JF\
Environmental Protection
AgMcy
Offlwof
PMticidM and Toxic SubnanoM
Wwninqion OC 20460
Deramnti 1981
Metaiaxyl
N-(2,6-Dimethylphenyl)-
N-(methoxyacetyl) alanine
methyl ester
Pesticide Registration
Standard
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METALAXYL
PESTICIDE REGISTRATION STANDARD
Denise Keehner Project Manager (SPRD)
Rose Allison Project Manager (SPRD)
Henry Jacoby Product Manager (RD)
Jane Talarico Product Manager (RD)
June, 1981
Office of Pesticides and Toxic Substances
Environmental Protection Agency
401 M Street, SW
Washington, DC 20460
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TABLE OF CONTENTS
Page Number
Chapter One 1
How to Register Under a
Registration Standard 1
Chapter Two
Agency Position on Metalaxyl 10
1. Introduction 10
2. Description of Chemical 10
3. Regulatory Position 11
4. Regulatory Rationale 11
5. Criteria for Registration
Under the Standard 12
6. Acceptable Ranges and
Limits 13
7. Required Labeling 15
8. Tolerance Reassessment 16
Chapter Three 17
Data Requirements and Data Gaps 17
Chapter Four 38
Product Chemistry of Metalaxyl 38
A. Manufacturing-Use Metalaxyl 38
B. Emulsifiable Concentrate Metalaxyl ... 41
Chapter Five 43
Environmental Fate of Metalaxyl 43
A. Use Summary 43
B. Manufacturing-Use Metalaxyl 49
Chapter Six 57
Toxicology of Metalaxyl 57
A. Manufacturing-Use Metalaxyl 57
B. Emulsifiable Concentrate Metalaxyl ... 64
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Chapter Seven 66
Residue Chemistry of Metalaxyl 66
A. Manufacturing-Use Metalaxyl 66
B. Formulations of Metalaxyl 78
Chapter Eight 79
Ecological Effects of Metalaxyl 79
A. Manufacturing-Use Metalaxyl 79
B. Emulsifiable Concentrate Metalaxyl ... 80
Bibliography 82
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Chapter 1
HOW TO REGISTER
UNDER A REGISTRATION STANDARD
Organization of the Standard
Purpose of the Standard
Requirement to Re-register Under the Standard
"Product Specific" Data and "Generic" Data
Data Compensation Requiremnets under FIFRA 3(c)(l)(D)
Obtaining Data to Fill "Data Gaps"; FIFRA 3(c)(2)(B)
Amendments to the Standard
Organization o_f the Standard
This first chapter explains the purpose of a Registration
Standard and summarizes the legal principles involved in
registering or re-registering under a Standard. The second
chapter sets forth the requirements that must be met to
obtain or retain registration for products covered by this
particular Registration Standard. In the remaining chapters,
the Agency reviews the available data by scientific discipline,
discusses the Agency's concerns with the identified potential
hazards, and logically develops the conditions and requirements
that would reduce those hazards to acceptable levels.
Purpose of_ the Standard
Section 3 of the Federal Insecticide/ Fungicide, and
Rodenticide Act (FIFRA) provides that "no person in any
State may distribute, sell, offer for sale, hold for sale,
ship, deliver for shipment, or receive (and having so
received) deliver or offer to deliver, to any person any
pesticide which is not registered with the Administrator [of
EPA]." To approve the registration of a pesticide, the
Administrator must find, pursuant to Section 3{c)(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
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the proposed pesticide. But the established approach to
making these findings has been found to be defective on two
counts:
First, EPA and its predecessor agency, the United
States Department of Agriculture (USDA) , routinely reviewed
registration applications on a 'product by product1 basis,
evaluating each product-specific application somewhat
independently. In the review of products containing similar
components, there was little opportunity for a retrospective
review of the full range of pertinent data available in
Agency files and in the public literature. Thus the 'product
by product' approach was often inefficient and sometimes
resulted in inconsistent or incomplete regulatory judgements.
Second, over the years, as a result of inevitable and
continuing advances in scientific knowledge, methodology,
and policy, the data base for many pesticides came to be
considered inadequate by current scientific and regulatory
standards. Given the long history of pesticide regulation
in several agencies, it is even likely that materials may
have been lost from the data files. When EPA issued new
requirements for registration in 1975 (40 CFR 162) and
proposed new guidelines for hazard testing in 1978 (43 FR
29686, July 10, 1978 and 43 FR 37336, August 2, 1978), many
products that had already been registered for years were
being sold and used without the same assurances of human
and environmental safety as was being required for new
products. Because of this inconsistency, Congress directed
EPA to re-register all previously registered products, so as
to bring their registrations and their data bases into
compliance with current requirements [See FIFRA Section
Facing the enormous job of re-reviewing and calling-in
new data for the approximately 35,000 current registrations,
and realizing the inefficiencies of the 'product by product1
approach, the Agency decided that a new, more effective
method of review was needed.
A new review procedure has been developed. Under it,
EPA publishes documents called Registration Standards, each
of which discusses a particular pesticide active ingredient.
Each Registration Standard summarizes all the data available
to the Agency on a particular active ingredient and its
current uses, and sets forth the Agency's comprehensive
position on the conditions and requirements for registration
of all existing and future products which contain that
active ingredient. These conditions and requirements, all
of which must be met to obtain or retain full registration
or re-registration under Section 3(c)(5) of FIFRA, include
the submission of needed scientific data which the Agency
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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)(0).
The Standard will also serve as a tool for product
classification. As part of the registration of a pesticide
product, EPA may classify each product for "general use" or
"restricted use" [FIFRA Section 3(d)]. A pesticide is
classified for "restricted use" when some special regulatory
restriction is needed to ensure against unreasonable adverse
effects to man or the environment. Many such risks of
unreasonable adverse effects can be lessened if expressly-
designed label precautions are strictly followed. Thus
the special regulatory restriction for a "restricted use"
pesticide is usually a requirement that it be applied only
by, or under the supervision of, an applicator who has been
certified by the State or Federal government as being
competent to use pesticides safely, responsibly, and in
accordance with label directions. A restricted-use pesticide
can have other regulatory restrictions [40 CFR 162.11(c)(5)]
instead of, or in addition to, the certified applicator
requirement. These other regulatory restrictions may
include such actions as seasonal or regional limitations on
use, or a requirement for the monitoring of residue levels
after use. A pesticide classified for "general use," or
not classified at all, is available for use by any
individual who is in compliance with State or local regu-
lations. The Registration Standard review compares infor-
mation 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
classifed for "restricted use." If the Standard does
classify a pesticide for "restricted use," this determination
is stated in the second chapter.
Requirement _to Re-register Under the Standard
FIFRA Section 3{g), as amended in 1978, directs EPA to
re-register all currently registered products as expeditiously
as possible. Congress also agreed that re-registration
should be accomplished by the use of Registration Standards.
Each registrant of a currently registered product to
which this Standard applies, and who wishes to continue to
sell or distribute his product in commerce, must apply for
re-registration. His application must contain proposed
labeling that complies with this Standard.
EPA will issue a notice of intent to cancel the regist-
ration of any currently registered product to which this
Standard applies if the registrant fails to comply with the
procedures for re-registration set forth in the Guidance
Package which accompanies this Standard.
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"Product Specific" Data and "Generic" Data
In the course of developing this Standard, EPA has
determined the types of data needed for evaluation of the
properties and effects of products to which the Standard
applies, in the disciplinary areas of Product Chemistry,
Environmental Fate, Toxicology, Residue Chemistry, and
Ecological Effects. These determinations are based
primarily on the data Guidelines proposed in 1978 (43 PR
29686, July 10, 1978, and 43 FR 37336, August 2, 1978), as
applied to the use patterns of the products to which this
Standard applies. Where it appeared that data from a
normally applicable Guidelines requirement was actually
unnecessary to evaluate these products, the Standard indicates
that the requirement has been waived. On the other hand, in
some cases studies not required by the Guidelines may be
needed because of the particular composition or use pattern
of products the Standard covers; if so, the Standard explains
the Agency's reasoning. Data guidelines have not yet been
proposed for the Residue Chemistry discipline but the
requirements for such data have been in effect for some time
and are, the Agency believes, relatively familiar to registrants.
Data which we have found are needed to evaluate the registra-
bility 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 require-
ments apply to which product categories. (See the second
chapter). The various kinds of data normally required
for registration of a pesticide product can be divided
into two basic groups:
(A) data that is "product specific," i.e., data that
relates only to to the properties or effects of a
product with a particular composition (or a group
of products with closely similar composition);
and
(B) "generic" data that pertains to the properties or
effects of a particular ingredient, and thus is
relevant to an evaluation of risks and benefits of
all products containing that ingredient (or all
such products having a certain use pattern),
regardless of any such product's unique composition.
The Agency requires certain "product specific" data for
each product to characterize the product's particular
composition and physical/chemical properties (Product
Chemistry), and to characterize the product's acute toxicity
(which is a function of its total composition). The applicant
for registration or re-registration of any product, whether
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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 end-use products is also required where the exact
formulation may affect efficacy and where failure of efficacy
could cause public health problems.
All other data needed to evaluate pesticide products
concerns the properties or effects of a particular ingredient
of products (normally a pesticidally active ingredient, but
in some cases a pesticidally inactive, "inert," ingredient).
Some data in this "generic" category are required to
evaluate the properties and effects of all products containing
that ingredient [e.g., the acute LD-50 of the active ingredient
in its technical or purer grade; see proposed 40 CFR 163.81-l(a),
43 FR 37355].
Other "generic" data are required to evaluate all
products which both contain a particular ingredient and are
intended for certain uses (see, e.g., proposed 40 CFR
163.82-1, 43 FR 37363, which requires subchronic oral
testing of the active ingredient with respect to certain use
patterns only). Where a particular data requirement is
use-pattern dependent, it will apply to each end-use product
which is to be labeled for that use pattern (except where
such end-use product is formulated from a registered manu-
facturing-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, the
subchronic oral study would not be relevant to the evalua-
tion of the manufacturing-use product either.
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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 use patterns from his labeling at
the time he re-registers his product. An applicant for
registration of a new product under this Standard may
similarly request approval of only certain use patterns.
Data Compensation Requirements under FIFRA 3(c)(1)(D)
Under FIFRA Section 3(c)(l)(D), an applicant for
registration, re-registration, or amended registration must
offer to pay compensation for certain existing data the
Agency has used in developing the Registration Standard.
The data for which compensation must be offered is all data
which is described by all the following criteria:
(1) the data were first submitted to EPA (or to its
predecessor agencies, USDA or FDA), on or after
January 1, 1970;
(2) the data were submitted to EPA (or USDA or FDA) by
some other applicant or registrant in support of
an application for an experimental use permit,
an amendment adding a new use to a registration,
or for re-registration, or to support or maintain
in effect an existing registration;
(3) the data are relevant to the Agency's decision
to register or re-register the applicant's product
under the Registration Standard, taking into
account the applicant's product's composition
and intended use pattern(s);
(4) the data are determined by EPA to be valid and
usable in reaching regulatory conclusions; and
(5) the data are not those for which the applicant
has been exempted by FIFRA Section 3(c)(2)(D) from
the duty to offer to pay compensation. (This
exemption applies to the "generic" data concerning
the safety of an active ingredient of the applicant's
product, not to "product specific" data. The
exemption is available only to applicants whose
product is labeled for end-uses for which the
active ingredient in question is present in the
applicant's product because of his use of another
registered product containing that active ingredient
which he purchases from another producer).
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An applicant for re-registration of an already registered
product under this Standard, or for registration of a new
product under this Standard, accordingly must determine
which of the data used by EPA in developing the Standard
must be the subject of an offer to pay compensation, and
must submit with his application the appropriate statements
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 some or all of the "product specific"
aspects of the applicant's product. In such a case, the
applicant may choose to cite that data instead of submitting
data from tests on his own product, and if he chooses that
option, he would have to comply with the offer-to-pay
requirements of Section 3(C)(1)(D)for that data.
Each applicant for registration or re-registration of
a manufacturing-use product, and each applicant for registration
or re-registration 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 re-registration (or new registration)
under this Standard is found in the Guidance Package for
this Standard.
Obtaining Data to Fill "Data Gaps"; FIFRA 3(c)(2)(B)
Some of the kinds of data EPA needs for its evaluation
of the properties and effects of products to which this
Standard applies have never been submitted to the Agency
(or, if submitted, have been found to have deficiencies
rendering them inadequate for making registrability decisions)
and 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)
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data to fill such "gaps" and submit those data to EPA. EPA
must allow a reasonably sufficient period for this to be
accomplished.
If a registrant fails to take appropriate and timely
steps to fill the data gaps identified by a Section 3(c)(2)(B)
order, his product's registration may be suspended until
the data are submitted. A mechanism is provided whereby two
or more registrants may agree to share in the costs of
producing data for which they are both responsible.
The Standard lists/ in its summary second chapter, the
"generic" data gaps and notes the classes of products to
which these data gaps pertain. The Standard also points out
that to be registrable under the Standard, a product must be
supported by certain required "product 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 product1 basis. (Although
the Standard will in some cases note which data that EPA
does possess would suffice to satisfy certain "product
specific" data requirements for a category of products with
closely similar composition characteristics.)
As part of the process of re-registering currently
registered products, EPA will issue Section 3(c)(2)(B)
directives requiring the registrants to take appropriate
steps to fill all identified data gaps — whether that
data in question is "product specific" or "generic" —
in accordance with a schedule.
Persons who wish to obtain registrations for new
products under this Standard will be required to submit
(or cite) sufficient "product specific" data before their
applications are approved. Upon registration, they will
be required under Section 3(c)(2)(B) to take appropriate
steps to submit data needed to fill "generic" data gaps.
(We expect they will respond to this requirement by entering
into cost-sharing agreements with other registrants who
previously have been told they must furnish the data.)
The Guidance Package for this Standard details the steps
that must be taken by registrants to comply with Section
3(c)(2)(B).
Amendments _to the Standard
Applications for registration which propose uses
or formulations that are not presently covered by the
Standard, or which present product compositions, product
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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
than amend the Standard to cover the new registration.
Each Registration Standard is based upon all data
and information available to the Agency's reviewers on
a particular date prior to the publication date. This
"cut-off" date is stated at the beginning of the 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
"data gaps" have been filled and the submitted data have
been reviewed, the Agency will revise the Registration
Standard. Thereafter, when the Agency determines that the
internally maintained addenda have significantly altered the
conditions for registration under the Standard, the document
will be updated and re-issued for publication.
While the Registration Standard discusses only the
uses and hazards of products containing the designated
active ingredient(s), the Agency is also concerned with
the potential hazards of some inert ingredients and impurities.
Independent of the development of any one Standard, the
Agency has initiated the evaluation of some 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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Chapter II
REGULATORY POSITION
A. Introduction
This chapter describes in detail the Agency's regulatory
position on products which contain metalaxyl as the sole
active ingredient. The regulatory position adopted by the
Agency incorporates a number of considerations. Foremost
among these considerations is an analysis of the registra-
bility of products containing metalaxyl based on the risk
criteria found in Section 162.11(a) of Title 40 of the U.S.
Code of Federal Regulations. The Agency's determination is
presented below, and the rationale for this decision follows
the position.
In addition to the basic regulatory decision and rationale,
this chapter includes the following: criteria for the
registration of metalaxyl products under the Standard;
acceptable ranges and limits for product composition, acute
toxicity, and use pattern/application method; required
labeling; tolerance reassessment.
The scientific basis for a decision presented in this
chapter can be found by reading the various disciplinary
chapters (Chapters IV- VIII) which provide summaries of
available scientific data on metalaxyl. References to
Agency guidelines for testing are provided when appropriate.
In instances where the data requirements differ from the
guideline requirements, the rationale is presented in the
footnotes of the table.
B. Description of Chemical
Metalaxyl [N-(2,6-Dimethylphenyl)-N-(methoxyacetyl) alanine
methyl ester] is a white to beige, odorless crystal.
Metalaxyl is a fungicide, registered for use in tobacco,
ornamentals, and turf. Currently there are no permanent
tolerances for the use of metalaxyl on food or feed crops.
However, use on a variety of field and vegetable crops may
be anticipated. See Chapter V for additional information on
use patterns.
Metalaxyl is the accepted common name for the chemical* It
is also known under the trade or company names Ridomil ,
Subdue , Apron , and "CGA 48988". The Chemical Abstracts
Registry (CAS) number for metalaxyl is 57837-19-1 and the
EPA Shaughnessy number is 113501.
Ciba-Geigy Corporation is the sole producer and registrant.
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C. Regulatory Position for Products Containing Metalaxyl
Metalaxyl as described in this Standard may be registered
for sale, distribution, reformulation, and use in the United
States. Considering information available to the Agency
from the open literature and provided by the registrant as
of May 30, 1981 (excluding residue data for pending tolerances)
the Agency finds that none of the risk criteria found in
Section 162.11(a) of Title 40 of the U.S. Code of Federal
Regulations were met or exceeded for metalaxyl.
The information available to the Agency at the time of the
development of this Standard was adequate to indicate that
for the use currently registered, metalaxyl should not cause
unreasonable adverse effects when used in compliance
with proper label directions and precautions. Metalaxyl
products currently registered may be reregistered subject to
the conditions imposed for data requirements or other
requirements of this Standard. New products may be registered
under this Standard, and are subject to the same requirements.
D. Regulatory Rationale
EPA is authorized to issue conditional registrations for new
chemicals under certain special circumstances (FIFRA s. 3(c)
(7)(c)). These include cases where the early registration is
in the public interest and should not under proposed usage
conditions cause unreasonable adverse effects on the environ-
ment. Metalaxyl was first registered for the formulation of
fungicides in 1979 and for use in a formulated product on
tobacco in 1980. This use was found to be in the public
interest because large potential economic losses due to blue
mold in the tobacco crop were anticipated in the 1980 growing
season.
