as part of the standard procedure. Differentiation between endosulfan
and aramite residues is made by a specific aramite detection method (Gunther
et al.f 1951, MRID GS014024).
Method III is a microcoulometric gas chromatographic procedure for the analysis
of endosulfan in milk and animal tissues. The sensitivity is 0.01 ppm, it is
adequate for enforcement purposes, and the method is also adequate for
endosulfan sulfate analysis. This method was submitted by FMC with Pesticide
Petition No. 8F0632 (FMC, 19??, MRID 00003703).
4. Tolerance Levels
a. Present U.S. Tolerances
According to 40 £FR 3tB0.182 tolerances are established for total residues of
endosulfan and its metabolite endosulfan sulfate in or on raw agricultural
commodities as follows:
2 parts per million in or on apples, apricots, artichokes, beans, broccoli,
brussel sprouts, cabbage, cauliflower, celery, cherries, collards,
cucumbers, eggplants, grapes, kale, lettuce, melons, mustard greens,
nectarines, peaches, pears, peas (succulent type), peppers, pineapples,
plums, prunes, pumpkins, spinach, strawberries, summer squash, sunflower
seeds, tomatoes, turnip greens, watercress, and winter squash.
1 part per million in or on alfalfa hay, almond hulls and cottonseed.
0.5 part per million in milk fat (reflecting negligible residues in milk),
and in or on sugarcane.
0".3 part per million in or on alfalfa (fresh).
• V .,.« .. j. . *-i..\ ! •'•
0.2 part per million in or on carrots, sweet corn (kernels plus cob with
husks removed), sweet potatoes; and in meat, fat, and meat by-products of
cattle, goats, hogs, horses, and sheep.
0.2 part per million (negligible residue) in or on almonds; filberts;
macadamia nuts; mustard seed; pecans; potatoes; rape seed; safflower seed;
straw of barley, oats, rye, and wheat; and walnuts.
0.1 part per million (negligible residue) in or on blueberries; grain of
barley, oats, rye, and wheat; and sugar beets (without tops).
58
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b. International Tolerances
The FAO/WHO Maximum Residue Limit (MRL) for endosulfan are found in Table 2.
Like the U.S. tolerances, the FAO/WHO MRLs are for the total combined residues
of endosulfan and endosulfan sulfate.
The following commodities (as fruits and vegetables) have the same U.S.
tolerances and FAO/WHO MRLS:
apples, apricots, artichokes, beans, blueberries, broccoli, brussels sprouts,
cabbage, carrots, cauliflower, celery, cherries, collards, cucumbers,
eggplants, grapes, kale, lettuce, melons, mustard greens, nectarines,, peaches,
pears, peas (succulent type), peppers, pineapples, plums, potatoes, prunes,
pumpkins, spinach, strawberries, summer squash, sunflower seed, sweet potatoes,
tomatoes, turnips greens, watercress, and winter squash.
59
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TABLE 2
International Tolerances (in ppm)
CROP FAQ/WHO CANADA MEXICO U. J5.
Alfalfa (fresh)' 0.3 0.3
Alfalfa (hay) 1.0 1.0
Almonds 0.2 nr
Almond (hulls) 1.0
Apples 2.0 2.0 2.0 2.0
Apricots 2.0 2.0 2.0
Artichokes 2.0 1.0 2.0 2.0
Beans 2.0 1.0 2.0 2.0
Blueberries 2.0 0.1 nr
Broccoli 2.0 2.0 2.0 2.0
Brussels sprouts 2.0 2.0 2.0
Ccfobage 2.0 2.0 2.0
Carrots 0.2 0.2 0.2
Cauliflower 2.0 1.0 2.0
Celery 2.0 1.0 2.0 2.0
Cherries 2.0 2.0 - 2.0
Collards 2.0 2.0
Corn (sweet, kernels plus
cx±> with husk removed) 2.0 0.1 nr 0.2 0.2
Cottonseed 1.0* 1.0 1.0
Cucunbers 2.0 1.0 2.0 2.0
Eggplants 2.0 1.0 2.0 2.0
Filberts 0.2 nr
Grapes 2.0 1.0 2.0 2.0
Kale 2.0 2.0
Lettuce 2.0 2.0 2.0 2.0
Macadamia Nuts 0.2 nr
Meat, fat, and meat by-
products of cattle, goats,
horses and sheep 0.2** 0.1 0.2
Melons 2.0 1.0 2.0 2.0
Milk fat (reflecting neg-
ligible residues in milk) 0.5 0.1 0.5
Mustard greens 2.0 2.0
Mustard seed 0.2 nr
Nectarines 2.0 2.0
Peaches 2.0 2.0 2.0 2.0
Pears 2.0 2.0 2.0 2.0
Peas (succulent type) 2.0 0.5 2.0 2.0
Pecans 0.2 nr 0.2 nr
Peppers 2.0 1.0 ' 2.0
Pineapples 2.0 2.0 2.0
Plums (including prunes) 2.0 2.0 2.0
Potatoes 0.2 0.1 nr 0.2 nr 0.2 nr
Pumpkins (including squash) 2.0 1.0 2.0
60
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TABLE 2, continued
CROP FAQ/WHO CANADA Mexico U.S.
Rape seed 0.2 nr
Safflower seed 0.2 nr
Small grains (grains of
barley, oats, rye, and wheat) 0.1 nr
Small grains (straw of barley,
oats, rye, and wheat) 0.2 nr
Spinach 2.0 2.0 2.0 2.0
Strawberries 2.0 1.0 2.0 2.0
Summer squash 2.0 1.0 2.0 2.0
Sugarbeets (without tops) 2.0 0.1 nr 0.1 nr
Sugarcane 0.02 nr 0.5
Sunflower seeds 0.1 nr 2.0
Sweet potatoes 0.2 0.2 0.2
Tea (dried) 30.0*** 24
Tomatoes 2.0 1.0 2.0 2.0
Turnip greens 2.0 0.1 nr 2.0
Walnuts 0.2 nr
Watercress 2.0 1.0 2.0
Winter squash 2.0 2.0 2.0
nr= negligible residues
* FAD/WHO: Cottonseed= 1.0 ppm; Cottonseed oil= 0.5 ppm.
** Carcass Fat
*** Dryr manufactured tea
The Canadian MRLs include endosulfan and endosulfan sulfate.
The negligible residue basis (nr) may or may not include endosulfan sulfate.
Mexican tolerances may or may not include endosulfan sulfate.
61
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5. Residues in Plants and Animals
The reported residue studies for many of the registered uses on raw
agricultural products and by-products or feed items are adequate. Several
crops or their by-products or feed items are not adequately supported by the
residue data. Please refer to the chart in Chapter III for a listing of the
citations, which are grouped by the crop listed.