Metalaxyl was first registered for use on tobacco with several
conditions. These conditions included submission or generation
of data in several scientific disciplines, i.e.:
- groundwater and soil monitoring be conducted to assess
whether the potential for metalaxyl to leach demonstrated
by environmental fate data could contaminate groundwater;
- submission of a 96-hour fish LC for rainbow trout
and bluegill using the emulsifiabie concentrate (EC)
formulation;
- submission of a 48-hour LC5Q for aquatic invertebrates
using the EC formulation;
- submission of an invertebrate life-cycle test using the
technical chemical; and
- a 90-day subchronic inhalation study using the technical
chemical in smoke (40 CFR 163.82-4)
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The Agency has evaluated submitted data in the area of
fish and wildlife and has found that under the proposed
usage metalaxyl should not cause unreasonable adverse
effects on the environment. Other data are still outstanding
and a further assessment of effects of metalaxyl on man and
the environment from the current use pattern will be
made at the time of submission.
E. Criteria for Registration Under the Standard
To be subject to this Standard, metalaxyl products must meet
the following conditions:
- contain metalaxyl as the sole active ingredient;
- be within acceptable standards of product composition;
- be within acute toxicity limits;
- be labeled for acceptable uses; and
- bear required labeling.
Manufacturing-use metalaxyl products must bear label directions
for formulation into acceptable end-uses.
The applicant for registration or reregistration of metalaxyl
products subject to the Standard must comply with all terms
and conditions described in this Standard, including commitment
to fill data gaps on a time schedule specified by the Agency
and, and when applicable, offer to p'ay compensation to the
extent required by 3(c)(l)(D) and 3(c)(2)(D) of the Federal
Insecticide, Fungicide, and Rodenticide Act [FIFRA] as
amended, 7 U.S.C. 136(c)(l)(0) and 136(c)(2)(D).
FIFRA s. 3(c)(1)(D)(i) provides special "exclusive use"
protection for any pesticide product first registered after
September 30, 1978, that contains an active ingredient not
found in any previously-registered product. The active
ingredient, metalaxyl, was first registered on June 12,
1979 for the formulation of fungicides (EPA reg. no. 100-
601) by Ciba-Geigy Corporation. The period of "exclusive
use" lasts for 10 years after the initial registration.
The Bibliography portion of this Standard indicates which
data are subject to this "exclusive use" provision.
With respect to other data, FIFRA s. 3(c)(1)(D)(ii)
provides that data submitted after December 31, 1969 to
support an existing registration or for reregistration
may not be used to support the registration of another
applicant for 15 years following the date that the data
were originally submitted unless the applicant has made
an offer to pay compensation for that data.
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F. Acceptable Ranges and Limits
1. Manufacturing-Use Metalaxyl
a. Product Composition Standards
To be covered under this Standard, manufacturing-use metalaxyl
products must contain metalaxyl as the sole active ingredient.
Manufacturing-use metalaxyl with any percentage of active
ingredient is acceptable under this Standard (with appropriate
certification of limits).
b. Acute Toxicity Limits
The Agency will consider registration of manufacturing-use
products containing metalaxyl regardless of the toxicity
category, provided that the labeling of such products bears
appropriate precautionary statements.
c. Use Patterns
To be covered under this Standard, manufacturing-use metalaxyl
products must be labeled for formulation into end-use
fungicides which are intended for outdoor, nondomestic,
terrestrial, nonfood applications.
Metalaxyl, as of May 30, 1981 was registered only for
outdoor, non-domestic, terrestrial, non-food applications.
The Agency will consider changed and additional use
patterns with appropriate submission and/or citation
of data that supports the finding that metalaxyl does
not cause unreasonable adverse effects on man and the
environment.
The Agency will consider additional non-food (non-
domestic) terrestrial outdoor uses of metalaxyl provided
any required data are cited or submitted for the registra-
tion of the use and the use will not result in an unacceptable
risk to applicators or users of the site. The Agency has a
fairly complete data base on which to base an assessment of
this category of use.
The Agency received petitions for tolerances of metalaxyl
(including the 2,6-dimethylaniline moiety) in or on several
raw agricultural commodities and in meat, milk, poultry, and
eggs. The Agency also received a tolerance petition for
feed additive tolerances. The Agency is considering these
tolerances and will consider any additional proposed tolerances
on food and feed crops provided that applicants for the
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registration of the additional crop(s) submit a petition(s)
proposing a tolerance level for each crop, supply appro-
priate residue data, and demonstrate that the establish-
ments of the tolerance is adequate to protect public
health. Applicants must also demonstrate that the additional
food crop-use pattern(s) will not result in an unacceptable
risk to applicators or to field workers.
The residue chemistry data base for the proposed food
crop uses is in review. The food crop uses are not toxicologi-
cally supported without the submission of additional chronic
toxicology data in the areas of chronic feeding/ oncogenicity
and mutagenicity.
The Agency will consider metalaxyl products for domestic
or residential use as defined in 40 CFR 162.3 and in 40
CFR 162.16. This use may require child resistant packaging
or an exemption from child resistant packaging if proposed
metalaxyl products demonstrate acute hazards as defined in
40 CFR 162.16(c)(2).
2. End-Use Metalaxyl - Emulsifiable Concentrate (EC)
a. Product Composition Standard
End-use metalaxyl products with any percentage of active
ingredient are acceptable under this Standard with appropriate
certification of limits.
Inert ingredients in food-use formulations must be cleared
for such use under 40 CFR 180.1001. As of April 1, 1981,
metalaxyl is not registered for a food use. However, an
experimental use (with a temporary tolerance) exists for
metalaxyl on potatoes. All inert ingredients in EC metalaxyl
are cleared.
b. Acute Toxicity Limits
The Agency will consider registration of any end-use
metalaxyl product under this Standard provided that it
falls under acute toxicity categories acceptable for
general use and bears appropriate precautionary labeling.
If a proposed end-use product is accepted for (general)
domestic or residential use and it has established acute
toxicity ratings of Category I for primary eye irritation or
Categories I and II for acute oral toxicity, acute dermal
toxicity, acute inhalation and/or primary dermal toxicity,
the product may require child resistant packaging or an
exemption from child resistant packaging.
-14-
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c. Use Patterns and Application Methods
To be registered under this Standard, end-use products of
metalaxyl must be labeled as fungicides for use on one or
more of the following sites:
food uses non-food uses
none as of tobacco
5/30/81 conifers
ornamentals
turf
The Agency finds that current dosage rates and application
methods are acceptable under this Standard. These rates
are summarized in Chapter V.
A rotational crop restriction or a rotational crop
tolerance is required because metalaxyl residues have
been demonstrated to be available to subsequent crops
after the initial treatment with metalaxyl. All end-use
metalaxyl products intended for agricultural use must
bear labeling of the appropriate rotational crop
restriction or a rotational crop tolerance must exist
for the appropriate crops.
g. Required Labeling
All manufacturing-use and end-use metalaxyl products must
bear appropriate labeling. The guidance package for this
Standard contains specific information regarding label
requirements.
1. Manufacturing-Use Products
a. Use Pattern Statements
All manufacturing-use metalaxyl products must list on the
label the intended end-uses of formulated products produced
from the manufacturing-use products. All metalaxyl labels
must bear the following statement:
"For Formulation into End-Use Fungicides".
b. Precautionary Statements
The guidance package provides an updated list of all
precautionary statements which must appear for this type of
product.
-15-
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2. End-Use Metalaxyl Products
The guidance package provides an updated list of all pre-
cautionary statements which must appear for this type of
product.
A rotational crop restriction is supported by data and
is required for end-use products intended for agricultural
use. Under "directions for use" and "note to user", the
following restriction must appear:
"If replanting is necessary, tobacco may be replanted
immediately. Do not make a second application of
[metalaxyl product]. Tobacco corn or root crops
may be planted during the fall following treatment
provided they are plowed down and not used for food
or feed. Other crops may be planted 18 months
following application."
H. Tolerance Reassessment
A temporary tolerance of 0.05 ppm in or on potatoes has been
established for metalaxyl in association with an experimental
use permit (100-EUP-l). The Provisional Acceptable Daily
Intake (PADI) is based on the 90-day subchronic oral rat
study (Drake 1977, 0011) with a no-observed effect level
(NOEL) of 250 ppm. The NOEL equates to 12.5 mg/kg/day.
A 2000-fold safety factor is used to calculate the PADI
because the toxicity study on which it is based is a sub-
chronic study.
PADI = 12.5 mg/kg/day = 0.0062 mg/kg/day
2000
The maximum permissable intake (MPI) for a 60 kg person is
0.3750 mg/day. For potatoes the theoretical maximum residue
contribution (TMRC) equals 0.0041 mg/day/1.5 kg based on the
tolerance level of 0.05 and a food factor of 5.43. This
equates to approximately 1.09% of the PADI.
-16-
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Chapter III
DATA REQUIREMENTS AND DATA GAPS
Manufacturing-use Metalaxyl
Table 1, entitled Metalaxyl Generic Data Requirements,
includes those data that pertain to the properties or
effects of metalaxyl as an active ingredient. Thus, these
data are relevant to an evaluation of the risks and benefits
of all products containing metalaxyl. Providing data to
fill indicated gaps is the primary responsibility of the
manufacturing-use product registrant(s). Registrants of
end-use products which are not exempted by FIFRA Section
3(c)(2)(D) are also responsible for the submission of these
data. Applicants for the registration or reregistration of
manufacturing-use metalaxyl products must acknowledge
reliance on existing data which fill indicated data require-
ments under FIFRA 3(c)(l)(D). These data are listed under
the column entitled Bibliographic Citation in this table.
CIBA-GEIGY, the sole registrant of metalaxyl products, is
entitled to exclusive use of these data for a ten year
period, starting on June 12, 1979 [FIFRA s. 3(c)(1)(D)(i)].
These data may not be used to support any application for
registration without the written permission of CIBA-GEIGY.
Table 2, entitled Metalaxyl Product-Specific Data Requirements
for Manufacturing-Use Products, includes those data that
relate only to the properties or effects of a product with a
specific composition. Thus, these data are required of each
product to characterize the product's particular composition
and physical/chemical properties, and acute toxicity.
Providing data to fulfill these data requirements for a
particular product is the responsibility of each applicant
for the registration or reregistration of a manufacturing-use
metalaxyl product. If the Agency has in its possession
product-specific data which fulfill a data requirement for
a particular product, this is indicated in the guidance
package accompanying this Standard.
Applicants for the registration of new manufacturing-use
metalaxyl products must submit all required product specific
data or establish that the proposed product is substantially
similar to another product for which the Agency has received
acceptable product-specific data.
If the Agency has determined that one or more existing
manufacturing-use metalaxyl products are substantially
similar, then this, too, is indicated. Product-specific
data need not be acknowledged under FIFRA 3(c)(l)(D) unless
-17-
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the Agency or a registrant has established that a product is
substantially similar to another product for which the
Agency has received acceptable product-specific data. If
this should occur, the registrant(s) of the former product(s)
is required to acknowledge reliance on these data.
End-Use Products of Metalaxyl
Registrants of end-use metalaxyl products not exempted by
FIFRA Section 3(c)(2)(D) are responsible for the submission
of "generic" data described in Tables 1 and 2 of this
Chapter, in addition to the product-specific data listed in
Table 3.
Registrants of all end-use metalaxyl products are advised
that if data are not generated to fill generic data require-
ments for the manufacturing-use product(s), these registra-
tions will be suspended. If continued availability of the
manufacturing-use product is desired, these data must be
supplied.
Table 3, entitled Metalaxyl Product-Specific Data Requirements
for End-Use Products, includes those data that relate only
to the properties or effects of an end-use product with a
specific composition.
-18-
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Table I
Ftotalaxyl Product-Chemistry (Sec Chapter IV)
Generic Data Requirements
Guidelines
Citation
163.61-8(1)
163.61-8(2)
163.61-8(3)
163.61-8(4)
163.61-0(5)
163.61-0(6)
163.61-8(7)
tlame of
Test
Color
Odor
Melting Point
Solubility
Stability
Octanol /water
partition
coefficient
Physical State
Are Dnta
Required
Yea
Yea
Yes
Yea
Yes
Yes
Yes
Ccnpositlon
Ibdmlcal Grade
ltd in leal Grade
Tfedmlcal Grade
'Itedmlcal Grade
Vedinical Grade
Itedmlcal Grade
'Itedmlcal Grade
Itoos EPA Have
Data to Partially
or totally Satisfy
this Requirement
Yes
Yea
Yes
Yes
Yes
Mo
Yes
Olbllogra|jliic
Citation
Clba-Gelgy Corp.
1978; 0160
Ciba-Gelgy Corp.
1978; 0160
Ciba-Gelgy Corp-
1970; 0160
Ciba-Gelgy Corp.
1978; 0160
Clba-Gelgy Corp.
1978; 0160
Clba-Gelgy Corp.
1978; 0160
Must Additional Data be
Sulnittcd under PIFIW
3(c)(2)(D)7 If so, months
allowed Cor sulinission
Cmn ptibllslied date of
standard
^
ttoV
NO*/
ttoi/
No1-/
Yes/6 months
Noi/
Provided that the teclmlcal material used is Clba-Gelgy mctalnxyl.
Data requirements are current na of July 1981. l(c*fcr to
(kildance Package for updated requirements.
-19-
-------
Tahiti 1 (Cont'd)
Mctalaxyl Product CliemisUy (Sec Chapter IV)
Generic Data ltei]ulrcin?nts
Guldel iiics
Citation
163.61-0(8)
163.61-8(9)
163.61-8(10)
163.61-8(11)
name of
Test
Density or
Specific Gravity
Dolling Point:
vapor Pressure
1*1
Ace Data
Required
Yea
No
Yes
Yes
Docs EPA Have
Data to Partially
or totally SatlsCy
Conposltion this Requirement
Technical Grade Yea
Technical Grade Yes
Technical Grade Mo
Bibliographic
Citation
Ciba Gelgy Corp.
1978} 0160
Clba Geigy Corp.
1978; 0160
Must Additional Data be
Submitted under FIFRA
3(c)(2)(B>? 1C so, mouths
allowed Cor submission
from published date oC
standard
noi/
.*>!/
Yes/6 montlia
I/ Provided that the technical material used Is Ciba-Geigy nctalaxyl.
Uata requirements are current as oC July 1901. Refer to
Guidance Package Cor updated requirements.
-20-
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Tjble 1 (Coiit'd)
Hetalaxyl Rnviroiinental Fate (See Chapter V)
(teneric Uata Requirements
GlllllullltCS
Citation
]G3.62-7(b)
16J.62-7(c)
!63.62-0(b)
J63.62-0(c)
163.62-8(0
Name oE
Test
Hydrolysis
rtiotoilcgradat 1 on
Aerobic soil
nutabol Ian
Anaerobic sol 1
metabolism
Mlcrobial
metabolism
(2) eCCecta of
microbes oil
pesticides
(3) effects of
pesticides on
microbes
Are Data
Keqnlred
Yes
Yea
Yes
Yes
Yes
Yes
Docs EPA Have
Data to Partially
or totally Satisfy
Composition tills Requirement
•technical or Radio- Yes
labeled Analytical
Grade
'technical or Radio- Yes
labeled Analytical
Grade
technical or Radio- Yes
labeled Analytical
Grade
Itedinlcal or Radio- Yes
label Analytical
Grade
Bibliographic
Citation
Durkliard
1976 | 0076
Burkliard
1979 i 0100
EUgehausen
1978 i 0081
Ellcjehausen
1970 j 0001
Ercecjovich
1979; 0102
Ercegovlchi Bogus
1979;0103
lircegovlcli,
Vallejo, Bogus
1979 » 0104
Must Additional Data be
Sulinltted under P1FRA
3(c)(2)(D)7 If so, nontlis
allowed for sulxnisslun
fran publlslicd dale of
standard
Ito
Ib
tto
1)0
Reserved^-
i §
nisatyea*
T/The requirement for tlie siibnission of data Is currently reserved pending the development of protocols by tie Agency.
Data requirements are current as of July 1901. liefer to
Guidance Package for updated requlreincnta.
-21-
-------
Table 1 (Cont'd)
Metalaxyl Envlroiincntal Fate (Sec Chapter V)
Generic Data Requirements
Guidelines
Citation
163.62-8(g)
163.62-9(b)
l6J.62-9(c)
l63.62-9(d)
ir>3.G2-10(b)
Name of
Test
Activateil
Slurlgc
Metabolism
Leaching
Vblatillty
Adsorption/
desorption
Terrestrial field
dissipation
(2) ornamentals
and LurC uses
Hoes EPA llavc
Itota to Partially
Are Data or totally Satisfy
Required Composition this Requirement
Yes Technical or Radio-
labeled Analytical
Grade
Yes-' Technical or Radio- Yes
late led Analytical
Grade
Yes^/ Technical or Radio- Yes
labeled Analytical
Grade
Yoa^ Yes
Yes Representative Yes
formulation
Yes
Bibliographic
Citation
Doebbler
1979; 0101
Glinlski
1970; 0105
Guth 1976;
0087
Guth 1978;
0009
Ourkhard
1977; 0077
Guth 1978;
0008
Ellgehausen
1977; 0079
0080
Ellgehausen
1977; 0079,
0000
Must Additional Data be
iJulunitted under FIFRA
3(c)(2)(D>? If so, nuiiUis
allowed for sulinlssion
Train publislirxl date oC
standard
Itoservcdi/
No
Mo
No
Mo
I/ 11n re>]uireinent for the siilxnionion of data is currently being reserved pending the development of protocols by Lhe Agency.
?./ Ro]uli:od on casc-by-cane Ixisls for ooninerclal grcenlioiisc, orchard, or field/vegetable crop uses that Involve significant exposure.
3/ Ro(|istrant would have tlie option of conrlucting eltlier a leaching or an adsorption/desorptlon study for terrestrial field
applications.
Data requirements are current as of July 1981.
Guidance Package for iqxlated ruiuiremeiits.
-22-
Itefcr to
-------
Table 1 (Cont'cl)
tfetalaxyl Environmental Kate (Sec Chapter V)
Generic IJata Itoiuireiiients
(In Moll lieu
Citation
Name of
Test
Ate (Vita
Required Composition
Hoes h'PA Have
Data to Partially
or totally Satisfy
this Requirement
Bibliographic
Citation
Hiist Additional Data be
Siilmi tted unld- FIFMA
)(c)(2)(D)7 If so, months
al lower! Cor sulinlssion
from published date of
stamiarU
KiJ.62-IO(f)
163.62-1 Kb)
163. 62-1 1 (d)
163.62-13
Combination
and tank mix
Field dissipation
Accumulation
in rotational
crops
Yes
DC or nnn-radio-
labeled tedmical
g trade
Radlolabeled
Analytical Grade
Followed by
Formulation
Yes
Fioh accumulation
Disposal am)
Technical or
labelcd Analytical
Gratte
Yes
Fi seller, Cassidy
1979; 0004,0082
Foster, Fisdier,
Cassidy 1970;
0086
Hamilton, Fisdier,
Cassidy 1979;
0000, 0091
Ciba-Celfjy Coi-p.
1979; 0129
fadd, Hilson
1979; 0093
(add, Enos
1979; 0092
Mo
No
tto
Grouixlwater
Monitor ing
Yes
Yesi/
Heaervud-
Ycs/24 months
T7 Itata tu'infTod on a case-by-casr! lias la for UlP's containing nore than one active Ingredient, intended for use as a ainponcnt In tank
mixtures or custanarily aiiplled serially with another peaLicMo product.
2/ '11 ie requirement for the sulmissioii of data is currently reserved pending the develctnant of protocols by the Agency.
I/ l{<>|ulied Iccausu inotalnxyl is cxiiecteil to loach jn sorely soils and roach water.
4/ Re|iiireel becauoo of strong leaching proclivity and potential to reach groundwatcr.
5/ Studies in progrusss.
Data ro'iuiroiieuts are ciiLrcnL as of .luly 1901.
Culd.incu Pacltarje Cor ii|xlatcd rcquiremnnts.
liefer to
-23-
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Table 1 (ContM)
Motalaxyl Toxicology (See Chapter VI)
Generic Data Requirements
Guidelines
Citation
ir,3.01-l
163.81-2
163.82-1
163.82-2
163. (12- 3
163.82-4
Must Additional Data be
Submitted under flFHA
Itooa EPA Have 3(c)(2)(0)? 1C so. nontha
Ikita Lo Martially allowed Cor submission
llarne of Are Data or totally Satisfy Bibliographic Cran publislted date oE
Test Required Composition this Requirement Citation standard
Acute Oral Yes Tedmlcal Grade Ves
Ibxlclty
Acute Denial Yes Technical Grade Yes
tbxiclty
Subchixxiic Yes Tedmical Grade Yes
Oral Toxic! ty
Subclironic Yes1' Technical Grade Yes
21-Oay Ucrmal
Toxlclty
Subchrcnlc lk>
90-day Dermal
Itaxicity
SubchronJc Yes2/ Tcdmlcal Grade Ilo3/
Inlialation in Smoke
Ibxlclty
Sadisse, (lathe fJo
1976; 0026
Sadisse, Ullinann I Jo
1976 t 0029
Drake 1977; 0011 Ho
Finn 1977; 0012
(teWard ct al.. No
1900; 0045
'Ibxigenics tto
1980; 0041
Coale Yes/12 nontlLS
19BO; 0037
T/ Itequircu for use on turf.
2/ Requirerl for metalaxyl use on tobacco (see also Residue Chemistry)
3/ .Stifly in progress. Pilot study only in Agency files.
Data requirements arc current as of July 1901.
Guidance Package for updated requirements.
-24-
neCer to
-------
Talile 1 (Confd)
Metalaxyl U>xicolnjy (Sec Chapter VI)
Generic Data Kequiienents
Must Additional llnta Ixj
Submitted under K1FRA
Does I3PA Have 3(c)(2)(l))7 1C so. months
Data Lo Partially allowed Cor submission
Guidelines Mane of Ate Data or totally Satisfy Dihllorjraphic Ertin published date of
Citation Test Required Caajxisitlnn Lhis Heijiiireiittnt Citation standard
JGJ.8J-1 Clu-onlc Feeding1' lto!/ 'technical Grade
I63.UJ-2 flnoogcnicityl/ tk>{/ 'Itdmlcal Orade
16J.U3-J •Iteratoqcnlcity Yes -technical Grade Yes
163.03-4 Itoproductinn1/ No1/ TcdmlcaJ Grade
IG3.U4-2 Mutaqenicity Ito / Itedmical Grade
llirouijh 4
Life Science
Rescardi
J900; 004.1
Life Science
DC search
1980 j 0043
Fritz i978|
0014
Fritz 1970 i
0042
Cozens et al.
1980; 0044
Ami, Muller
1978 i 0001
Fritz 1970;
0013
No3/
,lo3/
Ito
No
Ito4/
161.85-1
Yes
2/
•technical Grade
Yua
Ito
llaiitock 1977;
(Ml 15
llaiiilxxJc 19711}
0016
T7"HiilTTeijuTrod tor ciirrcnFIy recjlstercil nonfoal uses of meFalaxyl; i-6T]iiIred~ih ordor to set a penianent toloranco or tjrant an exenipFIon
for a tolerance tor a Toad use or to supjort this use toxicolojioally. Petitions to scL tolerances have been Bulnuittcd to tlie Agency.
2/ RcHjuiccd to set teuforary tolemncc m potatoes.
3/ Patliolocjy siuniiaiy tables mist be rcsiibnitted to incli*le lumix^r of organs examined for nmilxir oE aniinal examine - to support a food-crop
use.
4/ Additional imiltl-leat evidence is roijuired in order to toxicolocjically sng^ort a food use.
Itata requireiicnta are current as of July I9UI. Refer Lo
Guliiance IMckacjc for updated requirements.
-25-
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163.71-3
Table 1 (Confd)
Hetalaxyl Bcolngloal Bffccts (Sec Chapter VIII)
Generic Data Requirements
Guidelines
Citation
J63.71-1
163.71-2
(hist Additional Data be
admitted under FIFKA
ftrxs KPA Have 3(c)(2)(D)7 If so, irontlis
tat a to Partially allowed (or sulmlsslon
riame of Are Data or totally Satlaty Bibliographic from [xiblishml dale oC
Test Required Composition this Requirement Citation standard
Avian Single-Dose Yes 'technical Grade Yea
Oral U>50
Avian Dietary Yes Technical Grail1; Yes
IC50
Beavers, Fink
1977; 0051
Reavers, Fink
1977; 0052| 00-33
Saclisso, UlJjiiann,
1976, 0061
No
Mo
Kiinmllan Acute
Ibxiclfcy
Ho
163.71-4
163.71-5
Avian Reproduction No
Simulated and Actual Ho
Field Testing Cor
Manuals and Birds
Data requirements are current as of July 191!I.
Guidance Package Cor updated requirements.
-26-
ItoCer to
-------
Tal>lc I (Cont'd)
ftotal.ixyl Rcolocjic.il ECEocts (See Chapter VIII)
Generic tot a nopilrennnLs
Guide linos
Citation
163.72-1
(lame of
Test
Fish Acute ICgo
Are Data
Acquired
Yea
Does EPA Have
Data to Partially
or totally Satisfy
Composition this Rcquitaneiit
Itechnical Grade
Yes
nlbliograplilc
Citation
KratuSf
fhist Additional Data be
Sulinltted under FIFIIA
3(c)(2)(0)7 If so, nnntlis
allowed for submission
Ctxin (Nibllahed rVito of
standard
Mo
163.72-2 Acute Toxlclty to Yes
Aquatic Invertebrates
•technical Grade
Yes
163.72-3 Acute Toxlclly to No
l&taurlne ami
Marine Organisms
163.72-4 niJjryo-larvae aul Yea
Life-cycle Studies
of Fish and AqiiaLlc
Tnvortebralcs
1C3.72-5 Aquatic Organism No
Toxlclty ami Kesidue
Studies
163.7^-6 Simulated or ActiMl No
field Testing for
Aquatic Organisms
I/
'technical Grade
Yes
00-36
Sachssc, uatlio
1976; 0059
Fratus,
Dusccnfusco 1970;
0055
ftaCam 1979; 0067
l«Blanc, Cary Nu
1478; 0058
leDlanc, Cary
1977; 0057
McCann 1979; 0068
E.G. & G Bionomics I to
1980; 0062, 0063
77 An aquatic invarlel-irate'ITfe-cyl1! test (prefornhly
volinnc of uso, petslsLence and iioljillty.
anaF"is rejulred because of inetalnxyl's proposed uso pattcrn, potent 1 n 1"
Data rctjulrcincntn are current as of. .July 1'Jdl.
Guidance Package for uprl.itc.il rctjuirciiiont-s.
Refer to
-27-
-------
Ifeble 1 (Conb'd)
Ifetalaxyl Rcologcial Effects (Sec Chapter Vtlf)
Generic Data Reijiiircnents
Guideline!!
Citation
Phytoxlclty^/
163.122-1
163.122-1
163.122-2
Mains oE
Test
Target Area
Hiytotoxlclty
Aquatic Macropliytes
Algae
Arc Data
Required
Yes
Yea
Yes
Does EPA Have
Data to Partially
or totally Satlafy
Composition this Requirement
1C No
•technical Grade Ho
Ted in leal Grade No
Must Additional Data lie
Submitted under FIFRA
3(c)(2)(B>? If so, ncnths
allowed Cor submission
Bibliographic from published date of
Citation sLarelaixi
Yes/24 months-/
Yes/24 months-/
Yes/24 months^/
I/ Guli to linen proposed Hovanlier 1980.
2/ Fran date of implementation of Suljpart J.
Data requirements are current as of July 1981.
Guidance Package for updated requirements.
-28-
ReCer to
-------
•table 1 (Cotit'd)
Metalaxyl Rcologlcal Effects (See Chapter VIII)
GcnecJc Data neqiilranonta Cor DnulsiCJahlc Concentrate (EC) Products
Guide lines
Citation
J61.72-1
J6J.72-2
ttiine of
Test
Fish AciiLe
'So
Acute Toxic I ty
to Aquatic
Invertebrates
Are Dita
Required
Yesi/
Yesi/
Composition
n:
IE
Does El'A Have
Data to Partially
or totally Satisfy
this Requirement
Yes
Yen
Must Additional Data be
Siilxnltto! under FIKRA
3(c)(2)(D|? 1C so, montlis
allowed for suhnlsslon
Blbllogra|>liic fixm published dale of
Citation standard
McCann IJu
1979; 0064, 0065
McCann Ito
I979| 0060
I/ Data required cor formulation because of dlCtcrcntlal toxlcity lieLwocn technical and formulation.
I Vita requirements are curtent as of July 1981.
nildcince Package for uplaterl requlreiicnta.
ItcFcr to
-29-
-------
I (Cont'cl)
Metalaxyl Residue Chemistry (See Chapbcr VII)
Generic Data Requirements for Manufacturing-Use Products
Guide 1 Ines llame oC Arc Data
Citation Test Iteqiiired
Ulitake, Yes
Distribution,
and Metabolism
in Plants
Metabolism Yes
in Animals
Analytical Yes
Methods
Nature oC Yes
Residue in
1obacco
Does EPA Have
Data to Partially
or totally Satisfy Bibliographic
Composition this Requirement Citation
Radlolaheled Yes Gross 1977;
Analytical Grade 0132
Fl seller, Cassldy
1978; 0099
Foster, Fischer,
Cassldy 1970;
0086
Radlolabeled Yes Fischer, Foster,
Analytical Grate Cassldy 1978;
0131
llambock 1977,
1978; 01)15. 0016
Seim
1978, 0143
Yes Balasubramanlan,
Nixon 1978;
0117
Balasubrainanian,
Ross, 1978;
0120
Kadiolalieled Yes Honeycutt,
Analytical Cassidy 1978;
Grade 0106
Honeycutt,
Fischer,
Cassldy 1979;
0136
Musk Additional Data Ijc
Suljnitted uiuler FIFKA
3(c)(2)(l))7 1C so, months
allowcil for submission
Cran published date of
standard
ttov
No1'2/
No'/
No
I/ Data suECiclcnt to satisfy requirements for teiiporary tolerance only.
2/ For any future permanent tolerance request or expansion oŁ the experimental use program,
tolerance proposals Cor residues in neat, milk, poultry, and egys are required.
large animal feeding studies and
Data requirements are current as oC July 1981.
rHildance Package Cor upilatcd requirements.
-30-
IteCcr Lo
-------
Table 1 (Cont'd)
Metnlaxyl Residue Chemistry (Sec Chapter VII)
Generic liata Requirements (or Manufacturing-Use Products
Ruidcllncs
Citation
Maine of
liest
Are Data
Required Composition
Does EPA Have
iBta to Partial!/
or totally Satisfy
this Requirement
Bibliographic
Citation
Must Additional Data lie
Sulinittecl under FIKRA
3(c)(2)(U|? 1C BO, nonUia
allowed for sulinlsslon
f ran piibl Ishcd date of
standard
Nature of
Itesklne In
Cigarette
Sinoko
Pyrolysla
I'rochicts
Residue Data
Flelil
'KAxicoo
Potatoes
Heat, Milk,
Poultry and
Eggs
Storage
Stability
Yes
Yes
Yea
Yes
Yes*
Yes
Raliolabeleil
technical grade
In cigarettes
Itidiolahclecl
technical grade
in cigarettes
•typical
Fotimilation
Typical
FoMnulatlon
Yes
Yes
Yes
Yes
No
Cibn-Gcigy Corp.
1970; 0127
llonoycutt,
Szolics,
Slnoncaux,
Cassidy 1979; 0119
lloiicyciitt,
GTOlica,
Cassldy 1978; 0137
llotieycutt,
Szollcs,
Cassidy 1978; 0137
Ciba-Oeigy Corp.
1978; 0120
Ciba-Oeiyy Coiv*
1978; 0126
Mo
I/
Yns/12 nontha
I/ IViln sJrricient to satisfy requlreiicnts~Zbr ten{x>rary tolerance only.
2/ For any future [jcnmiiont tolerance reijucst or expansion of tlie cxperlncntal use program, large animal feeding studies aitl
loletanco proposals For residues in imat, milk, poultry, ami djqs are required.
IJnLa rcc]uireiiRnts are current as of July 1'JUI.
Guidance Packarjo for Ufxiaterl requirements.
Motor to
-31-
-------
•table 2
Product Chemistry (See Chapter |V)
Netalaxyl Product-Specific rmta Requirements Cof tlanufacturing-Uso Products
Guidelines
Citation
J6.1.61-J
163.61-4
163.61-5
161.61-6
163.61-7
163.61-0(7)
163.61-8(8)
163.61(10)
163.61-8(11)
163.61-0(12)
Maine of Are Data
Test Required Caiqposltlon
Product Identity Yes MLJP
aivl Disclosure oC
Ingredients
Description of Yes HIP
Manufacturing Process
Discussion of Yes HIP
Formation of
thiint. Ingredients.
Declaration and Yes HUP
Certification of
Ingredient Limits
Product Analytical Yea HIP
Methods and Data
Physical State Yes HIP
tensity or Specific Yes HIP
Gravl ty
Vapor Pressure Yes MIP
pll Yes HJP
Storage Stability Yes HUP
Must AdrUtional Data be
Submitted under riKRA
Itoes EPA Have 3(c)(2MD)? If so, months
Data to Partially allowed Cor submission
or totally Satisfy Bibliographic from published da to of
this Requirement Citation standard
Yes Clba-Gcigy Corp. fto
1978; 0160
Yos1/ Clba-Geigy Corp. t*j
1978; 01GO
Ito Ycs/6 months
Yes Ciba-Gelgy Corp. Mo
1978; 0160
Yes2' Clba-Geigy Corp. No
1978; 0160
Yes Clba-Geigy Corp. No
1978; 0160
Yes Clba-Geigy Corp. No
1978; 0160
Yes Clba-Geigy Corp. No
1978; 0160
No Yes/6 imntlis
No Yes/6 imntlis
I/ He discuss Ion should include side reactions and factors such
given to tic quality control methods.
2/ Quantitative procedures will be needed for tlie unintentional
as toifx>rature and reactant Infxiritles. Consideration slnuld also bo
iiqiurlties if such impurities are present in the product.
Data requirements are current as of July 1981. Refer to
Guidance Package for updated rcquirenents.
-32-
-------
Tahle 2 (CoiiLM)
Product Chemistry (Sec Chapter IV)
Hc.-t.ilci.xyI ['rorlncL-Speclf ic llara KO«IIIIreiinnts for Mnnuf.-ictur ing-Use Products
Guidelines
Citation
IfiJ. 61-8(13)
163.61-11(14)
163.61-8(15)
163.61-8(10)
Maine of
Tost
FlniimihilUy
Oxidizing or
IteducliK] Action
Cxplonlveness
Corrcwion
('hnracterlstlcs
Are Delia
Requirctl
Yes
Yen
Yes
Yes
Composition
till'
MJP
nip
rup
IXX2S Ef'A Have
Data to Partially
or totally Satisfy
this Requirement
Mo
H}
No
Ho
ftint Additional Data Ix?
Submitted inn lee FIFRA
3(c)(2)(D)7 If so, months
alJuwod Cor sulmisslon
nihllocji-aphic fran published tlite of
Citation staiklard
Yea/6 months
Yes/6 nmitlia
Yos/6 months
Yes/6 months
Data re<|ul remonts arc current as of July 19U1. Refer to
Hildance Piidcage Tor ufdated rcijulreinents.