The established tolerances for the following crops are considered adequate and
appropriate:
Almonds and Almond hulls Peas
Apricots Pecans
Beans Plums and Prunes
Blueberries Potatoes
Broccoli Rapeseed (oil crop)
Brussels sprouts Safflower
Cabbage Small grains (wheat, barley, oats and rye)
Cauliflower Spinach
Collards Strawberries
Corn (sweet) Sugar beets (without tops)
Cottonseed Sugarcane
Filberts Sunflower
Kale Sweet potatoes
Macadamia nuts Tea
Mustard greens Turnip greens
Mustard seed (oil crop) Walnuts
Nectarines Watercress
Peaches
Residue data for total endosulfan in or on the following crops are required:
Alfalfa (seed crop) Melons, pumpkins, winter squash
Artichokes Peppers
Celery Squash (summer)
Cherries Tomatoes
Cucumbers Apple pomace
Eggplants Grape and Raisin wastes
Lettuce Pineapple bran
Tomato pomace
Residues of endosulfan and endosulfan sulfate in meat and milk resulting from
the registered uses are considered Category 1 of 40 CFR 180.6(a) for the
following crops or by-products: alfalfa (fresh and hay), almond hulls, small
grains (wheat barley, oats, and rye). Category 1 states that finite residues
will actually be incurred in meat and milk from feed use of the raw
agricultural commodity including its by-products.
Several registered uses on crops which may result in residues in by-products or
feed items are considered Category 2 of section 180.6(a). This applies to
apples, grapes, tomatoes, pineapple bran, and sugarcane bagasse. Category 2
62
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states that it is not possible to establish with certainty whether finite
residues will be incurred, but there is a reasonable expectation of finite
residues.
Feeding studies reflecting residues of endosulfan and endosulfan sulfate in
poultry anfl eggs are adequate in showing the possible transfer of residues to
poultry arid eggs. Residues are not expected in poultry and eggs from
registered uses of erdosulfan (Category 3 of section 180.6(a)).
6. Dietary Intake
The following reports were reviewed as a series of articles detailing the
results of Food and Drug Administration Total Diet Program/Marketbasket
Survey. Basic Total Diet samples represent a two week supply of food items,
and proportions of a 16 to 19-year old male, a high consumption diet. The food
items are prepared for consumption and composited into 12 classes of similar
foods. Each class in each sample is a "composite". Analytical methodology is
the appropriate multiresidue method, as modified, and all reported residues are
confirmed. The size and scope of the program has varied, therefore, one year's
results are not directly related to another year. However, the important
information is the baseline or frequency of occurrence of pesticide residues in
human food items as consumed.
This series of reports by the FDA shows the results of the Total Diet/Market-
basket survey program for the years 1969 to 1975 for composites of similar food
crops. During 'this period, 112 of 2100 composites examined showed trace to
measurable amounts of endosulfan and/or endosulfan sulfate.
The highest composite showed 0.44 ppm (FY73) in leafy vegetable composite, but
generally the residue levels were less than 0.05 ppm. By crop grouping,
endosulfan was found most frequently in leafy vegetables, 59 of 175 composites;
garden fruits, 22 of 175 composites; fruits, 18 of 125 composites; potatoes, 12
of 125 composites; and oils, fats and shortening, 1 of 30 composites.
The results of these surveys can be found in Table 3.
7. Residues in Tobacco
The occurrence of endosulfan residues in tobacco and tobacco products has been
investigated for a number of years. Although tobacco is not considered a food
product, the presence of the pesticide is of interest to account for the total
daily intak'je. " °
Domanski and Sheets (1973, MRID 05010468) showed the mean level of endosulfan
and endosulfan sulfate in auction market tobacco varies by tjeographic origin
(range 0.7 to 3.4 ppm), by tobacco type (range <0.2 to 14 ppm) and by year.
. 63
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Table 3 RESULTS OF MARKET BASKET SURVEY
CROP GROUPING
PERIOD
FREQUENCE OP
RESPONSE
PPM FOUND
REFERENCE
Leafy Vegetables
Garden Fruits
Fruits
en Potatoes
Oils, fats and
S heartening
June 1966 to April 1967
June 1969 to April 1970 7 of 30
June 1970 to April 1971 15 of 30
June 1971 to July 1972 7 of 35
August 1972 to July 1973 17 of 30
August 1973 to July 1974 8 of 30
August 1974 to July 1975 5 of 20
June 1966 to April 1967
June 1969 to April 1970 5 of 30
June 1970 to April 1971 2 of 30
June 1971 to July 1972 6 of 35
August 1972 to July 1973 4 of 30
August 1973 to July 1974 3 of 30
August 1974 to July 1975 2 of 20
June 1966 to April 1967
June 1969 to April 1970' 3 of 30
June 1970 to April 1971 5 of 30
June 1971 to July 1972 6 of 35
August 1972 to July 1973 4 of 30
June 1966 to April 1967
June 1969 to April 1970 3 of 30
June 1970 to April 1971 2 of 30
June 1971 to July 1972 1 of 35
August 1973 to July 1974 6 of 30
June 1966 to April 1967
June 1969 to April 1970 1 of 30
<0.001
<0.001 to 0.04
<0.001 to 0.063
<0.001 to 0.028
<0.001 to 0.439
<0.001 to 0.012
<0.001 to 0.022
<0.001
0.001 to 0.005-
<0.001 to 0.061
<0.001
<0.001 to 0.002
<0.001 to 0.016
<0.001 to 0.006
<0.001
0.002 to 0.008
<0.001 to 0.045
<0.001 to 0.020
<0.001 to 0.002
0.002 to 0.008
<0.001 to 0.007
<0.001
<0.001 to 0.016
<0.001
0.185
Duggan and Lipsconb, 1969, MRID 05007360
Corneliusson, 1972, MRID 05003701
Manske and Corneliusson, 1974,. MRID 05005175
Manske and Johnson, 1975, MRID 05005255
Johnson and Manske, 1976, MRID 05005157
Manske and Johnson, 1977, MRID 05005254
Johnson and Manske, 1977, MRID 05003080
Duggan and Lipsconb, 1969, MRID 05007360
Corneliusson, 1972, MRID 05003701
Manske and Corneliusson, 1974, MRID 05005175
Manske and Johnson, 1975, MRID 05005255
Johnson and Manske, 1976, MRID 05005157
Manske and Johnson, 1977, MRID 05005254
Johnson and Manske, 1977, MRID 05003080
Duggan and Lipsconb, 1969, MRID 05007360
Corneliusson, 1972, MRID 05003701
Manske and Corneliusson, 1974, MRID 05005175
Manske and Johnson, 1975, MRID 05005255
Johnson and Manske, 1976, MRID 05005157
Duggan and Lipsconb, 1969, MRID 05007360
Corneliusson, 1972, MRID 05003701
Manske and Corneliusson, 1974, MRID 05005175
Manske and Johnson, 1975, MRID 05005255
Manske and Johnson, 1977, MRID 05005254
Duggan and Lipsconb, 1969, MRID 05007360
Corneliusson, 1972, MRID 05003701
-------
Dorough et al. (1973, MRID 05003464) studied the effects of various harvest
intervals upon the amount of endosulfan remaining on cured tobacco from top,
middle or the bottom of the plant. Increased curing time or increased harvest
intervals beyond 14 days did not reduce endosulfan residues. Residues were
highest on top leaves but the distribution of endosulfan I and II, and
endosulfan sulfate varied in different plant positions.