-33-
-------
'toxicology (Sec Chapter VI)
Hetalaxyl Product-Specific fW|-.a Requirements Cor Manufacturing-Use Protlucts
Guidelines
Citation
163.81-1
163.81-2
163.81-3
163.81-4
163.81-5
163.81-6
Maine of Arc Data
Test Required Canposition
Acute Oral Yes* HUP***
•Ibxicity
Acute Denial Yes* HUP***
Toxicity
Acute Inhalation Yes MUP*»*
Ibxicity
Primary Bye Yes** HIP***
Irritation
Primary Dermal Yes IIJP***
Irritation
Dermal Yea HUP*"
Sensitization
Must Additional Data be
Sulini tied under P1FRA
Dues EPA Have 3(c)(2)(B>? IE so, months
Data to Partially allowed Gor sulmission
or totally Satisfy Dihlicxjraphlc [ran publlslieil date of
this Requirement Citation standard
Yes Sadisse, Dathc
1976; 0026
Yes Sadisse, Ullmann
1976; 0023
No
Yes Sadisse, Ulliraiui
1976; 0031
Yes Sadisse, Ullmann
1976; 0032
Yen Sadisse, Ullamn
1976; 0033
No
No
llol/
No
Ito
No
Technical melalaxyi aiirt tlw manuEacturing-use product have been determined to be the same. These requirements may be rilled by
data required in Table 1 entitled: "Mctcilaxyl Toxicology Generic Data Requirements for flaiuiCacturlng-Use Products".
" A demonstration ot t*l between 1 and 3 or 12 and 14 or a demonstration of dermal irritability will be sufficient to categorize
a product as an ocular irritant and additional testing will not he roqulced.
*** Required for cadi manuEacturlnq-use product or substantially similar product.
I/ A determination is first required whether Mill' metalaxyl produces a respirable vapor and/or 208 or more of the aerodynamic
e<|ulvalent oC the product la composed of participates not larger than 10 microits in dininutcr.
Data requirements are current as of JuJy 1981.
Guidance Package for updated reqiilrencnto.
-34-
IteEer lo
-------
liihlo j
Prcxluct Chemistry (Sec Clmpter IV)
Matalaxyl Product-Specific Data Itoc|tiirutnent9 for Eul-llno Products
Guidelines
Citation
Itunc of Are Data
Test Kcquired
MiisL AihlLtional Data be
Sulxnlttetl undnr FIFRA
(Toes HPA Have 3(c)(2)(U)? IF so, nnnl.lis
nnta to Partially allowed for sulinlsa Ion
or totally Satisfy UibliograiJlilc from fniljl Islioil d.ite of
Composition this Uequiccncnt Citation standard
Plniilsiflable Concentrate (BC) formulations1'
I6J.61-3
163.61-4
161.61-G
Ifi 1.61-7
I6J. 61-11(1)
163.61-8(2)
163.61-0(7)
161.61-0(8)
161.61-8(9)
163.61-8(10)
ProlucL Identity
and Disclosure of
Ingredients
VCR
nr>ncrlption of yes
Manufacturing Process
Mcclaration ami
Certification of
Ingredient Limits
Product Analytical
Methods
Color
Odor
Physical State
Ucnsity or Sfiecific
Gravity
Dolllirj Point
Vaiwr Pressure
YPS
Yes
Yes
Yes
Yns
Yen
Yes
Yes
rt Yes Cilia-dclgy Coip. Na
1976; 0161
I3J Yus CiUi-Gelgy Corp. tto
1976; 0161
PC Yes Cilxi-Oclgy Corp. Ikj
J978; 0161
IE Yes Ciba-Gelgy Corp. No
1978; 0161
1C Ito Yoa/6 nontlis
HJ Ho Yes/6 imnths
ETJ No Yos/6 nrxitlin
rr Yos CilH-Goigy Corp. Mo
1970; 0161
HC Yes Cilia-Gelgy Coip. iki
1978; 0161
Ei: Yes Ciba-ntii ex [it for Registration rio. "TOo::6"67"(Rli1oiiirr"5E)
requirements are current as of July 1981. Ittfer to
fiuldance Package for updated rerjui reiiRiits.
-35-
-------
Table 3 (Coiit'd)
Product Chemistry (Sec Cliapter IV)
Product-Specific liata Ruiiiirenenhs Cor End-Une Products
Guidelines
Citation
163.61-0(11)
163.61-0(12)
163.61-0(13)
163.61-0(14)
163.61-0(15)
163.61-0(16)
163.61-0(17)
163.61-0(10)
llame oC Are liata
Vest Required
HI Yes
Storage Stability Yea
Flaimiabillty Yea
Ox id i zing or Yea
Reducing Action
Rxplosivcness Yes
Mlsclbillty Yes
Viscosity Yes
Corrosion Yes
Character Istlcs
Conposltlon
FC
1C
n:
EC
IE
1C
PC
HC
Must Additional Data Lo
Submitted under FIFKA
Itoesi EPA Have 3(c)(2)(U)? If so, months
rtita to Partially allowed Cor suljnission
or totally Satisfy Bibliographic Cram publisliecl dato oC
tills Requirement Citation standard
Yes Ciba-.
1970; 0161
Mo
tto
Yes/6 inontha
IJo
Yes/6 months
tto
No
No
Data requirements are current as oC July 1901. Refer to
Guidance Package for updated requirements.
-36-
-------
Til.lo 1 (l-cxil M)
•»>xlc'ilor|y (Sot* Clini-tin- VI)
Pir»Uic:t-fi|]RCiflc Ucitn Knijulroiirnln for nml-l'nr> Prolncln
RuMellnei
Citation
Hauls triable
J61.BI-1
161.81-2
161.111-1
lfil.ni-4
ir,3.ni-5
ir,i.Bl-6
•Lima of
Test
Aro \\ita
licijulrci] Composition
IXMR RI'A Have
IVila to IMtt Lilly
or total ly Satisfy
tlila Itecjulionieiit
Citation
Stil initial uixl-.-r FIIKA
Mc)(2)(ll)7 IE an. iinnth-i
allowr^l for stilinlnslm
c f nr»n pild Ishcil tj.itc? or
staivlard
Concentrate (EC) Fonnulatlona
ACT ite Oral
•loxlclty
Acute Denial
•Ibxlclty
Aaitc Inhalation
•lox lolly
Primary Rye
Irritation
l'i limry Itennil
IrrltatJon
Itetnnl
I/ \/
Yes Gadi iiralnct
Yes1/ liidi prrxlmrl'/
Yes1/ Ridi iii-alnnt'/
I / i/
Yen Kadi prxxlnct
Yen1/ Ridi ptoluct1/
Yun1/ Kadi praluct'/
Yes
Yes
Partial2/
Yes
Yea
Yea1/
Kaiv,
Plcclrillo
1978; 0010
Kaiv,
Plc-cirlllo
1970; 0017
Plcclrillo
1978; 0021
Plcclrillo
19781; 0021)
Kaiv,
Plculrllio
1970; 0019
tto
Ho
•to?/
llo
Ho
Ih
"t'estlfiy "Z7:ni: inct.ilaxyl"Fn3~niinfilaiiCniUy BirariflF"Eo~257riT inr-talaxyl RC.
2/ A |iilrorl> acVJItloivil clnta la not presently rejnlreO.
~\/ Uitn oil todinloil nliuwn little (loniol scnaltlxatlon OIK! may Lie extrapolated to EC.
Ihta rciiiilrcineiitn .ire curient -in of .Inly 19F1I. KcCer tr>
(or ii|-xtiteil
-37-
-------
Chapter IV
PRODUCT CHEMISTRY
Manufacturing-Use Metalaxyl
Introduction
Chemical Identity
Manufacturing Processes
Formation of Unintentional Ingredients
Active Ingredient Limits in Pesticide Products
Product Analytical Methods and Data
Physical and Chemical Properties
Emulsifiable Concentrate (EC) Metalaxyl
Manufacturing Processes
Active Ingredient Limits in Pesticide Products
Product Analytical Methods and Data
Physical and Chemical Properties
Introduction
FIFRA 3(c)(2)(A) requires the Agency to establish guidelines
for registering pesticides in the United States. The Agency
requires registrants to provide quantitative data on all
added ingredients, active and inert.
To establish the composition of products proposed for
registration, the Agency requires data and information not
only on the manufacturing and formulation processes but also
a discussion on the formation of manufacturing impurities
and other product ingredients, intentional and unintentional.
Furthermore, to assure that the composition of the product
as marketed will not vary from the composition evaluated at
the time of registration, applicants are required to submit
a statement certifying upper and lower composition limits
for the added ingredients, or upper limits only for some
unintentional ingredients. Subpart D of the Proposed
Guidelines (43 FR 29696, July 10, 1978) suggests specific
precision limits for ingredients based on the percentage of
ingredient and the standard deviation of the analytical
method.
In addition to the data on product composition, the Agency
guidelines also require data to establish the physical and
chemical properties of both the pesticide active ingredient
and its formulations. For example, data are needed concerning
the identity and physical state of the active ingredient
-38-
-------
such as melting and boiling point data, ambient vapor
pressure and solubility. Data are also required on the
properties of the formulated product to establish labeling
cautions e.g., flammability, corrosiveness or pesticide
storage stability. The Agency uses these data to characterize
each pesticide and to determine its environmental and health
hazards.
Chemical Identity
"Metalaxyl" is the common name accepted by the American
National Standards Institute (ANSI) for the chemical N-(2,6-
Dimethylphenyl)-N-(methoxyacetyl)-alanine methyl ester.
C-CH2OCH3
Ciba-Geigy Corporation, presently the sole manufacturer of
metalaxyl in the United States, has assigned metalaxyl the
experimental number "CGA-48988" (forRthe active ^ngredient),
and the trade names Ridomil , Subdue , and Apron .
The Chemical Abstracts Registry (CAS) number for metalaxyl
is 57837-19-1 and the EPA Shaughnessy number is 113501. The
common name, metalaxyl, will be used throughout this standard
in lieu of other chemical or trade names.
Manufacturing Process
A manufacturing process for technical metalaxyl has been
submitted to the Agency. (Ciba-Geigy Corporation 1978; 0160),
Because this type of information is considered to be con-
fidential business information, a discussion of the specific
procedures, equipment and manufacturing conditions required
for commercial production of metalaxyl cannot be published
in this standard. The manufacturing process as submitted by
Ciba-Geigy Corporation and the identification of impurities
are detailed separately in the Confidential Appendix for
internal Agency use.
The discussion of the manufacturing process should be more
thorough and cover the factors related to the amounts of the
toxicologically significant components and impurities
present in the technical product. In addition to the basic
reactions, the discussion should consider side reactions
and factors such as temperature and reactant impurities.
-39-
-------
Formation of Unintentional Ingredients
Additional information is needed concerning the toxicologically
significant components and impurities. Quantitative procedures
are needed for the unintentional impurities, nitrosamines for
example, if such impurities are present.
Active Ingredient Limits in Pesticide Products
The components of technical metalaxyl have been identified
(Ciba-Geigy Corporation 1978, 0160). This is confidential
business information and cannot be listed here but is listed
separately in the Confidential Appendix. Clarifying infor-
mation is needed on some components. These components are
listed in the Confidential Appendix. Technical metalaxyl
contains approximately 90% active ingredient.
Product Analytical Methods and Data
An analytical method for the determination of technical
metalaxyl, its related compounds, and impurities in the
technical product, has been submitted to the Agency. A
description may be found in the Confidential Appendix
(Heinrichs 1978, 0164).
A description is not found in this standard but is detailed
separately in the Confidential Appendix.
Validation data are needed to establish the reliability of
this method. Analytical results are needed for five or more
samples of the technical product which are representative of
the manufacturing process.
Physical and Chemical Properties (Ciba-Geigy Corp.
1978, 0160)
Technical
Color: White to beige
Odor: Odorless
Physical State: Crystalline
Solubility: Water - 00.7%
Methanol - 65.0%
Benzene - 55.0%
Hexane - 00.9%
Isopropanol - 27.0%
Methylene Chloride - 75.0%
-40-
-------
1
9
10
5
7
>200
115
12
>200
>200
Stability: Stable up to 300° C; slight exothermic reaction
up to 450°C
Melting Point: 71-72°C
Vapor Pressure: 2.2 X 10~6 Torr at 20°C
Density: 1.21 g/cm3 at 20°C
Hydrolysis Rate: Temperature pH Half-life, days
20°
50°
Dissociation Constant: No measurable dissociation
Molecular Weight: 279.34
Emulsifiable Concentrate (EC) Metalaxyl
Manufacturing Processes
A manufacturing process for EC metalaxyl has been submitted
to the Agency (Ciba-Geigy Corp. 1978, 0161). This is con-
fidential business information and is detailed separately
in the Confidential Appendix.
Composition of EC Metalaxyl
The components of a formulation of EC metalaxyl have been
identified in Ciba-Geigy Corp. 1978 (0161) and in the
confidential statement of formula supplied to the Agency.
Product Analytical Methods
An analytical method that determines metalaxyl in formulations
has also been submitted and a description may be found in
the Confidential Appendix (Heinrichs 1978, 0166). This
method is adequate for the formulated product. If the
method of technical metalaxyl is validated by data then this
method would be suitable for enforcement purposes.
Physical and Chemical Properties (Ciba-Geigy Corp. 1978; 0161)
Miscibility: Forms stable emulsion in water
pH (10% solution): 3-6; 3 is irritating to the eyes and
skin, 6 is noncorrosive
-41-
-------
Boiling Point: 155 _+ 5°C
Flash Point (TCC): 92°F, typical or 33.3°C
Specific Gravity: 1.01, typical
Viscosity: 2.31 + 0.05, typical (Cannon Fenske Viscometer)
Vapor Pressure: 3mm Hg at 20°C, typical
Explosive Characteristics: None reported
Corrosion Hazard: Not corrosive to tin or steel
Oxidizing/Reducing Potential: None
Weight a.i./gallon: 2 Ib a.i./gal, typically or 239 gm/L
Decompo-
Storage Stability: Temp. Time Assay(S) sition
Original 24.9
50° 4 weeks 25.3 0
8 weeks 25.8 0
24 weeks 25.5 0
-42-
-------
Chapter V
ENVIRONMENTAL FATE
Use Summary
Environmental Fate - Manufacturing-Use Metalaxyl
Hydrolysis
Photodegradation
Soil Metabolism
Microbial Metabolism
Leaching, Adsoprtion/Desorption
Volatilization
Field Dissipation
Fish Accumulation
Rotational Crop Accumulation
Potential for Groundwater Contamination
Groundwater Monitoring
Analytical Methods
Labeling Restriction — Rotational Crops
Use Summary
Metalaxyl is federally registered as a preplant soil
incorporated systemic fungicide on tobacco, (1) for use in
the field before transplanting for control of black shank
(Phylophthora parasitica var. Nicotianae) and Blue Mold
(Ceronospora tabacina) on all types of tobacco, and (2) for
use in tobacco plant beds for control of blue mold and
damping-off (Phythium spp.).
Metalaxyl is also federally registered as a soil or foliar
treatment on ornamentals, conifers and turf to control
damping off and blight, caused by Pythium spp. and Phytophthora
diseases such as root and crown rot.
Metalaxyl is formulated as an emulsifiable concentrate (EC)
containing 25.114 active ingredient and known under the trade
names of Ridomil and Subdue .
Application is made once a season, before planting, by spray
tank broadcast and incorporated in the top two to four
inches of soil prior to transplant. Registered application
rates are listed in Table 1.
-43-
-------
A special local needs registration exists in Florida for use
of metalaxyl on non-bearing citrus. Emergency exemptions
have been granted for use of metalaxyl on potatoes in Maine
and hops in Idaho, Oregon, and Washington. An experimental
use permit has been approved by the Agency for use of
metalaxyl on potatoes (1979-1981; renewed 1981-1983).
Potential sites of use include: nonbearing citrus, cottonseed,
soybeans, wheat and certain vegetable crops.
-44-
-------
TABLE 1; Registered Application Rates - Metalaxyl
FORMULATION SITE PEST/DISEASE
TYPE OF
APPLICATION
RATE RANGE
25.11% EC
Tobacco
Black Shank
Blue Mold
Pythium
(damping off)
Broadcast
Incorporated
in top 2-4
inches of
soil
1/2 - 1 gal/acre
1.5 gal if
disease levels
>60%
Tobacco
Plant Bed
Blue Mold
Pythium
(damping off)
1 qt/acre
in 50 gals.
of water
Pennsylvania
only
2 qts/acre in
50 gals, of
water
Field
Planted
Tobacco
Flue cured
Tobacco
Blue Mold
Black Shank
1-2 qts/acre
2-4 qts/acre
Burley
Blue Mold
Black Shank
2 qts/acre
4-6 qts/acre
-45-
-------
Subdue 2E Metalaxyl
Formulation: 25.11% EC
Site Pest or Disease
Type of Application
Rate Range
Foliage Plants
Aglaonema
Aphelandra
Dieffenbachia
Peperomia
Philodendron
Pothos
Schefflera
Pythium
Phytophthora
Soil Drench
Soil depth 4 inches
or less
Soil depth of more
than 4 inches
Soil mix
0.4-1.2 Ł1. ozs. with 100
gals of water to 800
sq. ft.
0.4-1.2 fl. ozs. with 100
gals of water to 400-600
sq. ft.
0.1-0.4 fl. oz. with each cu,
yd. of soil mixture
Azalea
Phytophthora
(root and
crown rot)
Phytophthora
(shoot blight)
Soil Drench
Soil depth 4 inches
or less
Soil depth of more
than 4 inches
Foliar Spray
1.2-4.0 fl. ozs. with 100 gals
of H2O to 800 sq. ft.
1.2-4.0 fl. ozs. with 100 gals
of H2O to 400-600 sq. ft.
1.2-2.4 fl. ozs. with 100 gals
of H_O. Spray to runoff.
-46-
-------
Subdue 2E Metalaxyl
Formulation: 25.11% EC
Site Pest or Disease
Type of Application
Rate Range
Bedding Plants
Ageraturn
Aster
Carnation
Chrysanthemum
Coleus
Geranium
Impatients
Marigold
Pansy
Salvia
Snapdragon
Verbena
Vinca
Zinnia
Flowers
African violet
Carnation
Chrysanthenum
Geranium
Poinsettia
Pythium
Phytophthora
Soil Drench
at seeding
At transplanting
Soil mix at seeding
and at transplanting
0.25-0.5 fl. 02. with 100
gals of H_O to 800 sq. ft,
0.5-2.0 fl. oz. with 100
gals of H2O to 800 sq. ft,
0.1-0.2 fl. oz. with each
cu. yd. of soil mix.