Keil et al. (1973, MRID 05003122) report that parathion is more persistent
through at least the first day, when a mixture of parathion and endosulfan is
applied than when parathion alone is applied. This report confirms results in
a 1971 study (Keil et al., 1972, MRID 05003032).
Domanski and Guthrie (1974, MRID 05003705) report the average content of total
endosulfan in 1972 cigars was 0.41 ppm (range <0.20 to 0.64 ppm) and concluded
that these residues were little different than those cigars in 1969 and 1971.
Residues of endosulfan and endosulfan sulfate in various tobacco sold during
1973 are reported below (Domanski et al., 1974, MRID 05003864).
Tobacco Product Range (ppm) Mean
Cigarettes
Cigars
Little cigars
Smoking tobacco
Chewing tobacco
Snuff
0.36 to 1.27
0.08 to 1.03
0.15 to 0.26
0.08 to 0.61
0.06 to 0.86
0.06 to 0.17
0.83
0.37
0.22
0.37
0.36
0.12
Gibson et al. (1974, MRID 05003058) reported on chlorinated hydrocarbon
pesticides in Kentuckey burley tobacco for 1963 to 1972. Endosulfan residues
appeared in one-third of the 1968 auction samples and by 1969 endosulfan became
a general contaminant of burley tobacco. Residue levels (0.23 ppm in 1968)
rose to over 4.0 ppm in 1972.
Domanski et al. (1975, MRID 05004622) report on the endosulfan and endosulfan
sulfate residues in 1972 U.S. auction market tobacco. The mean level in flue-
cured tobacco across geographic areas was 0.75 ppm, with a range of 0 to 7.77
ppm. The percentage incidence for residues of endosulfan increased from 22
percent in 1970 to 56 percent in 1972. Burley tobacco in North Carolina was
low at 0.06 ppm (mean), and highest in Kentucky at 4.85 ppm (mean). For fire-
cured tobacco in Tennessee, the mean residue was 7.34 ppm while in Virginia it
was 2.45 ppm. Dark air-cured tobacco in Tennessee was 10.23 ppm (mean) and in
Virginia 0.63 ppm (mean). In Maryland, light air-cured tobacco resulted in a
mean of 1.34 ppm.
Johnson et al. (1975, MRID 05004164) found that freeze-drying of tobacco shreds
resulted in a 43 percent reduction of total endosulfan residues.
Thorstenson and Dorough (1976, MRID 05004164) did not find endosulfan residues
in 1969 research grade cigarettes, but 1974 research cigarettes contained
endosulfan accounting for 20 to 38 percent of total chlorinated pesticides on
these cigarettes. Purchased cigarettes showed endosulfan residue levels of 0.2
ppm (1971), and 0.8 to 1.0 ppm (1972 to 1975).
65"
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Frank et al. (1977, MRID 05004013) reported that the mean level of endosulfan
residues in cured tobacco leaf in Southern Ontario during 1972-1975 ranged from
2 to 5 ppm, with endosulfan sulfate comprising 40 to 65 percent.
Chopra and Mahfouz (1977, MRID 05003004) reported on the metabolism of
endosulfan I and II, and endosulfan sulfate through separate treatments of
tobacco leaf. Metabolites found were endosulfan sulfate, endosulfan diol
(trace), endosulfan ether, and endosulfan lactone. Endosulfan I was found on
endosulfan sulfate treated leaves but rot endosulfan II, indicating conversion
of endosulfan sulfate to endosulfan I. Furthermore, it was found the
intraconversion between endosulfan I and II, and possible metabolic pathway for
direct hydrolysis of endosulfan I and II and endosulfan sulfate to endosulfan
diol. A possible reaction converting endosulfan hydroxyether to endosulfan
ether and endosulfan lactone is proposed. Additionally, endosulfan I was the
metabolite of endosulfan sulfate on green tobacco leaves, while endosulfan II
was the main metabolite of endosulfan sulfate on cured tobacco leaves.
Chopra et al. (1978, MRID 05003138) investigated the pyrolytic degradation of
endosulfan I. The pyrolysis products were endosulfan I and II, endosulfan
ether, hexachlorocyclopentadiene, chlorcbenzenes, methyl chloride,
dichloromethane, chloroform, carbon tetrachloride, 1,1-dichloroethylene, 1,1-
dichloroethane, trichloroethylene, and tetrachloroethylene. From these
reaction products in a nitrogen atmosphere, the following endosulfan
degradation..products may occur in tobacco and cigarette smoke: endosulfan I and
II, endosulfan sulfate, endosulfan ether, endosulfan lactone, mono-, di-, tri-,
and tetrachlorcbenzenes, and hexachlorocyclopentadiene.
B. LABELING REQUIREMENTS
Labeling of endosulfan products should bear a warning or restriction against
use, storage, or disposal of endosulfan formulations in a manner likely to
result in contamination of human food items.
Each use of registered endosulfan products must bear appropriate use
directions, warnings, limitations, or restrictions. For food crops, the
restrictions include such aspects as the maximum permitted dose, the timing and
frequency of application, duration of any preharvest interval, and grazing,
foraging, or feeding restrictions to prevent the transfer of residues to
animals. These restrictions, limitations or label instructions are based upon
adequate residue data.
The current labeling of end-use products should be retained in the present
format for all crops and formulations with the following exceptions:
Nut Crops;
Almonds, Filberts, Macadamia Nuts, Pecans, Walnuts.
"Do not graze livestock on orchard crops or grasses in treated areas."
Tree Fruit Crops;
Apples, apricots, cherries, nectarines, peaches, pears, plums and prunes.
.66
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"Do not feed cull fruits to animals nor allow livestock to graze treated
orchards."
Corn (Field, grown for seed)
"Do not feed forage or ensilage to livestock or allow livestock to graze in
treated fields."
"Do not make more than five applications."
Eggplants
Dusts:
"Do not exceed 1.0 pounds active ingredient endosulfan per acre."
Bnulsifiable Concentrates or Wet table Povdersi
"Do not exceed 0.5 pounds active ingredient endosulfan per acre"
Pumpkins
Bnulsifiable Concentrate:
"Do not apply within one day of harvest."
Peas (seed crops)
"Do not apply more than two tines during the fruiting season. Do not feed
treated vines to livestock or allow livestock to graze in treated fields. Use
only on peas to be harvested by combine.
Turnip Greens
"Do not apply to turnips grown for roots."
C. SUMMARY 0_F DATA GAPS
Data will need to be submitted on the residues of endosulfan and endosuj.fan
sulfate on a number of crops and animal foodstuffs. The specific crops are
listed in the Data Requirement Charts in Chapter III.
67
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VIII. ECOLOGICAL EFFECTS
A. Ecological Effects Profile
B. Ecological Effects Hazard Assessment
C. Summary of Data Gaps
ECOLOGICAL EFFECTS .-PROFILE'
Endosulfan, as noted earlier in the Use Summary section in Chapter V, is an
insecticide applied to agricultural and commercial • ornamental crops. It may be
applied by ground or aerial equipment to these crops and as a result of these
methods of application, some potential exists for the exposure of nontarget
terrestrial and aquatic organisms. A scientifically sound data base on the
toxicity of technical and end-use endosulfan to nontarget organisms is not
complete, and additional testing and monitoring will be required as noted in
the Data Requirement Charts. in Chapter III.
1 . Avian Stud ies
A mallard duck oral ID™ study was* performed' with technical endosulfan and
the LDc value was found to be 34.4 mg/kg (Hudson et al., 1972, MRID
05003462). A study conducted on starlings found the LDcn value to be 35
mg/kg (Schafer, 1972, MRID GS014015). Technical erdosulfan can therefore be
considered to be highly toxic to avian species.
One dietary study tested several species using = technical- endosulfan (Hill et
al. 1975, MRID 00022923) and resulted in the following LC50 values: young
Bobwhite quail- 805 ppm; Japanese quail- 1250 ppm; Ring-necked pheasant-r 1275
ppm; and mallard duck- 1053 ppm. Technical endosulfan can therefore be
considered slightly ^ to- moderately? toxic to upland .game birds -and waterfowl when
administered- in isubacute dietary tests..
2. Aquatic Organism Stu3 ies
A 48 hour LCcjQ study using technical endosulfan was performed on the water
flea (Daphnia magna), resulting in an LCtQ .value-: of .166 ppb (Macek et
al., 1976, MRID 05008271). Two studies tested technical endosulfan with scuds
and obtained the following results: 48-hour LC50 for Gammarus lacustris • is
9.2 ppb (Sanders, 1969, MRID 05009242) and the 96-hour LC5Q for Gammarus
fasciatus is 6 ppb ( Sanders -, ,1972 , MRID 05017538 ) . Technical endosulfan . is
considered to be very highly toxic to freshwater ^invertebrates.
Utilizing an 86% technical sample of endosulfan, the 96-hour LCco value for
rainbow trout was determined to be 0.37 ppb (EPA, 1976, MRID GSOI4012). The 96-
hour LCcQ for an unspecified percentage of technical endosulfan was found to
be 1.5 pp) for rainbow trout (Macek, 1969, MRID 05003107).
One acute 96-hour LC50 study (EPA, 1976, MRID GS014011) tested the 50%
wet table powder formulation on rainbow trout, and found the LCcg value to be
0.47 ppb. A 4% dust formulation was tested on rainbow trout by Ludeman (1972,
MRID GS014010) and the 96-hour LC50 value is 28 ppb. These acute toxicity
data indicate that technical, wettable powder, and dust formulations of
endosulfan are very highly toxic to coldwater fish. Results from three 96 hour
LCjjQ studies on bluegill sunfish are reported in Table 4.
68
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Table 4
Tbxicity of Technical Endosulfan to Bluegill Sunfish
Composition
86% Technical Endosulfan
96%. Technical Endosulfan
96% Technical Endosulfan
LC,
50
100% Technical Endosulfan 1.7 ppb
2.08 ppb
3.3 ppb
(soft water)
4.4 ppb
(hard water)
Reference
Buccafusco and Sleight, 1976,
MRID GS014014
EPA, 1976, MRID GS014012
Pickering and Henderson, 1966,
MRID 05014941
Pickering and Henderson, 1966,
MRID 05014941
These LC^Q values demonstrate that technical endosulfan is very highly toxic
to warmwater fish, regardless of water hardness.
69
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Two additional studies were available on the acute toxicity of technical
endosulfan to warmwater fish. In the first, Pickering and Henderson (1966,
MRID 05014941) found the LC50 value for an unspecified guppy to be 3.7 ppb in
soft water, and Macek et al. (1976, MRID 05008271) found the LC5Q for the
fathead minnow to be 0.86 ppb. These results help to confirm the very high
toxicity of technical endosulfan to warmwater fish.
A few studies were conducted on exotic fish. The multiplicity of similar
values provides for confidence in extrapolating the results to native North
American fish. Amminikutty et al. (1977, MRID 05003103) found the 96 hour
LC50 value for the widow tetra (Qymnocprymbus tertnatzi) to be 1.6 ppb,
using a 35% emulsifiable concentrate formulation. Basak and Konar (1976, MRID
05004792) found the following 96 hour LC5Q values using the 35% emulsifiable
concentrate formulation: Tilapia mossanbicus - 1.4 ppb; Cyprinus carpio (opmmon
carp)- 0.9 ppb; and Heteropenustes fossilis - 1.5 ppb. The above values reveal
that the 35% emulsifiable concentrate formulation is very highly toxic to these
fish.
Three acute toxicity tests were conducted using technical endosulfan with
marine/estuarine fish and are reported in Table 5.
Schimmel (1979, MRID 05005824) also studied the acute effects of technical
endosulfan on estuarine invertebrates. The 96 hour LC5Q values for the 100%
technical material were 0.04 ppb for pink shrimp and 1.3 ppb for grass shrimp.
Technical endosulfan is considered to be very highly toxic to estuarine
invertebrates.
The Schimmel study also examined the bioaccumulation potential of endosulfan in
striped mullet, an estuarine fish. Using 100% technical endosulfan at a
concentration in the water of 0.8 ppb, after 28 days the concentration factor
was 2249 in edible tissue and 2755 in the whole body. No detectable residues
could be found after 48 hours depuration.
In a study by Roberts (1975, MRID 05003062), mussels and scallops were exposed
to 450 ppb technical endosulfan for 24 hours. Observations showed a 50 percent
reduction in byssal attachment, probably resulting from a reduction in pedal
activity or blockage of synthesis of byssal components.
4. Mphibian Studies
There is sufficient information to characterize the field toxicity of
endosulfan to amphibians as highly toxic. In using an unknown formulation,
Mulla (1962, MRID 05020175) found that 0.1-0.5 pounds of active ingredient per
acre was "toxic" to bullfrogs. No details were elucidated as to the toxic
effects. In another experiment, Mulla (1963, MRID 05011390) found moderate
mortality to tadpoles at 0.1 pound active ingredient per acre (endosulfan II)
and complete kill at 0.5 pounds per acre (endosulfan I).
70
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Table 5
Acute Toxicity of Technical Mosul fan to Marine/Estuarine Fish
Composition
Species
Unspecified Technical
100% Technical Enflosulfan Pinfish
100% Technical Endlosulfan Spot
LC
50
96% Technical Erdosulfan Striped Bass 0.2 ppb
Striped Bass 1000 ppb
0.3 ppb
0.09 ppb
100% Technical Endosulfan Striped Mullet 0.38 ppb
Reference
Earnest, 1970,
MRID 00001328
Korn et al., 1974,
MRID 05000819
Schimmel, 1979,
MRID 05005824
Schimmel, 1979,
MRID 05005824
Schimmel, 1979,
MRID 05005824
All the values indicate that technical endosulfan is very highly toxic to
marine/estuarine fish.