Pythium
Phytophthora
Soil Drench
Soil depth 4 inches
or less
Soil depth of more
than 4 inches
0.5.2.0 fl. ozs. with 100 gals
of H2O to 800 sq. ft.
0.5-2.0 fl. ozs. with 100 gals
of H2O to 400-600 sq. ft.
-47-
-------
Subdue 2E Metalaxyl
Formulation: 25.11% EC
Site Pest or Disease
Type of Application
Rate Range
Woody
Ornamentals
Other than
Azalea
Acuba japonica
Andromeda
Arborvitae
Ceanothus
Ilex
Pinus thumbergii
Savin Juniper
Tarn Juniper
Shore juniper
Pittosporum
Rhododendron
Pythium
Phytophthora
Soil Drench
Soil depth 4 inches
or less
Soil depth of more
than 4 inches
1.0-4.0 fl. ozs. with 100 gals
of H2O to 800 sq. ft.
1.0-4.0 fl. ozs. with 100 gals
of H2O to 400-600 sq. ft.
Conifers
Phytophthora
Broadcast spray
Seedbeds and Plug
Plantings
2-0 transplants*
1*2 yr. old seedling
newly transplanted]
2-1/2 pts in 50 gals of
per acre
5 pts in 50 gals of H-O
per acre
Turf
Pythium Blight
Pythium Damping
Off and Pythium
Blight
Broadcast spray
Established turf
Newly seeded areas
1-2 fl. ozs. in 3-5 gals of
H2O per 1,000 sq. ft.
1-2 fl. ozs. in 5-10 gals
of H2O per 1,000 sq. ft.
-48-
-------
Environmental Fate - Manufacturing-Use Metalaxyl
Hydrolysis
Metalaxyl appears to be resistant to hydrolysis under
"normal" environmental conditions (pH, temperature). Under
test conditions, at pH 5, 7, and 9 and at 20-30°C/ the
half-life of metalaxyl is greater than 4 weeks.
The half-life varies from 5 hours to 5 days at pH 9-10 at
50-70°C. The half-life of the parent compound is 12 days
in 0.1 NHC1 at 70°C. Under prolonged or exaggerated
conditions significant hydrolysis does occur. One degradation
product [N-2,6-dimethyl phenyl-N-(2-methoxyacetyl) alanine
(CGA-62826)] was found (Burkhard 1976, 0076).
Photodegradation
Metalaxyl is also stable to soil surface photolysis under
conditions likely to be found in the environment. In
a study by Burkhard (1978, 0078), the results showed that
there was no difference between covered and exposed soil
samples, following C analysis and gas liquid chromato-
graphic (GLC) analysis of extracts from test soils.
However, metalaxyl does photodegrade in water. A half-life
of 1 week was reported for metalaxyl in water following
exposure to sunlight. Degradation products include:
N-(2,6-dimethylphenyl)-N-methoxy acetyD-alanine (CGA-62826)
(5%), 4 unidentified polar compounds (totaling 17%), and
some volatile compounds (12%). Aqueous photolysis in the
presence of photosensitizers greatly accelerates photo-
degradation of metalaxyl, to a half-life of 1 hour (Burkhard
1979, 0100).
Soil Metabolism
Ellgehausen (1978, 0081) studied the fate of metalaxyl in
soil under aerobic; aerobic/anerobic; and sterile/aerobic
conditions. In soil under aerobic conditions, metalaxyl
degrades with a half-life of about 7 weeks. The only major
soil degradation product was CGA-62826. The CGA-62826 then
breaks down to non-extractable material and CO_. Under
anaerobic soil conditions, metalaxyl degrades with a half-
life of about 9 weeks with CGA-62826 being the major product
but persisting longer than the 7 weeks under aerobic
conditions. Extractable metalaxyl declined approximately
3% from 31 days after treatment to 89 days after treatment.
This indicates soil microbes contribute to its breakdown
under non-sterile conditions.
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Microbial Metabolism
At current use rates, metalaxyl will not affect soil microbe
growth/ metabolism of cellulose/ protein/ starch/ or nitrifica-
tion (Ercegovich 1979, 0102; Ercegovich, Bogus 1979, 0103;
Ercegovich/ Vallejo, Bogus 1979, 0104).
Two studies (Doebbler 1979/ 0101; Glinski 1978, 0105)
investigated the effects of metalaxyl on the activated
sludge process. The studies have only been reviewed by the
Agency for adverse effects on the environment. Metalaxyl
is essentially unchanged by the treatment process, and will
be discharged from the treatment plant with the effluent.
In the study by Glinski (1978, 0105), levels of 50 and 100
mg metalaxyl per liter inhibited the breakdown of organic
carbon. This mechanism allows metalaxyl to build up and
pass unchanged through the system in the effluent.
Leaching, Adsorption/Desorption
Metalaxyl and its aged soil residues are readily leached in
sandy soils, low in organic matter (Guth 1976, 0087, Guth
1978, 0089). Metalaxyl leaches less as the soil increases
in organic matter content.
Guth 11978, 0089) studied the leaching characteristics of
aged C-metalaxyl residues in two soils, sand and silty
loam. After 30 days of aerobic aging, 97.4% and 99.2% of
the activity was extractable from the sandy and silt loam
soils respectively. The results after leaching are (in % of
applied C-metalaxyl):
soil % remaining soil eluate
sandy 16.1. 79.2
silty loam 34.9 48.7
About 70% of the activity remaining in the soil was extracted
with methanol and water. Of the metalaxyl found in the eluate
of the sandy soil, 56% was parent metalaxyl, 31% was the
major degradation product, CGA-62826, 1% was an unknown
polar metabolite, and 12% was unaccounted. In the eluate of
the silty loam soil, 70% was parent metalaxyl, 18% was
CGA-62826/ 1% was an unknown polar metabolite and 11% was
unaccounted.
Soil adsorption of metalaxyl is minor (Guth 1978, 0088).
This is supported by the leaching results which show metalaxyl
to be a strong leacher.
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Volatilization
The volatilization rate is directly proportional to the
initial soil concentration of metalaxyl, the soil temperature,
and the air flow rate across the soil surface. It is
inversely proportional to greater soil adsorption capacities.
Under typical use conditions, less than 0.5% of the applied
metalaxyl would be lost due to volatilization (Burkhard
1977, 0077).
Field Dissipation
Under field conditions, the fate of metalaxyl in soil is
similar to that under lab conditions except for the shorter
half-life of two weeks under field conditions. The major
soil degradation product formed was CGA-62826. CGA-62826
breaks down to nonextractable material and CO^. The
soil metabolism of metalaxyl was studied in tne field by
Ellgehausen (1977, 0079, 0080), Fischer and Cassidy (1978,
0099; and Foster, Fischer, Cassidy (1978, 0086).
Long term field dissipation studies were established at
several locations under normal conditions to determine the
persistence of metalaxyl after application to potatoes and
tobacco (Ciba-Geigy Corporation 1980, 0125, 0149, 0141).
The additional data cannot be fully interpreted because of
flaws in the study. However, these data do not add new
information about the field dissipation of metalaxyl.
Fish Accumulation
Exposure of fish to the parent compound or soil aged residues
will not result in accumulation values above 10X in the
whole fish (Ladd, Wilson 1979, 0093). During 14 days
of depura-tion, 80% and more of the accumulated residues will
be discharged (Ladd, Enos 1979, 0092). Tests indicate
little, if any, potential for bioaccumulation. Hydrolysis
data, which shows the parent compound to be stable under
conditions of this experiment, support the conclusion that
fish were exposed to unchanged parent metalaxyl during the
exposure period.
Rotational Crop Accumulation
The amount of metalaxyl taken up by several field crops
after a period of time subsequent to application of metalaxyl
has been studied. Crops that were studied include spring
oats, corn, lettuce, soybeans, sugarbeets, potatoes, and
wheat. Amount of metalaxyl remaining in the soil and
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available to crops was characterized (ratio of organic
soluble material to non-extractable). Crops were planted
from 33 weeks to 36 weeks after the last of six applications
of 14C-metalaxyl at 0.4 Ib ai/acre at 14-day intervals
except for wheat which was planted immediately afer the same
rate and intervals of application.
14
For spring oats, the highest total C-metalaxyl levels (0.33 ppm)
were found during the early periods of sampling in the whole
plant and declined to 0.21 ppm at 11 weeks of growth. At
33 weeks after the last application when spring oats was
planted, the soil residues were in the ratio of 7:10 organic
extractable to non-extractable. This ratio changed over the
next 11 weeks to 1:4 (Fischer, Cassidy, 1979; 0084).
14
Corn will not take up C-metalaxyl residues in excess of
0.06 ppm in any plant part during growth through maturity.
At planting (35 weeks after the last application of metalaxyl),
the soil residues were in the ratio of 1:1 organic extractable
to non-extractable. This ratio changed over the 21 weeks of
the study to 1:12 (Fischer, Cassidy 1979; 0082).
14
Lettuce takes up C-metalaxyl residues. Highest total of
C levels (0.11 ppm) were found during the early periods
of sampling and declined to 0.06 ppm at 9 weeks of growth.
These levels were found in the whole plant. The soil
residues at planting 33 weeks after the last metalaxyl
application were in the ratio 4:5 organic extractable to
nonextractable. This ratio changed over the next 11 weeks
to 1:6 (Fischer, Cassidy 1978; 0083).
14
Soybeans will take up C-metalaxyl residues at levels of
0.2 to 0.8 ppm (calculated as parent compound). Most of the
activity remains extractable from the plant during all
stages of plant growth. At planting which was 36 weeks
after the last application of metalaxyl, the soil residues
were in the ratio of 1:1 organic extractable to non-extractable.
This ratio changed over the next 20 weeks to 1:7. The
parent compound at levels of 0.2 to 0.3 ppm persist in the
soil for more than a year after multiple applications
(Hamilton, Fischer, Cassidy 1979; 0090).
Sugarbeets will take up C-residues at levels of 0.16 ppm
at 6 weeks growth, but this level will drop to 0.02 ppm at
20 weeks, and will probably be even lower at maturity. The
soil residues when the sugarbeets were planted at 33 weeks
after the last application of metalaxyl were in the ratio of
3:4 organic extractable to non-extractable. This ratio
changed over the next 20 weeks to 1:7. The parent compound
will also persist in the soil at levels of 0.2 - 0.3 ppm for
more than a year after multiple applications (Hamilton,
Fischer, Cassidy 1979; 0091).
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Wheat planted immediately after a series of applications of
C-metalaxyl results in C residues being taken up by
wheat at all stages of growth (Fischer, Cassidy 1973;
0085). Highest total residue levels (3.97 ppm) are found
during the early periods of growth when the plants would be
subjected to fall grazing. The activity in the soil changes
from primarily organic soluble to primarily non-extractable
during the 43 weeks post-application. This study does not
serve as a rotational crop study since there was not at
least a 30-day period between the final application of
metalaxyl and planting.
Soil samples were taken periodically when potatoes were
tested with metalaxyl(Foster, Fischer, Cassidy, 1978; 0086).
The analyses.of post-treatment soil samples showed the
balance of C-activity to change from a ratio of organic
extractable to non-extractable of 10:1 after the second
treatment to 35:1 after the sixth treatment. Characterization
of the soil activity two weeks after the last treatment
showed 68.7% to be parent compound and 19.8% to be CGA-62826
[(N-(2,6-dimethylphenyl)-N-methoxyacetyl) alanine]. These
results show that soil degradation of parent metalaxyl is
evident but a half-life cannot be calculated because of the
repeat applications. The soil activity is primarily in the
form of parent compound and CGA-62826.
Rotational crop studies (Ciba-Geigy Corporation 1979, 0129)
were conducted applying metalaxyl at 0.5 Ib to 1.0 Ib
ai/acre six times to potatoes and then planting winter
wheat, corn, sugarbeets, soybeans and ryegrass as rotational
crops. In addition, metalaxyl was applied as a preplant
incorporated broadcast to tobacco at 3 and 6 Ib. ai/acre.
Soybeans, corn, and sweet potatoes were planted as rotational
crops.
Winter wheat was planted as a rotational crop and early
forage, spring forage, harvest straw and grain were analyzed
for total metalaxyl residues. Winter wheat planted in
rotation to metalaxyl treated potatoes will pick-up metalaxyl
residues containing the 2,6-dimethyl aniline moiety even
when the wheat is planted 13-1/2 months after the last
treatment. Higher residue levels are taken up by wheat
planted before the 13-1/2 months.
Field corn was planted as a rotational crop after metalaxyl
treated potatoes. Silage stage forage, fodder, and grain
were analyzed for total metalaxyl residues. Corn will take
up 0.2 ppm metalaxyl residues at 5 weeks growth but at 9
weeks, the grain is found to contain less than 0.05 ppm.
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Sugarbeets were planted as a rotational crop and early
forage, late forage and roots were analyzed for total
metalaxyl residues. Sugarbeets, planted 10 months after
6 applications of metalaxyl do not pick up detectable
residues (0.05 ppm) in the roots when harvested at 4 months.
However, the forage does contain residues.
Forage of soybeans planted as a rotational crop after
potatoes was analyzed for total metalaxyl residues. Soybeans,
planted 10 months after application of metalaxyl, picked up
residues in the forage when harvested at one month's growth.
Metalaxyl was applied at 0.5 Ib ai/acre to potatoes and rye
grass was planted as a rotational crop. Rye grass forage
was analyzed. Rye, planted 2-1/2 weeks after the last
metalaxyl application to potatoes and harvested at one
month's growth (forage stage) picked up detectable residues.
It is not known whether residues available for pick up by
rotational crops will be different due to a single 3 Ib
ai/acre application or 6 biweekly 0.5 Ib ai/acre applications
as in these studies.
Soybeans were planted as a rotational crop after a single
preplant incorporated broadcast application of tobacco at
either 3 or 6 Ib ai/acre. Forage, fodder and bean samples
were anlayzed for total metalaxyl residues. Soybeans,
planted 13 months after application of metalaxyl and harvested
at 1-1/2 and 5 months growth picked up residues. In another
rotational planting of soybeans, 13-1/2 months after application
of metalaxyl to tobacco, immature forage, fodder and grain
samples were analyzed for metalaxyl total residues. This
analysis shows that soybeans harvested at 2 and 4-1/2 months
growth picked up residues.
Corn was also grown as a rotational crop after metalaxyl
treated tobacco. Silage stage forage, fodder, and grain
samples were analyzed for total residues. Corn, planted 12
months after a single preplant incorporated application of
metalaxyl and harvested at 2 and 5 months of growth did not
pick up detectable residues of metalaxyl at either treatment
rate.
Sweet potatoes were planted as a rotational crop after
metalaxyl treated tobacco and early forage, mature roots,
and tops were analyzed for metalaxyl total residues. Sweet
potatoes, planted 13 months after a single application of
metalaxyl showed no detectable residues picked up by the
roots or tops at 6 months growth. At 3 months growth (the
early forage state), residues were detected. The maximum
label rate for tobacco is 3 Ib ai/acre. All rotational
studies using metalaxyl treated tobacco had treatment rates
of 3.0 and 6.0 Ibs ai/acre.
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The rotational crop data support a rotational crop restriction
of one application of metalaxyl per season. If replanting
is necessary a second application of metalaxyl should not be
made.
The data also supports planting small grain cover crops
provided they are plowed down and not used for food or feed
purposes. If corn is planted, the label must carry the
restriction of not to be planted until 12 months following
treatment. The restriction on planting root crops should
allow planting of the root crops sugar beets and sweet
potatoes at 12 months following treatment. The 12-month
restriction on rotating to sugarbeets and sweet potatoes may
be extended to all root crops with the submission of rotational
carrot data showing no detectable residues when planted 12
months following treatment. Other crops may be planted 18
months following treatment.
Potential for Groundwater Contamination
Metalaxyl and its soil aged residues readily leach in
loamy and silty soils low in organic matter. Leaching is especially
strong in sandy soils, posing possible groundwater contami-
nation problems . Hydrolysis in groundwater has little effect
on the degradation of metalaxyl, but microbes would degrade
it. Under the influence of soil microbes, parent
material will decline steadily while total amounts of
degradation product CGA-62826 and non-extractable material
will increase.
%non-
Time %parent(Metalaxyl) %CGA-62826 extractable
1 mo. 60 30 6
3 mo. 19 48 20
6 mo. 5 33 ' 37
12 mo. <2 23 38
Therefore, several factors, such as how fast leaching
occurs, amount of rainfall, presence of soil microbes and
depth of the water table will determine the relative amounts
of metalaxyl and its degradation products reaching groundwater.
If groundwater contamination is shown, long term toxicological
testing, similar to that required for a food-crop use, may
be required.
Groundwater Monitoring
Groundwater monitoring studies were being conducted in
Maryland and Florida as a condition of registration.
Data provided to the Agency so far, showed no detectable
metalaxyl residues in soil samples below 18 inches from
the surface. Similarly, well water analysis showed no
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detectable residues in any of the analyzed samples. Soil
and water analyses were performed at 30 day intervals for
219 days following treatment.
The data discussed above were generated from studies
conducted on tobacco farms in Florida and Maryland.
Additional monitoring/ from a site in Indian River,
Florida, has been terminated. The Agency is considering
the need to require additional monitoring.
Analytical Methods
Ciba-Geigy method no. A6-323 determines the residues of
metalaxyl and its acid metabolite in soil. Treated soil
is extracted with 50% aqueous methanol which is then made
basic with NaOH. The parent compound is removed from this
by extraction with dichloromethane which is then cleaned up
and subjected to gas chromatographic (GC) analysis with a
flame ionization detector. Residues of the acidic metabolite
CGA-628 26 [N-(2,6-dimethylphenyl)-N-(2-methoxyacetyl)
alanine] are removed from the basified solution by acidifi-
cation with HC1 and partitioning with dichloromethane which
is evaporated to dryness and reacted with diazomethane which
converts the acid metabolite via methylation to the parent
compound which is cleaned up and detected as parent compound
(Nixon 1978, 0096).