-71
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5. Nontarget Soil and Surface Invertebrate Studies
In studies with various species of parasitic wasps, endosulfan was found to be
low in toxicity (Davies and McLaren, 1977, MRID 05004003 and Bartlett, 1966,
MRID 05005640) and as moderately to highly toxic (Bartlett, 1963, MRID 05003978
and Searle, 1965, MRID 05005572). One study indicated that endosulfan was not
sufficiently selective against a pest species to be useful in integrated
control (Coutin and Coulon, 1966, MRID 05005993). The addition of oil was
found to significantly reduce toxicity of endosulfan to one species of
parasitic wasp (Searle, 1964, MRID 05006416). The available information
indicates that endosulfan toxicity to parasitic wasps is highly variable,
depending on formulation, route of exposure, and test species.
A similar situation exists with regard to endosulfan toxicity to predaceous
beetles. Studies indicate low toxicity (Bartlett, 1966, MRID 05005640 and
Teotia and Tiwari, 1972, MRID 05013372), high toxicity (Bartlett, 1963, MRID
05003978), or a toxicity range from low to high, depending on formulation, life
stage of insect, etc. (Kundu and Sharma, 1974, MRID 05004542; Colburn and
Asquith, 1971, MRID 05004007; and Bartlett, 1966, MRID 05005640). Data from
two studies (Croft and Nelson, 1972, MRID 05009345 and Bartlett, 1964, MRID
05004148) indicate that endosulfan is moderately to highly toxic to predaceous
mites in the genus Amblyseius.
6. Beneficial Insect Studies
Endosulfan was shown to be low in toxicity to honey bees in two laboratory
studies (Clinch, 1967, MRID 05008936 and Johansen, 1972, MRID 05000837), and
moderately toxic in six studies (Atkins and Anderson, 1967, MRID 00001999;
Stevenson, 1978, MRID 05001991; Harris and Svec, 1969, MRID 05011163; Palmer-
Jones, 1958, MRID 05004413; Okada and Hoshiba, 1970, MRID 05013090; and
Stevenson, 1968, MRID 05004151). Several field studies reported no adverse
effects on exposed colonies of honey bees (Palmer-Jones and Forster, 1963, MRID
05004412; Palmer-Jones, 1959, MRID 05004414; Palmer-Jones et al., 1959, MRID
05004794; and Gorecki, 1973, MRID 05012881).
With regard to other pollinators, endosulfan tests proved to be relatively
nontoxic to Indian honey bees (Singh et al., 1974, MRID 05003360 and Attri and
Sharma, 1969, MRID 05004597), highly toxic to alkali bees (Johansen, 1972, MRID
05000837), and moderately to highly toxic to the alfalfa leafcutter bee
(Johansen, 1972, MRID 05000837 and Tatei et al., 1977, MRID 05013358).
B. ECOLOGICAL EFFECTS HAZARD ASSESSMENT
1. Introduction
Endosulfan products are registered for a wide variety of sites, including large
and small acreage commercial field and food crops, fruit trees, nuts, and
ornamental trees, shrubs, and plants. Several greenhouse uses are also
reg istered.
The outdoor uses are of particular concern for fish and wildlife safety.
Applications to watercress, a relatively minor commercial crop, is however, the
most hazardous use for aquatic organisms since this requires a direct
72
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application to water. There are documented reports of fish kills resulting
from uses on tomatoes, lettuce and cropdusting. These reports can be found in
the Agency's files.
The mechanisms of mobility providing for contamination of aquatic sites
following applications of endosulfan to terrestrial crops may include runoff,
soil erosion (with bound residues), and drift. Drift may provide for
contamination of nonterrestrial sites, while direct contamination of aquatic
sites results from the watercress use. Leaching has not been addressed in the
submitted studies, therefore the attendant hazard potential is not assessable
at this time.
While the submitted studies are not sufficient to fully assess the
environmental fate and mobility of endosulfan at this time (see Chapter V), a
consideration of several of its known physico-chemical characteristics is
essential to this initial hazard assessment.
2. aquatic Hazard Assessment
Freshwater invertebrate tests indicate that sensitivity to endosulfan greatly
increases with time of exposure and that toxicity may be species specific. The
lethal levels are taken to be 6-10 ppb in acute exposure situations. Acute
mortalities are expected even in cases of very low aquatic contamination, and
certainly in aquatic use patterns.
Considering known toxicological data, significant acute adverse effects are
expected for all freshwater and marine/estuarine fish and invertebrates exposed
to aquatic residues (at levels "0.5 ppb) of endosulfan and its metabolites.
Some species may be severely affected at t).25 ppb. Acute effects include
mortality at greater than or equal to 50 percent of exposed populations.
Bioaccumulation and histopathological subacute adverse effects have been
demonstrated in aquatic organisms including fish, and are likely to occur at
low ambient levels. The likelihood of adverse reproductive effects on fish or
aquatic invertebrates is not assessable at this time due to data gaps, although
some effects on aquatic invertebrate spawning has been demonstrated.
Fish and aquatic invertebrate kill reports (MRID GS014016) suggest that levels
of endosulfan resulting in acute mortality are observed after label recommended
use on some field crops. Use on watercress is almost certain to result in
residues far exceeding LC^g values for all aquatic species tested. Aquatic .
residues at the application site greater than one-half the LC5g are clearly
exceeded in the watercress use pattern, where Agency calculations show 734 ppb
as the expected aquatic residue in a one-half acre-foot of water (367 ppb in
one acre-foot, 61 ppb in 6 acre-feet, 37 ppb in 10 acre-feet). However, the
likelihood of acute effects resulting from mobility of endosulfan residues from
the watercress use pattern is not assessable at this time because of toxicity
and field monitoring data gaps. Accordingly, the results from field monitoring
studies required by the environmental fate chapter will be needed to fully
assess the aquatic hazards resulting from direct applications to water and
those due to runoff, soil erosion and drift into freshwaters and estuaries.
Many of the crops covered by existing registrations are grown near or adjacent
to estuaries containing valuable fisheries resources. These resources are thus
exposed to contamination via runoff, soil erosion and drift. These are
73
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particularly important as habitats for breeding and brood rearing of many
estuarine and marine species. The required field monitoring must, therefore,
include estuarine habitats exposed by adjacent crop treatments. It should be
noted that adverse effects to estuarine species could be more pronounced due to
the variance of water flux in certain estuaries. This could result in
exposures resembling static conditions. Some estuarine species (spot, mullet,
pinfish, and shrimp) are affected at extremely low levels of endosulfan
(LCc0value for spot is 0.04 pfb). The Agency has fish kill reports of
instances when endosulfan has been measured in various aquatic components,
especially after aerial spraying of tomatoes. Ambient levels in affected
estuaries were measured as low as 0.14 ppb after these fish kills (MRID
GS014016).
The hazard to amphibians is poorly understood at this time. The Agency has
reviewed only two inconclusive field studies which showed "highly toxic"
effects. The Agency considers these hazards to be equal to or more severe
thanthose for fish, since the amphibian aquatic larvae may be more susceptible
to pesticidal effects. The larval amphibian hazards may be even more
pronounced than those for fish, as these larvae are frequently found in shallow
depths, such as pond edges, drainage/irrigation ditches and canals, temporary
ponds, flooded fields, swamps, bogs, shallow streams, and marshes. The
amphibian hazard assessment must await results from the field monitoring, as
required in the environmental fate chapter.
3. Terrestrial Hazard Assessment
Hazards to terrestrial species cannot be fully assessed because of the data
gaps, particularly in reproduction tests. Since aquatic monitoring is required
(see above) a crop by crop analysis will not be presented, but rather the
Agency will address residues and routes of intoxication in this standard.
Effects (or lack thereof) on avian and mammalian reproduction have not been
addressed in the submitted studies. This information is required to be
submitted. Dietary residues may result in adverse effects on avian
reproduction.
Avian and mammalian dietary toxicity via the drinking water route has not been
specifically addressed, but it is assumed to be at least as toxic as the feed
route, and may be more so due to the ease of absorption into the blood after
drinking. Volatilization, likewise, has not been specifically addressed in the
submitted studies and these data are required. Drift from applications of dust
and emulsifiable concentrate formulations could present an acute problem for
terrestrial species via inhalational and dermal exposure.
C. SIMMABY OF DATA GAPS
Data must be submitted to satisfy the following data requirements: avian single
dose oral LDcQ, avian reproduction, data on the acute LC^Q for a cold water
fish, acute toxicity to crabs and mollusks, and testing or all endosulfan
formulations on the acute toxicity to aquatic invertebrates and to estuarine
and marine organisms.
74
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IX. CASE BIBLIOGRAPHY
Guide to Use of This Bibliography
1. Content of Bibliography. This bibliography contains citations of all the
studies reviewed by EPA in arriving at the positions and conclusions stated
elsewhere in the standard. The bibliography is divided into two sections:
(1) citations that contributed information useful to the review of the
chemical and considered to be part of the data base supporting
registrations under the standard, and (2) citations examined and judged to
be inappropriate for use in developing the standard. This second part of
the bibliography exists in the Agency's files and does not accompany this
standard. Interested parties may request a copy from the Agency. Primary
sources for studies in this bibliography have been the body of data
submitted to EPA and its predecessor agencies in support of past regulatory
decisions, and the published technical literature.
2. Units of Entry. The unit of entry in this bibliography is called a
"study". In the case of published materials, this corresponde closely to
an article. In the case of unpublished materials submitted to the Agency,
the Agency has sought to identify documents at a level parallel to the
published article from within the typically larger volumes in which they
were submitted. The resulting "studies" generally have a distinct title
(or at least a single subject), can stand alone for purposes of review, and
can be described with a conventional bibliographic citation. The Agency
has attempted also to unite basic documents and commentaries upon them,
treating them as a single study.
3. Identification of Entries. The entries in this bibliography are sorted by
author, date of the document, and title. Each entry bears, to the left of
the citation proper, an eight-digit numeric identifier. This number is
unique to the citatiuons, and should be used at any time specific reference
is required. This number is called the "Master Record Identifier", or
"MRID". It is not related to the six-digit "Accession Number" which has
been used to identify volumes of submitted data; see paragraph 4(d)(4)
below for a further explanation. In a few cases, entries added to the
bibliography late in the review may be preceded by an eight-character
temporary identifier. This is also to be used whenever specific reference
is needed.
4. Form of the Entry. In addition to the Master Record Identifier (MRID),
each entry consists of a bibliographic citation containing standard
elements followed, in the case of materials submitted to EPA, by a
description of the earliest known submission. The bibliographic
conventions used reflect the standards of the American National Standards
Institute (ANSI),.expanded to provide for certain special needs. Some
explanatory notes of specific elements follow:
a. Author. Whenever the Agency could confidently identify one, the
Agency has chosen to show a personal author. When no individual was
75
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identified, the Agency has shown an identifiable laboratory or testing
facility as author. As a last resort, the Agency has shown the first
known submitter as author.
b. Document Date. When the data appears as four digits with no question
marks, the Agency took it directly from the document. When a four-
digit date is followed by a question mark, the bibliographer deduced
the date from evidence in the document. When the date appears as
(19??), the Agency was unable to determine or estimate the date of the
document.
c. Title. This is the third element in the citation. In some cases it
has been necessary for Agency bibliographers to create or enhance a
document title. Any such editorial insertions are contained between
square brackets.
^* "trailing Parentheses. For studies submitted to the Agency in the
past, the trailing parentheses include (in addition to any self-
explanatory text) the following elements describing the earliest known
submission:
(1) Submission Date. Immediately following the word 'received'
appears the date of the earliest known submission.
(2) Administrative Number. The next element, immediately following
the word 'under', is the registration number, experimental permit
nunber, petition nunber, or other administrative number
associated with the earliest known submission.
(3) Submitter. The third element is the submitter, following the
phrase 'submitted by'. When authorship is defaulted to the
submitter, this element is omitted.
(4) Volume Identification. The final element in the trailing
parenthesis identifies the EPA accession nunber of the volume in
which the original submission of the study appears. The six-
digit accession nunber follows the symbol 'CDL', standing for
"Company Data Library". This accession nunber is in turn
followed by an alphabetic suffix which shows the relative
position of the study within the volume. For example, within
accession nunber 123456, the first study would be 123456-A; the
second, 123456-B; the 26th, 123456-Z; and the 27th, 123456-AA.
76
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OFFICE OF PESTICIDE PROGRAMS
REGISTRATION STANDARD BIBLIOGRAPHY
Citations Considered to be Part of the Data Base Supporting
Registrations Under the Standard
MRID CITATION
00003746 American Hoechst Corporation (1965) Data Sheet for Endosulfan/Thio-
dan. (Unpublished study received Aug 20, 1971 under 2H2667;
CDL:225765-D)
00003756 American Hoechst Corporation (1968) Experimental" and Residue Data,
Assam, Northeast India. (Unpublished study received Aug 20,
1971 under 2H2667; CDL:225765-0)
05003103 Amminikutty, C.K.; Rege, M.S. (1977) Effects of acute and chronic
exposure to,pesticides, Thicdan B.C. 35 and Agallol '3' on the
liver of widow tetra Gymnocorymbus temetzi (Boulenger).
Indian Journal of Experimental Biology 15(3):197-200.
05002841 Archer, T.E.; Nazer, I.K.;-Crosby, D.G. (1972) Photodecomposition
of endosulfan and related products in thin films by ultraviolet
light irradiation. Journal of Agricultural and Food Chemistry
20(5):954-956.