This method has been validated (Balasubramanian et al. 1973,
0071). The percent of recoveries of the parent compound and
the acid metabolite from soils fortified in the range of
0.05 - 10.0 ppm averaged 97 ± 14 and 104 _+ 11, respectively.
Labeling Restriction — Rotational Crop Statement
"If replanting is necessary, tobacco may be replanted
immediately. Tobacco, corn or root crops may be planted the
year following treatment. Small grain cover crops may be
planted during the fall following treatment provided they
are plowed down and not used for food or feed. Other crops
may be planted 18 months following application."
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Chapter VI
TOXICOLOGY
Toxicology - Manufacturing-Use Metalaxyl
Acute Toxicity
Subchronic Toxicity
Subchronic Oral Toxicity
Subchronic Dermal Toxicity
Subchronic Inhalation Toxicity
Chronic Toxicity
Mutagenicity
Teratology
Reproduction
Chronic Feeding
Oncogenicity
Metabolism
Toxicology - Emulsifiable Concentrate (EC) Metalaxyl
Acute Toxicity
Toxicology - Manufacturing-Use Metalaxyl
Acute Toxicity
The acute oral LD50 of technical metalaxyl in rats is 669
mg/kg which suggests a moderate acute oral hazard to human
beings (Sachsse, Bathe 1976; 0026). In rabbits, the acute
dermal LD50 of technical metalaxyl is greater than 6000
mg/kg (Sachsse, Ullmann 1976; 0029) while the acute dermal
LD50 in rats is greater than 3,170 mg/kg (Sachsse, Bathe
1976; 0023). This suggests a moderate acute dermal hazard
to humans.
Technical metalaxyl is irritating to rabbit eyes (Sachsse,
Ullmann 1976; 0031). Corneal involvement was noted which
completely cleared 3 days after treatment. Technical
metalaxyl has a low potential for primary dermal irritation
in human beings. It was a mild irritant when applied to
rabbit skin (Sachsse, Ullman 1976; 0032). In guinea pigs,
technical metalaxyl demonstrated no skin sensitization
(Sachsse, Ullmann 1976; 0033).
Based on the toxicity categories in 40 CFR 162.10 technical
metalaxyl is a category III chemical for eye irritation,
acute oral and acute dermal hazards. Technical metalaxyl,
per se, is considered to pose little or no hazard based
on tTTe acute testing. Technical metalaxyl has a low hazard
potential as a skin irritant and may be placed in category
IV.
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Subchronic Toxicity
Subchronic Oral Toxicity
Two three-month dietary studies were conducted using technical
metalaxyl. The rat was the test species in one study (Drake
1977; 0011) and in the other study, the dog (Finn 1977;
0012).
In the rat 90-day dietary study, four groups totaling 180
rats received dosages of 50, 250, and 1250 ppm of 99%
technical metalaxyl while one group served as an untreated
control group. Two groups consisted of 25 male and 25
female rats each and 2 groups of 20 males and 20 females
each. Effects included minimal cellular hypertrophy in
parenchymal cells of five female rats receiving the highest
dose. No other changes attributed to treatment were observed.
The "No-Observed Effect Level" (NOEL) was 250 ppm based on
effects of minimal cellular hypertrophy in the highest dose
group. This study is adequate to assess the subchronic oral
toxicity of technical metalaxyl in the rodent (Drake 1977;
0011).
Technical metalaxyl was administered to 3 male and 3 female
dogs in two groups at 50 or 250 ppm while 4 male and
4 female dogs were treated at 1250 ppm and another group of
4 males and 4 females served as controls. No mortality or
changes in animal behavior were observed. Any macroscopic
findings were not treatment related. Microscopic examination
revealed no dose related necropsy or other findings. Blood
chemistry, hematology, and urine analysis; and ophalmoscopy
examinations indicated no treatment related findings. The
NOEL was 250 ppm. This is supplementary data because too
few animals (3/sex) were used (Finn 1977; 0012).
In addition, a six-month oral toxicity study was conducted
with technical metalaxyl in the dog (deWard et al., 1981,
0045). Fifty-six dogs (28 males and 28 females), six to
eight months old were randomly assigned to four treatment
groups. These treatment groups consisted of:
Group I (control) with 8 males and 8 females;
Group II (50 ppm) with 6 males and 6 females;
Group III (250 ppm) with 6 males and 6 females; and
Group IV (1,000 ppm) with 8 males and 8 females.
Two males and two females, each from Group I and IV were
randomly selected as recovery dogs.
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Mo dosage-related trends were noted in daily observations.
No statistically significant differences were observed in:
(1) body weights or weight gains; (2) weekly feed consump-
tion; (3) hematology parameters; or (4) clinical chemistry
parameters. No abnormalities or changes were observed in
the ophthalmic examinations and the Schirmer tear test
results conducted at the predose and terminal examinations.
Semi-monthly urinalysis parameters were all within normal
limits and no dosage related trends were detected.
Red blood cell count, hematocrit, and hemoglobin count
were significantly decreased for Group IV males compared
with control males at 60, 90, and 180 days. However,
all values were within normal limits and no clinical signs
of anemia were observed.
The most consistent clinical chemistry findings were in
alkaline phosphatase levels. Alkaline phosphatase levels
in Group IV (1000 ppm) male and female dogs were
significantly higher than in controls at 120, 150, and 180
day bleedings.
The liver/brain weight ratios of Group IV females dosed
at 1000 ppm were significantly increased compared with the
control. Absolute liver weights and liver/body weight
ratios of female and male dogs showed a trend of
increased liver weight with increased dosage. These
trends were not statistically signficant in either sex.
No other trends were detected in organ weights or ratios.
No treatment-related lesions were seen at gross necropsy
and during histopathological examination of the tissues.
The NOEL is considered to be 250 ppm in the diet of dogs
for six months. The lowest effect level (LEL) is
1000 ppm and the effects consisted of increased alkaline
phosphatase and liver/brain weight ratio.
This study is acceptable as a subchronic oral study in
a nonrodent.
Subchronic Dermal Toxicity
In the 21-day dermal study (Toxigenics 1980, 0041), the
powdered test material was applied under impervious binders
to the abraded and intact (clipped free of hair) skin of
rabbits. One half of each group and sex consisted of
rabbits with abraded skin. A control group plus three
test groups were employed. Each group consisted of 10
female and 10 male rabbits. The dosages used were 10,
100, 1000 mg/kg. The NOEL for the study is 1000 mg/kg/day.
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All animals except one in the 100 mg/kg group/ survived
the study. No significant differences/ when compared with
the controls were observed for food consumption, body weight,
hematology, clinical chemistry, or organ weight ratios.
The pathologic studies did not show any lesions that can be
attributed to the application of the test material. Nor is
there any pathologic evidence that the test material
influenced the development or severity of the spontaneous
infections and degenerative lesions exhibited by the
rabbits.
This study meets the requirements of an acceptable 21-day
dermal subacute study.
Subchronic Inhalation Toxicity
A 90-day smoke inhalation study is required if pesticide
residues in the smoke of treated tobacco are greater than
.1 ppm. Therefore, this subchronic inhalation study is
required for metalaxyl's use on tobacco. (See also the
Residue Chemistry, Chapter VII). Also, a metabolite of
concern of metalaxyl, 2.6-dimethylaniline is a pyrolysis
product of metalaxyl.
In a preliminary study (Coate 1980, 0037), rats, in four
groups of 10 male and 10 female rats each, were each
exposed to the smoke from 16 cigarettes per day. Three
groups received exposures to smoke from tobacco treated with
metalaxyl technical in weight proportions of 130, 3,900 and
13,000 ppm. One group was exposed to smoke from untreated
tobacco. The results indicate little or no toxic impact
from exposures to metalaxyl-spiked cigarette smoke. There
were no differences in pharmacotoxic signs observed and
there were no biologically meaningful hematology or serum
chemistry differences except slightly lowered calcium in
metalaxyl treated female groups versus the control group
that was dose-related. There were no meaningful organ or
organ/body weight differences nor remarkable gross pathology
differences.
Although exposed to about 40 minutes of a 64-fold range of
non-pyrolyzed technical metalaxyl and an undetermined amount
and range of its pyrolysis product, no important toxicological
effects have been seen to result. The NOEL is the high-dose
group (13,000 ppm of technical metalaxyl). This study
suffices as a range finding study for the 90-day smoke
inhalation study.
A 90-day smoke inhalation test is in progress; a report will
be submitted in the summer of 1981.
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Mutagenicity
The following studies represent only the minimun require-
ments for data on the potential heritable effects of
metalaxyl.
1. A mamalian in-vitro point mutation test.
2. A sensitive sub-mammalian point mutation test.
(Bacteria, fungi, insect).
3. A primary DNA damage test (i.e. sister chromatid
exchange or unscheduled DNA synthesis).
4. A mammalian in-vitrp cytogenetics test. If this
test suggests a positive result, a dominant lethal
or heritable translocation test may be required.
After results from these test systems and other toxicology
disciplines have been considered, additional testing may be
required to further characterize or quantify the potential
genetic risks.
Although the Agency's mutagenic testing requirements are
not final, the standards for these tests should be based on
the principles set forth therein (FR 43, NO. 163, Tuesday,
August 22, 1978). Protocols and choices of test systems
should be accompanied by a scientific rationale. Substitutions
of test systems for those listed above will be considered
after discussion with the Agency.
The requirements should be considered an interim guide and
not final Agency policy.
The mutagenic potential of metalaxyl was studied by Arni and
Muller (1978, 0001) and Fritz (1978, 0013). In Arni and
Muller, a salmonella/mammalian microsomal mutation study,
the technical chemical at 25, 75, 225, 675, and 2025 ug/
0.1 ml was tested with and without mammalian microsomal
activation to detect point mutations. The test strains were
TA 1535, TA 1537, TA 98, and TA 100. Metalaxyl was not
mutagenic in this study.
A mouse dominant lethal study using the technical chemical
was performed to evaluate cytotoxic or mutagenic effects on
male germinal cells (Fritz 1978; 0013). Single doses of 65
or 195 mg/kg were administered to groups of 20 male mice per
group. Each treated male was placed in a cage with 2
untreated females for 8 weeks to span the period of spermato-
zoon development. The data on mating ratios, the number of
implantations, and embryonic deaths were comparable in all
groups. No adverse toxicity was seen in treated males.
However, one male in the 195 mg/kg group died. No evidence
of test chemical mutagenicity was observed.
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Guerzoni and Mattioli (1979, 0501) studied the mutagenic
activity of new fungicides including Ridomil. Two microbio-
logical tests were conducted: (1) a mitotic gene conversion
with Saccharomyces cerevisiae (D4), and (2) a genetic forward
mutation with Schizosaccharomyces pombe (Pi). Reported
results in this summary stated that Ridomil showed no
mutagenic activity. This study has not been reviewed by the
Agency.
Teratology
Fritz (1978, 0014) tested rats for teratogenic or embryotoxic
effects of technical metalaxyl. Technical metalaxyl was
administered by intubation at 20, 60, and 120 mg/kg body
weight to groups of 25 rat dams from day 6 through 15 of
gestation. A fourth group of 25 pregnant rats served
as controls. Ratios of implantations and resorptions were
comparable in treatment groups to control groups. Sex
ratios of live fetuses from treatment groups to control
group were unchanged. No malformations were found in the
fetuses nor were the average weights of the fetuses of the
treated groups significantly different from the control
group. This study shows that technical metalaxyl is not
teratogenic in rats at doses up to 120 mg/kg and suffices to
assess the teratogenic potential of metalaxyl in rodents.
Chinchilla rabbits were given oral doses by intubation
of technical metalaxyl of 5, 10, and 20 mg/kg from Day
6 through Day 18 of pregnancy (Fritz, 1978, 0042).
Metalaxyl technical was not considered teratogenic in
rabbits at gavage does up to 20 mg/kg. The no-observed
effect level (NOEL) for fetotoxicity is 20 mg/kg.
Study results concluded that during the period of
treatment, food consumption was found to be slightly
reduced at the 10 mg/kg dose and markedly reduced at
the 20 mg/kg dose. In addition the average body
weight gain appeared to be slightly reduced in both
of these dose groups. However, the mean numbers of
corpora lutea and/or implantations were comparable
for all groups. The rates of embryo and/or fetolethality
(resorptions) were not significantly altered when
compared with the control group. The sex ratios were
comparable for all groups. The average weights of
the live fetuses were comparable for all groups.
This study suffices to assess the teratogenic effects
in nonrodents.
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Reproduction
To assess the effects of metalaxyl on reproduction over
3 generations, four groups of SPF rats of the Crl: COBS
(SD)BR strain were selected (Cozens et al. 1980, 0044).
The groups each consisted of 25 male and 25 female rats
and were dosed at 50, 250, and 1250 ppm of technical
metalaxyl while one group served as control. Throughout
the three generations, there were no consistent dosage
effects on adult animals in respect to signs of reaction,
mortalities, food consumption, water consumption, body
weight change, food conversion ratios, mating performance,
pregnancy rate, duration of gestation or findings at
terminal autopsy.
Data obtained from the teratology sacrifices of parent
females and first generation females did not indicate
any adverse effect resulting from the administration of
technical metalaxyl with respect to:
(a) mean litter parameters (as assessed by
pre- and post-implantation loss, litter
size, litter and mean fetal weights); or
(b) embryonic and fetal development (as assessed
by the incidence of major malformations, minor
anomalies and skeletal variants).
The NOEL for reproductive parameters and teratologic
parameters is considered to be 1250 ppm.
Chronic Feeding and Oncogencity
Data are not required for currently registered non-
food uses of metalaxyl. Data are required to set a
permanent tolerance or to grant an exemption from a
tolerance.
The 2-year rat feeding study (Life Sciences Research
1980, 0043) cannot be fully evaluated at this time.
In the submitted report, the non-neoplastic microscopic
pathology summary tables and the neoplastic summary
tables list only the number of animals examined and
not the number of various organs examined for the
number of animals examined. As reported, every organ
designated for every animal tested was examined
microscopically. The individual animal pathology
sheets do not demonstrate this.
These pathology summary tables must be resubmitted to
include the number of organs examined for the number
of animals examined. In addition, the determination
of the maximum tolerated dose (MTD) for the study
must be detailed.
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Metabolism
In the first study with rats (Hambock 1977, 0015) the
excreta and tissue distribution of C-metalaxyl.was
studied. Male amd female rats were dosed with C-metalaxyl
at 0.5 or 25 mg/kg. The excreta and expired C02 were
collected for analysis at 24-hour intervals. After six
days, the rats were sacrificed and the radioactivity in
various tissues was measured.
By the sixth day, almost all the administered radioactivity
was excreted in the urine and feces for both levels. The
amount of C02 expired was insignificant. Pooled urine
(0-24 hours) for male and female was analyzed by thin-layer
chromatography (TLC) and numerous metabolites were found in
urine. No parent metalaxyl was detected in these samples.
The residual radioactivity in all the tissues and organs was
very low except in the liver, which contained from 0.002-
0.004 ppm for 0.5 mg/kg dose rate and 0.146-0.255 for 25 mg/kg
dose rate.
The second study (Hambock 1978, 0016) was carried out to
isolate and identify the metabolites...Sixteen female rats
were dosed orally with 27.9 mg/kg of C-metalaxyl and
the urine and feces were collected for 48 hours. The urine
contained 63.5% of the administered dose and the feces, 32.8%.
The analysis of urine extracts showed the same patterns as
those reported from the previous study. The radioactivity in
the urine was fractionated. In 0-48 hour urine, 62.1% of
the metabolites were in the form of glucuronic acid conjugates
as shown by aglycone released by p-glucuronidase incubation.
At least 10 aglycones were released by enzyme treatment. It
was noted that metalaxyl is readily absorbed, degraded and
excreted by rats. The degradation of metalaxyl in the rat
proceeds primarily via (1) methyl ester hydrolysis (2)
N-dealkylation (3) methyl ester linkage (4) 2-(6)-methyl
oxidation and subsequent formation of conjugates with
glucuronic acid.
Toxicology - Emulsifiable Concentrate (EC) Metalaxyl
Acute Toxicity
The acute oral LD50 in male and female albino rats of 23.5%
emulsifiable concentrate (EC) metalaxyl is 1889.5 mg/kg of
bodyweight which suggests a moderate acute oral hazard to
human beings (Kapp, Piccirillo 1978; 0018). This corresponds
to toxicity category III. The acute dermal LD50 of this
formulation in rabbits is 3,571.5 mg/kg of body weight
(Kapp, Piccirillo 1978; 0017). This suggests a moderate
acute dermal hazard to humans and corresponds to toxicity
category III.
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This formulation is irritating to rabbit eyes causing
corneal opacity and conjunctival irritation persisting
through 7 days (Piccirillo 1978; 0020). Corneal opacity
persisted in two rabbits through termination on Day 14.
Conjunctival irritation, consisting of redness, chemesis and
discharge persisted through Day 14 in one animal. This
corresponds to category I, but the study was not continued
through 21 days to determine the irreversible nature of the
corneal involvement or irritation. This formulation has a
low potential for primary dermal irritation. It was a very
slight irritant when applied to rabbit skin (kapp, Piccirillo
1978; 0019). This corresponds to category III.
An acute aersol inhalations study in 6 male and 6 female
albino rats was conducted to determine the level of toxicity
of this formulation after exposure for four hours. The
nominal concentration of the test material generated in
the exposure chamber was calculated to be 3.38 mg/L of air.
No adverse effects were noted during the 4-hour exposure
period or during the succeding 14-day observation period.
TheQAgency finds this test to be supplemented because the
LC was not determined. However for the purposes of
precautionary labeling, the product could be placed in
category III.
A second modified formulation containing approximately the
same amount of active ingredient (24.9%) as the material
tested is substantially similar. The Agency has determined
with available information that this formulation should
reflect approximately the same acute toxicity profile
as the material tested. Additional testing of this second
EC formulation is not required at this time.
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Chapter VII
RESIDUE CHEMISTRY
Residue Chemistry - Manufacturing-Use Metalaxyl
Introduction
Uptake, Distribution, and Metabolism in Plants
Potatoes
Animal Metabolism
Goats
Rats
Analytical Methods
Nature of Residue in Tobacco
Nature of Residue in Cigarette Smoke
Pyrolysis Products
Residue Data
Field Tobacco
Potatoes
Meat/ Milk, Poultry and Eggs
Residue Chemistry - Formulated Metalaxyl
Required Labeling
Manufacturing-use Metalaxyl
Introduction
As discussed in the Use Summary (see Chapter IV), metalaxyl
was federally registered in 1980 for use on tobacco. The
Agency considers use of a pesticide on tobacco a non-food
use and does not require a tolerance or an exemption from
a tolerance. However, data are needed to assess the
exposure of human beings to residual products upon the
consumption of tobacco. Depending on the amount of residues,
such data include the nature of residue in tobacco and
cigarette smoke; and identification of pyrolysis products;
and field residue data.
EPA sets tolerances for pesticides used on growing crops.
The use of these pesticides will result in residues remaining
in or on food or feed. In addition to its tobacco use, an
experimental use permit (EUP) was submitted to the Agency
for use of metalaxyl on potatoes. In association with this
EUP (100-EUP-l), a temporary tolerance for this food use was
granted by the Agency. The temporary tolerance in or on the
raw agricultural commodity potatoes was set at 0.05 ppm.
Residue chemistry data for the proposed use of metalaxyl on
potatoes are discussed in this chapter. Additional data
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would be needed for the Agency to grant permanent tolerances
on potatoes. Additional tolerances would be required in
order to register a product for uses on other raw agricultural
commodities, including seed treatments, that may result in
residues in food and feed. Appropriate chronic toxicology
information is also necessary before a permanent tolerance
is set.
Other uses of metalaxyl include turf, conifers, non-bearing
citrus (Florida only) and ornamentals. These uses do
not require a tolerance or an exemption from a tolerance.
Uptake, Distribution, and Metabolism _in Plants
Potatoes
Available data indicate that metalaxyl (CGA-48988)
is absorbed into the potato plant (leaves and stems)
and is extensively metabolized. Little translocation
of residues occurs from the stems to the potato tubers.
Because of the low level of residues in the tubers, the
fate of the compound in potatoes is adequately defined.
The parent compound is the residue of concern.
In a study conducted near Basle, Switzerland (Gross 1977,
0132), eight-week old potato plants were sprayed until
runoff with phenyl- C-metalaxyl at a rate equivalent to
0.18 Ib ai/acre. The treatments were repeated 4 times at
10 day intervals. Mature plants with tubers were harvested
for analysis five weeks after the last treatment. The
plants were fractionated into tubers, leaves, stems and
roots and the distribution of radioactivity was determined.
About 1.5% of the total amount of radioactivity applied
occured in the plants at the time of harvest. The rest of
the radioactivity was lost, partly due to drift during the
application and partly due to volatilization from the leaf
surface. More than 90% of the plant radioactivity was
present in the shoots and was found to consist mainly of
polar acidic compounds. One of these was identified as
N-(2,6-dimethyl phenyl)-N(-methoxyacetyl)-alanine (CGA-62826).
Only 2.7% of the radioactivity was in the form of the
unchanged fungicide. The tubers contained 0.02 ppm metalaxyl
equivalents indicating little translocation of the activity
from the foliage to the tubers. The radioactivity consisted
exclusively of polar metabolites. It was also noted that
neither metalaxyl nor its degradation products were taken by
the tubers directly from the soil.
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Another study {Fischer, Cassidy 1978; 0099) was carried
out in New York State. White potatoes grown in field
plots were treated with 3 foliar applications of phenyl-
' C-metalaxyl. The first application was made six
weeks after plant emergence at the rate of 1.1 Ib ai/
acre (3X of the maximum proposed rate of application).
Subsequent applications were made at the same rate at 28
day intervals. Plant samples (tubers and stalks) were
taken immediately before and after each treatment and
at tuber maturity (18 weeks). It was determined that
the level of radioactivity in stalks decreased about
80% within 4 weeks after each spraying. The level of
radioactivity in the tubers decreased from 2.47 ppm at
the first treatment, when they were small roots to
0.14 ppm at the time of harvest. It appears that the
high levels in the tubers are due to contamination with
radioactive soil. Partition characterization of the
extractable radioactivity in the tubers and stalks indicate
that potatoes can metabolize C-metalaxyl extensively,
especially in the tubers. Characterization of the radio-
active metabolites in mature.stalks showed that 2.7% could
be accounted for as parent C-metalaxyl and 11.4% as
metabolite, CGA-62826. At maturity most of the radioactivity
in the stalks was soluble in organic solvents. Thus, a
large fraction of the metabolites appears not to be conjugated
with natural products.
An additional study (Foster, Fischer, Cassidy 1978; 0086)
was also carried out in New York State. White potatoes
grown in field plots were treated with 6 foliar applica-
tions of phenyl- C-metalaxyl. The first application at
0.4 Ib ai/acre was made six weeks after plant emergence.
Subsequent applications at the same rate were made at
14 day intervals. Only tuber samples were studied.
These tubers were weighed and the levels of radioactivity
ranged from <.003 to 0.094 ppm, metalaxyl equivalents.
This range is probably due.to contamination with treated
soil or translocation of C-metalaxyl. Because of low
levels, no further characterization of the radioactive
components was attempted.
Tobacco
See the Nature of Residue ^n Tobacco in this chapter.
Animal Metabolism
Goat
14
A lactating goat was administered phenyl- C-metalaxyl by
capsule at a level of 7.00 ppm in the feed for 10 con-
secutive days (Seim 1978, 0143; Fischer, Foster, Cassidy
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1978, 0131). Urine, feces, milk and expired CO- and
volatiles were collected daily for analysis. Blood was
collected every second day and on the day of sacrifice. One
day after the last dose, the goat was sacrificed and various
organs and tissues were sampled. Most of the administered
radioactivity was excreted by the time the goat was
sacrificed, 93.9% in urine, 11.6% in feces and <.002%
in expired volatiles and C02> Levels of radioactivity
in tissues at sacrifice, expressed as ppm equivalent to
C-metalaxyl, were all below 0.05 ppm except the liver
with 0.057 ppm. The radioactivity in milk ranged from 0.003
ppm equivalent to C-metalaxyl on the first five days to
0.008 ppm on the seventh day, the last day of milk production.
However, the quantity of radioactivity excreted as ng
equivalent to C-metalaxyl per day remained relatively
constant during the first seven days. Therefore, a true
plateau was reached on the first day at 0.003 ppm.
Characterization of the urine radioactivity by liquid
partioning, thin layer chromatography (TLC), and electrophoresis
show the components to be highly polar and all had organic
acid properties. The overall TLC portions of the metabolites
are similar in rats and goats treated with metalaxyl. The
only glycosidic enzyme to hydrolyse the urine complex was
glusulase.
Rat
[See the discussion of the rat metabolism studies (Hambock
1977, 1978; 0015, 0016) in the Toxicology Chapter VI.]
For the purpose of temporary tolerances, the above studies
adequately define the metabolism of metalaxyl (CGA-
48988) in animals. For any future permanent tolerance
request or expansion of the experimental use program,
additional metabolism data are needed on a goat or large
ruminant animal (cow) with identification of the residues
in milk and tissues.
Analytical Methods
The Agency requires the submission of, or reference to,
validated analytical methods suitable for obtaining
data on the nature and amount of pesticide residues
resulting from the proposed use. One method must be
suitable for tolerance enforcement. The regulatory
method for determination of a pesticide in raw agricultural
commodities must be capable of measuring the total toxic
residue from the pesticide.
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One analytical method, Ciba-Ceigy Method AG-325 (Bala-
subraraanian, Nixon 1978, 0117) determines the parent
compound (metalaxyl, CGA-48988) in potato tubers and
field tobacco. Only the parent compound required
analysis in potatoes because of the extremely low level
of residues and the lack of definite characterization of
metabolites.
The method employs methanol extraction, partitioning into
dichloromethane and then hexane and cleanup on an alumina
column. The purified residue is then taken up into
acetone and quantitated by gas chromatograph (GC) using
an alkali flame detector.
The lower limit of detection of this method is 0.05 ppm
for potatoes and 1.0 ppm for tobacco.
This method is adequate for determination of residues
of parent metalaxyl and is adequate for the determination
of the proposed tolerance in potatoes.
Available data indicate that the method is very specific
and no interferences will result from 66 out of 74 compounds
having tolerances on potatoes. The remaining 8 compounds
were not available for testing at that time and could not
definitely be excluded on the basis of their structure
(Balasubramanian, Ross 1978, 0119).
Although characterization of radioactive metabolites in
tubers could not be achieved because of low residue levels,
CGA-62826 (N-(2,6-dimethyl phenyl)-N-(methoxyacetyl)alanine)
was found in leaves and stalks. Thus, CGA-62826 is con-
sidered as a possible metabolite of metalaxyl which can be
present in tubers. To test this possibility, field samples
of potatoes exhibiting the highest residues of metalaxyl
were analyzed for CGA-62826 (Ciba-Geigy Corp. 1978, 0126).
In this procedure potato tubers are extracted with aqueous
methanol and extracts concentrated according to methodology
in AG 325. The concentrated extract is diluted with water,
acidified and metalaxyl and CGA-62826 are partitioned into
dichoromethane. The CGA-62826 is then extracted from the
dichloromethane solution into aqueous sodium hydroxide,
leaving parent metalaxyl in the organic phase. The aqueous
phase is acidified and the CGA-62826 is partitioned into a
second dichloromethane fraction. This organic phase is
evaporated to dryness and the resulting material is
reacted with diazomethane. After evaporation of the solvent,
residues of CGA-62826, which are converted to metalaxyl by
a methylation reaction, are cleaned up and detected in the
same manner as parent metalaxyl in analytical method AG
325.
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The above methods for analysis of metalaxyl and CGA-62826
for potatoes have not been evaluated in EPA laboratories.
This must be done before the establishment of any permanent
tolerance.
Method AG-330 (Balasubramanian, Ross 1978; 0120) determines
total residues as 2,6-dimethylaniline (DMA). Residues are
extracted with methanol-water, then a measured aliquot is
evaporated and refluxed overnight with phosphoric acid
in the presence of cobalt chloride. After reflux, the
solution is made alkaline and the DMA steam distilled,
derivatized with trichloroacetyl chloride, cleaned up
on an alumina column and analyzed by gas chromatograph
using alkali flame ionization detector in nitrogen-
specific mode. The limit of detection for residues in
tobacco is 1.0 ppm (in metalaxyl equivalents).
Compounds containing oxidized forms of DMA were not
detected satisfactorily, but six standard compounds related
to known metabolic products (containing DMA moiety) are
shown to give satisfactory recoveries (85 to 104%).
Twelve fortification studies using green and cured, bright
and burley samples fortified with 1 to 500 ppm parent
compound gave recoveries of 65 to 87% (avg. 72%).
14
Analyses of tobacco leaves treated with C-labeled
metalaxyl show that from 36%to 68% of extractable radio-
activity was detected with this method.
A comparison of parent and total residues (determined as
DMA) in green and cured field-treated (either SOW or 2E
formulation) gives total-to-parent ratios of 2.0 to 4.7,
averaging 3.5.
This method is adequate for determination of total residues
of metalaxyl (as DMA) in tobacco.
Nature of_ Residue jLn Tobacco
The nature of the residue for both cured and uncured
tobacco has been studied. The component residue profiles
of uncured bright and burley tobaccos are not significantly
different. Residues were characterized as either non-
extracted, organic (soluble in chloroform or methanol) or
polar (soluble in water). A decline in extractability was
noted in the cured tobaccos and is presumed to be an effect
of curing.
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In a greenhouse metabolism study (Honeycutt, Cassidy 1978,
0106), bright and burley tobacco were transplanted into
a Georgia-sandy-loam foil* For the bright tobacco,
radiolabelled phenyl- C-metalaxyl was added to the
transplant water at an amount approximating either 0.25 Ib.
or 0.50 Ib ai/acre. The phenyl- C-metalaxyl application
to the burley tobacco was incorporated into the soil at
approximately 6.0 Ib ai/acre. The resulting residues
present in the leaf fall into the three groups described
above.
14
Residues of C-metalaxyl per se average 42.5 ppiti in the
cured tobaccos. Total C-metalaxyl residues are about
155 ppm.. A standard cigarette prepared with either 10% or
40% of C-labeled,tobacco would be expected to contain
total residues of C-metalaxyl of 174to 68 ug. Cigarettes
(Ig) prepared with greenhouse-grown C labeled tobacco
contained 19 ug (10% blend) and 82.2 ug (regular blend)
when made with bright tobacco and 68.7 ug (regular blend)
when made with burley.
Based on the field residue studies (Ciba-Geigy Corp. 1978,
0127) 1.0 gm cigarettes prepared with bright tobacco treated
with 3.0 and 6.0 Ib metalaxyl per acre contain residues of
metalaxyl per sse of 31 and 68 ug, and total residues of
about 100 and 250 ug.
Another study concerns uptake and balance of labeled-
metalaxyl in field-grown bright tobacco (Honeycutt,
Fischer, Cassidy 1979; 0136). The soil was treated with
3 Ib ai/acre ring-labeled metalaxyl applied before
planting. Residue levels were considerably lower than
in greenhouse-grown tobacco, presumably due to decreased
availability of metalaxyl because of soil binding, and
were also lower than in field-grown burley tobacco.
Residue levels increased about threefold on curing. For
example, residues in 9 week-old leaves were 6.7 ppm for
green leaves and 21.5 ppm cured leaves. Cured bottom leaves
contained higher levels (21.5 ppm) than did cured top leaves
(7.3 ppm).
Balance data showed a decrease in organic radioactive
solubles from 49.1% at 5 weeks to 31.0% at 16 weeks and an
increase in aqueous soluble metabolites from 43.0% at 5
weeks to 61.5% at 16 weeks. These changes occur more
rapidly in field grown tobacco than in greenhouse tobacco.
Nonextractable radioactivity was low before curing, but rose
to 10-20% upon curing. Aqueous soluble polar metabolites
are higher in middle and upper cured leaves than in lower
ones, which suggests that age decreases the amount of polar
metabolites.
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Additionally, it was found that labeled metalaxyl is
transferred from treated to untreated leaves during curing.
The amount of transfer occurring is expected to be a
function of temperature and air flow rate in the curing
ovens.
Seven major unknown polar metabolites in field cured
tobacco each comprised more than 1% of the total radio-
activity in the leaf. Minor unknown metabolites (17)
were each less than 1% and no more than 10% of the total.
No parent metalaxyl was found. The TLC patterns are
qualitatively similar to greenhouse-grown bright and burley
tobacco. Apparently metabolism occurs faster under field
conditions than in the greenhouse.
In a greenhouse study, bright tobacco slips were treated by
a transplant water procedure of 0.5 Ib ai/acre with ring-labeled
metalaxyl, and the mature top leaves were harvested and
cured after 19 weeks (Honeycurr, Szolics, Simoneaus, Cassidy
1979, 0139). Residue levels were 93.7 ppm. Previous
studies at 12 weeks showed that polar metabolites could be
converted to nine aglycones, six of which corresponded to
unconjugated metabolites. Four of those aglycones have now
been identified primarily by GLC/MS, GLC/Fourier Transform
IR and two dimensional TLC. Collectively, these and the
parent compound account for 61% of the radioactivity in the
leaf.
Based on the data, soil residues of metalaxyl are picked up
and extensively metabolized. The major pathway appears to
be conversion of a metalaxyl ring methyl group to methoxy
group and conjugation of metalaxyl with glucose through this
methoxy group. A second and minor pathway is a conjugation
with glucose through the alanine carboxyl group of the
metalaxyl metabolite, CGA-62826.
Nature of the Residue in Cigarette Smoke
Honeycutt, Szolics, and Cassidy (1978, 0137) studied the
nature of metalaxyl residue in cigarette smoke. Four
batches of radiolabelled cigarettes were prepared according
to an accepted standard. Two batches were prepared with
blended bright tobacco using regular bright tobacco and
either 4% or 40% C-bright tobacco. Two batches were
similarly blended.with regular 14-C-burley tobacco. The
greenhouse-grown C-tobaccos from the metabolism study
(Cassidy, Ross 1978, 0123) were used in these cigarettes.
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The two types of tobacco have similar residue profiles. In
view of this only the smoke profile of the bright tobacco is
summarized in Table VII-1. The only components identified
were 2,6-dimethylanaline (DMA) and metalaxyl per se.
Approximately half of the C-activity present in these
cigarettes remained in the ash or butts, or was trapped as
14-C carbon dioxide in the smoke. The sidestream smoke
contained 75% of the radioactivity, while 25% was in the
mainstream smoke.
There are differences between greenhouse and field-grown
tobacco that significantly affect the smoking characteristics
of the tobacco. The differences were negligible for the
batches containing 4% radiolabelled greenhouse tobacco but
were significant for the regular blend cigarettes containing
40% greenhouse tobacco. This is shown by the distribution
of the tar residues (TPM-volatiles). The vapor phase (VP)
volatiles are the smoke residues that would probably be
inhaled through a cigarette filter.
14
The blend bright (4%) C cigarettes were the source for
these metalaxyl residues. They were the only residues
characterized by GLC. The regular blend (40%) C-metalaxyl
residue for co-chromatographic characterization by 2 dimensional
thin layer chromatography (2D-TLC) and high performance
liquid chromatography (HPLC).
14
The reported C-carbon dioxide (26.7%) and the calculated
C-metalaxyl remaining in the ash and butt (2.7% and 20%)
were also determined with these cigarettes.