00003711 Arnold, D. (1972) Report to Niagara Chemical Division, FMC Corpora-
tion: Mutagenic Study with Thicdan in Albino Mice: Request
No. NCT 459.99: IBT No. E1057B. (Unpublished study received Nov
17, 1972 under 3F1314; prepared by Industrial Bio-Test Labora-
tories Inc., submitted by FMC Corp., Philadelphia, Pa.; CDL:
092246-A)
05013674 Bandyopadhyay, S.; Bhattacharyya, P.; Mukherjee, N. (1979)
In-vitro sensitivity of Rhizobium species to some fungicides
and insecticides. Pesticides 13(1):22-23,25;
00003741 Baran, J. (1967) Report to Niagara Chemical Division, FMC Corpora-
tion: Two-Year Chronic Oral Toxicity of Thicdan Technical—Bea-
gle Dogs: IBT No. C3758. (Unpublished study including letter
dated Dec 5, 1967 from J.C. Calandra to John F. McCarthy, re-
ceived Dec 7, 1967 under 7F0632; prepared by Industrial Bio-Test
Laboratories, Inc., submitted by FMC Corp., Philadelphia, Pa.;
CDL:091100-A)
05002565 Beard, J.E.; Ware, G .W. (1969) Fate of endosulfan on plants and
glass. Journal of Agricultural and Food Chemistry
17(2) :216-220.
05010016 Bionetics Research Laboratories (1968) Evaluation of Carcinogenic,
Teratogenic, and Mutagenic Activities of Selected Pesticides
and Industrial Chemicals. Vol. I: Carcinogenic Study.
Bethesda, Md.: National Cancer Institute, Division of Cancer
Cause and Prevention. (National Cancer Institute report no.
NCI-DCCP-G3-1973-1-1; available from: NTIS, Springfield, VA;
PB-223 159)
-------
MRID CITATION
05002183 Boyd, E.M.; Dcbos, I.; Krijnen, C.J. (1970) Endosulfan toxicity
and dietary protein. Archives of Environmental Health
GS014014 Buccafusco, R.J. and Sleight, B.H. (1976) Acute toxicity of endosul-
fan to bluegill sunfish Lepomis macrochjrus. (Unpublished study
prepared by B3&G Bionomics, Wareham, Mass.; CDL:243084)
05003395 Burke, J.; Mills, P.A. (1963) Microcoulometric gas chromatographic
determination of Thicdan and Ted ion in green vegetables.
Journal of the Association of Official Agricultural Chemists
46(2):177-182.
05004978 Carey, A.E.; Gowen, J.A.; Tai, H.; Mitchell, W.G.; Wiersma, G.B.
(1978) Pesticide residue levels in soils and crops,
1971 — National Soils Monitoring Program (III). Pesticides
Monitoring Journal 12(3) :117-136.
00003795 Cassil, C.C.; Druimond , P.E. (1965) A plant surface oxidation
product of Endosulfan. Journal of Economic Entomology 58(2):
356-357. (Also_In unpublished submission received Apr 4, 1966
under 7F0526; submitted by FMC Corp., Philadelphia, Pa.; CDL:
090630-A)
00003761 Chin, W.T.; Stanovick, R.P. (1964) Metabolism of Thiod an Isomers
I and II by Dogs: M-1307. (Unpublished study received Jun 21,
1966 under 7F0526; submitted by FMC Corp., Philadelphia, Pa.;
CDL:090631-A)
05003801 Chopra, N.M.; Mahfouz, A.M. (1977) Further investigations into the
metabolism of endosulfan I, endosulfan II and endosulfan
sulfate in tobacco leaf. Beitraege zur Tabakforschung
9(3):176-179.
Chopra, N.M.; Mahfouz, A.M. (1977) Metabolism of endosulfan I,
endosulfan II, and endosulfan sulfate in tobacco leaf. Journal
of Agricultural and Food Chemistry 25(l):32-36.
Deema, P.; Thompson. E.; Ware, G .W. (1966) Metabolism, storage, and
excretion of Cr -Endosulfan in the mouse. Journal of Economic
Entomology 59(3) :546-550. (Also _In unpublished submission re-
ceived Jul 14, 1967 under 8F0632; submitted by FMC Corp., Phila-
delphia, Pa.; CDL:091099-A)
05003703 Dorough, H.W.; Huhtanen, K.; Marshall, T.C.; Bryant, H.E. (1978)
Fate of endosulfan in rats and toxicological considerations of
apolar metabolites. Pesticide Biochemistry and Physiology
8(3):241-252.
05003004
00004257
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MRID CITATION
00001328 Earnest, R. (1970) Annual Progress Report: 1970 Effects of Pesti-
cides on Aquatic Animals in the Estuarine and Marine Environ-
ment. (Unpublished study received Nov 26, 1976 under 241-132;
prepared by U.S. Fish and Wildlife Service, Fish-Pesticide
Research Laboratory, submitted by American Cyanamid Co.,
Princeton, N.J.; CDL:129448-W)
00003693 Elsea, J.R. (1957) Progress Report: Acute Oral Administration;
Acute Dermal Application; Acute Eye Application. (Unpublished
study received Jan 24, 1957 under 279-1182; prepared by Hazleton
Laboratories, submitted by FMC Corp., Philadelphia, Pa.; CDL:
100912-A)
05007645 Ely, T.S.; Macfarlane, J.W.; Galen, W.P.; Hine, C.H. (1967)
Convulsions in Thiodan workers: a preliminary report. Journal
of Occupational Medicine 9(2):35-37.
05003471 El Zorgani, G.A.; Omer, M.E.H. (1974) Metabolism of erdosulfan
isomers by Aspergillus niger. Bulletin of Environmental
Contamination and Toxicology 12(2):182-185.
05003053 Ernst, W. (1977) Determination of the bioconcentration potential
of marine organisms.—A steady state approach. I.
Bioconcentration data for seven chlorinated pesticides in
mussels (Mytilus edulis) and their relation to solubility
data. Chemosphere 6(11):731-740.
GS014009 Fahrig, R. (1974) Comparative mutagenicity studies with pesticides.
Int. Agency Res. Cancer (IARC) Sci. Publ. 10:161-181.
00003612 FMC Corporation (19??) Endosulfan: Analytical Method—Nut Crops.
(Unpublished study received Dec 15, 1969 under OF0922; CDL:
093220-B)
00003729 FMC Corporation (19??) Name, Chemical Identity and Composition of
Pesticide Chemical: [Endosulfan]. (Unpublished study including
letter dated Nov 17, 1970 from P.J. Boughton to Lee TerBush,
received Oct 30, 1970 under 1F1058; CDL:093371-F)
00003959 FMC Corporation (19??) Results of Tests of the Amount of Residues
Remaining and Description of Analytical Methods: [Thiodan].
(Unpublished study received Jun 21, 1966 under 7F0526; CDL:
095429-A)
00003703 FMC Corporation (19??) Thiodan: Analytical Method for Milk and Tis-
sues: Supplemental Information to Niagara Report M-1656. (Un-
published study received Aug 24, 1967 under 8F0632; CDL:092926-
D)
GS014006 FMC Corporation (1956) A report on investigations of HOE 2671.
(Unpublished study received Aug 3, 1956; prepared by Pharmacology
Institute, Goettinger, Germany; submitted by Agricultural Chem-
ical Division, FMC Corporation, Middleport, N.Y.; CDL-.090226)
-------
MRID CITATION
00003600 FMC Corporation (1958) Petition for the Establishment of a Toler-
ance for Thiodan on Strawberry and Peach.. .Including a Descrip-
tion of the Analytical Methods Used. (Unpublished study in-
cluding supplement, received Feb 9, 1960 under PP0237; CDL:
090265-A)
00003676 FMC Corporation (1964) Recovery of Thicdan Isomers and Sulfate from
Clarified Sugarcane Juice after Evaporation. (Unpublished 'study
including letter dated Apr 15, 1964 from W.C. Ferguson to T.H.
Harris, received Apr 15, 1964 under unknown admin, no.; CDL:
109877-A)
00003901 FMC Corporation (1964) Thiodan Residue Data on Sugarcane. (Unpub-
lished study received Feb 20, 1964 under unknown admin, no.;
CDL:109878-A)
00003642 FMC Corporation (1964) Thiodan: Analytical Method and Residue,.Data
in or on Sweet Potatoes. Includes method dated Feb 14, 1964.
(Unpublished study received Feb 18, 1964 under unknown admin.
no.; CDL:119693-A)
00003949 FMC Corporation (1965) Endosulfan and Endosulfan Sulfate Residues
on Field Peas (Shelled Peas and Pods). (Unpublished study re-
ceived Jul 1, 1969 under 279-1182; CDL:022704^A)"
00003917 FMC Corporation (1965) Endosulfan and Endosulfan Sulfate Residues
on Field Peas (Shelled Peas and Pods): Study I. (Unpublished
study received Jul 1, 1969 under 279-2659; CDL:002462-A)
00003796 FMC Corporation (1965) Results of Tests of the Amount of Residues
Remaining and Description of Analytical Method: [Thiodan]. (pp.
4-213 only; unpublished study received Apr 4, 1966 under 7F0526;
CDL:090630-B)
1 • ' f •
00003725 FMC Corporation (1966) [Residue Data of Endosulfan on Cotton].
(Unpublished study received Jun 8, 1970 under OF0929;
CDL:091584-B)
00003727 FMC Corporation (1967) [Residues of Endosulfan on Safflower 'Seed ]. ,,
Includes undated method. (Unpublished study received Jun 8,
1970 under OF0929; CDL:091584-E)
00004254 FMC Corporation (1967) Results of Tests of the Amount of Residues
Remaining and Description of Analytical Method: [Endosulfan].
(Unpublished study received May 29, 1970 under OF0922; CDL:
091576-A)
00003709 FMC Corporation (1969) [Foliar Application of Endosulfan on
Potatoes]. (Unpublished study received May 30, 1970 under
OF0925; CDL:091579-B)
-------
MRID CITATION
00003726 FMC Corporation (1969) Endosulfan Cotton: Processing Studies.
(Unpublished study received Jun 8, 1970 under OF0929; prepared
in cooperation with Texas A & M Univ., Cottonseed Products
Laboratory, CDL:091584-D)
!'' ' • v .
00003730 FMC Corporation (1970?) Results of Tests of the Amount of Residues
Remaining and Description of Analytical Method: [Endosulfan].
(Unpublished study received Oct 30, 1970 under 1F1058; CDL:
093371-1)
00003710 FMC Corporation (1970) Results of Tests of the Amount of Residues
Remaining and Description of Analytical Method: [Endosulfan]..
(Unpublished study received Sep 6, 1971 under 1F1028;
CDL:091905-B)
00003843 FMC Corporation (1971) Recovery of Endosulfan I, II and Endosulfan
Sulfate from Blueberries: M-2908. (Unpublished study received
'Sep 17, 1971 under 1F1034; CDL:091919-B)
00003713 FMC Corporation (1971) Results of Tests of the Amount of Residues
Remaining and Description of Analytical Method: [Endosulfan];
(Unpublished study received Nov 17, 1972 under 3F1314; CDL:
092246-C)
05003877 Frank, R.; Smith, E.H.; Braun, H.E.; Holdrinet, M.; McWade, J.W.
(1975) Organochlorine insecticides and industrial pollutants in
the milk supply of the southern region of Ontario, Canada.
Journal of Milk and Food Technology 38(2):65-72.
05004797 Frick, K.E. (1959) Further comparative toxicity tests against the
western cherry fruit fly. Journal of Economic Entomology
52(4)-769-770.
05017001 Gaikawad, S.T.; Samantaray, R.N.; Patnaik, S. (1973) Effect of
soil application of biocides on N, P, K availability and C, N
transformations in flooded rice soils. Journal of the.Indian
Society of Soil Science 21(3):263-269.
GS014007 Gains, T.B. (1969) Acute Toxicity Testing of Pesticides. Toxicol.
Appl. Pharmacol. 14(3):515-534.
00003743 Gorbach, S (1965) Investigations on Thicdan in the Metabolism of
Milk Sheep. Includes undated method. (Unpublished study in-
cluding report, received Dec 7, 1967 under 7F0632; prepared by
Farbwerke Hoechst ffi, Germany, submitted by FMC Corp., Phila-
phia, Pa.; CDL:091100-C)
00003744 Gorbach, S. (1973) Extraction of Endosulfan from Tea-Leaves. In-
cludes method dated Nov 4, 1973. (Unpublished study received on
unknown date under 2H2667; prepared by Farbwerke Hoechst PC,
Germany, submitted by American Hoechst Corp., North Hollywood,
Calif.; CDL:225765-A)
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MRID
05003222
GS014024
05007646
05003718
05003503
05004620
00022923
00003787
00003790
00003788
00003789
CITATION
Gorbach, S.G.; Christ, O.E.; Kellner, H.M.; Kloss, G.; Boerner, E.
(1968) Metabolism of endosulfan in milk sheep. Journal of
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00003786 Hinstridge, P.A. (1963) Project No. and Title: 15—Thiodan and
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i
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-------
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GS014003
CITATION
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-------
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00003587 Shuttleworth, J.M. (1971) Determination of Endosulfan and .Endosul-
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-------
MRID CITATION
00003784 Stanovick, R.P. (1965) Determination of Thiodan I, II and Sulfate
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-------
MRID CITATION
00003798 Tnornburg, W. (1966) Thicdan Residues on Treated Fresh Pineapple.
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MRID
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00003654 Ware, G.W.; Myser, W.C.; Treece, R.E.; Carey, W.E.; Tcrranova, A.C.
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