TABLE VII-1: Summary of the Residue Data for Cigarette Smoke
Component(s)
Metalaxyl
2,6-DMA
Polar (3)
Organic (4)
Other (22)
Total
% of the volatiles
recoverd
TPM-Volatiles 44%
MS(28%) SS(16%)
VP-Volatiles 6%
MS(036%) SS(4.74%)
7.5
0.7
2.0
4.2
14.4%
5.2
2.2
2.2
3.9
13.5
0.07
<0.01
0.15 (6)
0.13%
0.38
0.90
0.42 (22)
1.60%
63%
34%
About 100 micrograms is the total metalaxyl residue expected
in cigarettes prepared with bright tobacco treated with 3.0
Ib of metalaxyl per acre. For such cigarettes, the percentage
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of residues in Table VII-1 are also equivalent to the microgram
quantities of the components in the smoke. Similarly, for
cigarettes prepared entirely with bright or burley tobacco
treated at the maximum rate (6.0 Ib. ai/acre) the microgram
quantities of residues expected are factors of 2.5 and .23
respectively. These factors indicate that metalaxyl residues
per se average about 27.5% of the total residue. These
factors are based on the reported maximum residues of
metalaxyl per s_e_ which were reported in the field studies
and data from Table VII-1.
The nature of metalaxyl residue in cigarette smoke is
adequately understood.
Pyrolysis Products
Pyrolysis and distillation products of metalaxyl tobacco
metabolites into smoke as a result of the smoking process
were identified. One organic component and 2,6-DMA are
definitely pyrolysis products (Honeycutt, Szolics, Cassidy
1978; 0137). They are not found as components of the cured
tobacco, but were smoke components. Three organic components
in cured tobacco and smoke are probably distillation components.
Unlabelled pyrolysis products were not determined.
The possibility of these components is indicated by the
large proportion of C-carbon dioxide in the smoke.
The characterization of the pyrolysis products of metalaxyl
and its metabolites is marginally adequate.
Residue Data
Field Tobacco
Residue tests were conducted in North Carolina, Virginia,
Tennessee, Maryland, and Georgia (Ciba-Geigy Corp. 1978,
0128). Bright or burley tobacco was grown and harvested
according to the cultural practice of the respective areas.
The reported residues vary considerably.
Test plots at all locations were treated with a 50% wettable
powder (WP) formulation at rates of either 3.0 Ib. or 6.0
Ib. of metalaxyl per acre. In order to obtain a metalaxyl
emulsifiable concentrate (EC) formulation, crossover data,
plots in Maryland were also treated with at the same rates.
Differences between the formulations did not significantly
affect the metalaxyl residue in tobacco. Growing conditions,
e.g. greenhouse vs. field do affect the residue profile.
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Only metalaxyl residues per se were determined by the method
of Balasubramanian and Nixon (1978, 0117). Residues in
lower, uncured leaves at 12 weeks (84 days} treatment-to-harvest
interval were up to 3.5 ppra in bright tobacco treated the
the 3.0 Ib. ai/acre rate. At the 6.0 Ib. ai/acre rate,
residues in bright tobacco at the same intervals ranged up
to 9.2 ppm. However, residues in uncured composited burley
leaves at 109 days preharvest interval (PHI) were <1.0 ppm.
Residue in lower, cured bright leaves at 84 days preharvest
intervals with a 3.0 Ib. ai/acre treatment rate ranged from
3-31 ppm. At 6.0 Ib. ai/acre residues ranged from 4.6 -
68 ppm. In cured composited burley leaves at 109 days
PHI, residues were 6.3 ppm at 6.0 Ib. ai/acre treatment
rate.
Additional residue reports (Ciba-Geigy Corp. 1978, 0127)
contain results analyzed for total metalaxyl residues which
are detected as derivatives of 2,5-dimethylaniline (DMA).
These studies were conducted at the same locations as the
ones for which metalaxyl per sje were reported. Total
residues in lower green (uncured) leaves ranged from 1.2-25
ppm at 3.0 Ib ai/acre to 2.0-35 ppm at 6.0 Ib ai/acre.
Residues in composited green leaves (upper, middle and
lower) from one study were <1.0 ppm from treatment with
either 3.0 or 6.0 Ib. ai/acre. These results were analyzed
by the method of Balasubramanian and Ross (1978, 0120).
In the cured tobaccos, the lower leaves of bright tobacco at
84 days before harvest contained 7.9 to 83 ppm (at 3.0 Ib
ai/acre). At 6.0 ai/acre the values ranged from 15-179 ppm.
Middle leaves of bright tobacco at 122 days contained 8.6 to
16 ppm metalaxyl and 8.1 to 50 ppm from treatment with 3.0
and 6.0 Ib. ai/acre respectively. Upper bright leaves at
154 days PHI contained 6.0 to 12 ppm and 8.1 to 45 ppm from
treatment (3.0 and 6.0 Ib. ai/acre). Composited burley
leaves at 109 days PHI contained <1.0 to 6.1 and 1.5 to 21
ppm and composited bright leaves contained 44 to 49 ppm (13
ppm parent metalaxyl) and 199 to 228 ppm (53 ppm parent).
All samples were treated with either the EC formulation or a
WP formulation.
Maximum residues in cigarettes are calculated using the
tobacco with the highest residue levels which were 83 ppm
(residues determined as DMA) in lower cured leaves. From
the tobacco metabolism studies, the average ratio of radio-
labelled metalaxyl recovered as DMA total amount of radio-
labelled present was 55%. Therefore, the maximum level of
metalaxyl and all metabolites is estimated to be 151 ppm or
151 ug per 1 g standard cigarette of which 38 ug would be
in the mainstream smoke and likely be inhaled by a smoker.
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Potatoes
Residue tests were conducted in 1977 and 1978 in 4 states,
New York, Washington, Iowa, and Florida (Ciba-Geigy Corp.
1978, 0126). Metalaxyl was applied as a 50% WP formulation
at rates of 0.5 and 1.0 Ib. ai/acre. These rates are 1.33
and 2.67 times the maximum proposed rate of application.
A total of six foliar applications were made at approximately
2 week intervals. An additional test was conducted in
Florida in 1978 using a metalaxyl 2E formulation to obtain
crossover data. Potato tubers from three of these studies
using the 50% WP at 0.5 Ib ai/acre contained no detectable
residues (<0.05 ppm) of metalaxyl at a 1 day PHI. Results
from tests in New York and Iowa showed residues at levels of
0.07 to 0.18 ppm. At the 1.0 Ib. ai/acre treatment rate,
the residues ranged from <0.05 ppm to 0.23 ppm.
At the 7 day PHI, the tubers from plots sprayed at the 0.5
Ib. ai/acre rate contained no detectable residues «0.05
ppm). The tubers sprayed at 1.0 Ib. ai/acre contained
residues ranging from 0.08 to 0.99 ppm.
Potato tuber samples, at both PHI's treated at 1.0 Ib.
ai/acre and containing residues over 0.2 ppm of parent
metalaxyl (CGA-48988) were further analyzed for residues of
the metabolite, CGA-62826. No detectable residues (calculated
as parent metalaxyl) were found.
The results of residue tests in Florida with a metalaxyl EC
formulation show that this formulation will not result in
residues greater than those resulting from the use of the
50% WP formulation.
Available data are adequate to show that the residues of
metalaxyl in potato tubers from the proposed experimental
use will not exceed the proposed temporary tolerance of 0.05
ppm.
Meat, Milk, Poultry and Eggs
The metabolism studies on goat and rat show that metalaxyl
is rapidly metabolized and effectively excreted. Neither
animal retained significant quantities of metalaxyl or its
metabolites in the tissue and milk. Similar metabolites are
present in both goats and rats, so the metabolic pathways
are applicable to both animals.
If potatoes are part of the daily diet of feed animals, the
percentage of the diet may approach 50%. The results from a
three level meat and milk study are not available but the
results of the goat study may be extrapolated to cattle.
-77-
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The radiotracer feeding studies on a goat at 7 ppm in the
diet show that the plateau residue level in milk was 0.003
ppm (Fischer, Foster, Cassidy 1978; 0131). Since the
temporary tolerance is 0.05 ppm, the feeding level is 280
times the maximum calculated feeding level of 0.025 ppm. By
extrapolation from the results of the goat study, the
maximum residue expected in milk is ^003=.00001 ppm (0>01 ppb)
A similar extrapolation with the higher residue found in
goat tissues (0.057 ppm in the liver) shows that the maximum
residue expected is .057 nnm ~~-»
2QQ = -0002 ppm
A temporary tolerance for meat and milk is not required for
this experimental use permit on potatoes because the feeding
of potatoes for cattle is not a common practice under
current economic conditions and the maximum calculated
values are extremely low.
For any future permanent tolerance request or an expansion
of the experimental use program for food crops, large animal
feeding studies and tolerance proposals for residues in
meat, milk, poultry, and eggs are required.
Formulated Metalaxyl
Required Labeling
Tobacco
A second EC application of metalaxyl is not permitted for
one year and then only for tobacco.
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Chapter VIII
ECOLOGICAL EFFECTS
Ecological Effects — Manufacturing-Use Metalaxyl
Non-target Wildlife
Birds
Fish
Invertebrates
Aquatic Life-Cycle Studies
Ecological Effects — Emulsifiable Concentrate
Metalaxyl
Aquatic Organisms
Ecological Effects - Manufacturing-Use Metalaxyl
Non-target Wildlife
Birds
Manufacturing-use metalaxyl is practically non-toxic to
birds. The acute oral LD50 of technical metalaxyl to the
mallard duck is 1,466 mg/kg (Beavers, Fink 1977; 0051). An
eight-day dietary study on the mallard duck (technical
metalaxyl) yielded an LC50 greater than 10,000 ppm (Beavers,
Fink 1977; 0053). A bobwhite quail dietary study using
technical metalaxyl also resulted in an LC50 value
greater than 10,000 ppm (Beavers, Fink 1977; 0052).
Another 8-day dietary study conducted by Sachsse and Ullmann
(1976, 0061) on the Japanese quail also yielded values over
10,000 ppm. This test is classified by the Agency as
supplemental because the Japanese quail is not a recommended
species.
Fish
Manufacturing-use metalaxyl is practically non-toxic to fish.
Two 96-hour LC50 studies using technical metalaxyl on a
coldwater fish (rainbow trout) yielded LCSO's greater than
100 ppm (Fratus, Buccafusco 1978, 0056; Sachsse, Bathe 1976,
0059). McCann (1979, 0067) reports an LC50 value of 132 ppm
for rainbow trout.
In a warmwater fish (bluegill sunfish), two studies also
yielded 96-hour LC50 values greater than 100 ppm for
technical metalaxyl (Fratus, Buccafusco 1978, 0055; Sachsse,
Bathe 1976, 0059). An additional study on blue gills
yielded a similar LC50 value of 139 ppm (McCann 1979,
0067) .
-79-
-------
Additional values of greater than 100 ppm were also reported
in the catfish, carp, and guppy for technical metalaxyl
(Sachsse, Bathe 1976, 0059). These data provide only
supplemental information because the fish used in the test
are not acceptable test species.
Sachsse and Bathe (1976, 0059) provides only supplemental
data because of several additional deficiencies in the study
including: (1) the loading factor was excessive; (2) an LC50
value was not established (3) test vessels were aerated for
the trout; (4) tests were conducted at lower than normal
temperatures or over a fluctuating temperature range; and
(5) numbers of fish tested or the numbers of concentrations
were not adequate for the carp, catfish, and bluegill.
Invertebrates
LeBlanc and Gary (1978, 0058) reported a 48-hour LC50 value
of 28 ppm for technical metalaxyl on aquatic invertebrates
(Daphnia magna). This corresponds to slight toxicity in
aquatic invertebrates. McCann (0068) reports an LC50 of 121
ppm. A 48-hour LC50 value of 29.3 ppm was found in a
previous study that was judged supplemental in part due to
the use of combined data from separate tests. (Le Blanc
1977, 0057).
Embryo-larvae and Life-cycle Studies
An aquatic laboratory life-cycle test was conducted with
Daphnia magna as the test species. The test substance was
technical metalaxyl of 90.1% purity. The minimum threshold
concentration or the minimum toxicant concentration to elicit
an adverse response is greater than 1.2 mg/1 and less than
2.7 mg/1 (E.G. and G. Bionomics 1980, 0062).
An embryo-larvae study using the fathead minnow (Pimephales
promelas) was conducted with technical metalaxyl of 90.1%
purity. The minimum threshold concentration to minnow eggs
and fry is greater than 9.1 mg/1. That is, active ingredient
levels as high as 9.1 mg/1 had no adverse effects on percent
of eggs hatched, survival, or growth of fry. (E.G. and G.
Bionomics 1980, 0063).
Ecological Effects - Emulsifiable Concentrate (EC) Metalaxyl
Aquatic Organisms
Aquatic bioassays indicate differential toxicity of different
formulations of metalaxyl. This is apparently due to inert
ingredients. Therefore, prior to any registration of a new
formulation, the Agency will consider the need for aquatic
bioassays on that formulation.
-80-
-------
Formulated EC metalaxyl (27.9% a.i.) yielded 96-hour LC50
values in bluegill and rainbow trout of 27 ppm and 18.4
ppm respectively based on the EC formulation (McCann 1979;
0064, 0065). A 48-hour LC50 of 12.5 ppm based on this
formulation was found for Daphnia magna (McCann 1979, 0066).
These values indicate that EC metalaxyl is slightly toxic to
aquatic species.
-81-
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IX. CASE BIBLIOGRAPHY
Guide to Use of This Biblioqraphy
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 this standard. 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 corresponds closely to
an article. In the case of unpublished materials submitted to the Agency,
the Agency has sought to identify documents at a level parallel to a
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, a nine-digit numeric identifier. This number is
unique to the citations 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 a nine-character
temporary identifier. This is also to be used whenever a 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, tho
Agency has chosen to show a personal author. I Then no individual './as
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 date apnears as four digits with no
question narks, the Agency took it directly frcn the document. SThen a
four-digit date is followed by a question nark, the bibliographer
deduced the rate frcm evidence in the document. *ihen the date appears
as (19??), the Agency was unable to determine or estimate the date of
the document.
9-1
-------
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.
d. Trailing Parentheses. For studies submitted to us in the past, the
trailing parentheses include (in addition to any self-explanatory
text) the following elements describing the earliest known
submissions:
(1) Submission Date. Immediately following the word 'received1
appears the date of the earliest known submission, at the time
that particular document was processed into the Pesticide
Document Management System.
(2) Administrative Number. The next element, immediately following
the word 'under1, is the registration number, experimental permit
number, petition number, or other administrative number
associated with the earliest known submission, at the time that
particular document was processed into the Pesticide Document
Management System.
(3) Submitter. The third element is the submitter, following the
phrase 'submitted by1. When authorship is defaulted to the
submitter, this element is omitted.
(4) Volume Identification. The final element in the trailing
parenthesis identifies the EPA accession number of the volume in
which the original submission of the--study appears. The six-
digit accession number follows the symbol 'CDL1, standing for
"Company Data Library". This accession number is in turn
followed by an alphabetic suffix which shows the relative
position of the study within the volume. For example, within
accession number 123456, the first study would be 123456-A; the
second, 123456-B; the 26th, 123456-Z; and the 27th,123456-AA.
-------
OFFICE OF PESTICIDE PROGRAMS
PESTICIDE DOCUMENT MANAGEMENT SYSTEM
CASE BIBLIOGRAPHY
Section 1: Citations Considered to be Part of the Data Base Supporting
Registrations Under the Standard, and therefore entitled to
Exclusive Use Provision of FIFRA.
GS-0081:
:0001
:0117
:0071
:0120
:0119
:0121
:0051
Arm, P.; Muller , D. (1978) Salmonella/Mammalian-Microsome Mutagencity
Test with CGA-43988—Test for Mutagenic Properties in Bacteria:
Experiment No. 78-2514. (Unpublished study'received July 13, 1978
under 100-EUP-62; prepared bv Ciba-Geigy Ltd. , Basle, Switzerland;
CDL:234428-K)
Balasubrananian, K. ; Nixon, W. (1978) Gas Chromatcgraphic Residue
Determination of CGA-48988 in Crop Samples: Method AG-325.
(Unpublished study received October 31, 1979 under 100-607 prepared oy
Ciba-Geigy Corp., Greensboro, N.C. , CDL:241243-D)
Balasubramanian, K. ; Nixon, W; Ross, J. (1978) Validation of
Analytical Method AG-323 for the Determination of Residues of CGA-
48'J88 and its Acid Metabolite CGA-62826 in Soil: ABR-78048.
(Unpublished study received July 13, 1978 under 100-EUP-62; prepared
by Ciba-Geigy Corp. , Greensboro, N.C. , CDL:234438-B)
Balasubramanian, K; Ross, J. (1978) The Determination of CGA-48983
and its Metabolities in Tobacco as 2. 6-Dimcthylaniline using
Phosphoric Acid Reflux: Method AG-330 dated November 7, 1978.
(Unpublished study received October 31, 1979 under 100-607 prepared
by Ciba-Geigy Corp. Greensboro, N.C., CDL:241246-D)
Balasubramenian, K. ; Ross, J. (1978) Specificity of Analytical Method
AG-325 for the Determination of Residues of CGA-48988 in Potatoes:
ABR:78052. (Unpublished study received September 5, 1978 under 100-
EUP-1, 8G2121 submitted by Ciba-Geigy Corp. , Greensboro, N.C. , CDL:
097389-C)
Balasubramanian, K. ; Ross, J. (1979) Specificity of Analytical Method
AG-330 for the Determination of Total Residues of CGA-48988 in
Potatoes: ABR:79013. (Unpublished study received October 31, 1979
under 100-607 prepared by Ciba-Geigy Corp., Greensboro, N.C. , CDL:
241243-C)
Beavers, J. ; Fink, R. (1977) Acute Oral LD50-Mallard Duck CGA-48983
Technical, Final Report. (Unpublished study received July 13, 1978
under 100-EUP-62; prepared by Wildlife International Ltd. for Ciba-
Geigy Corporation, Greensboro, N.C. , CDL.-234439-D)
-------
:0052 Beavers, J. ; Fink, R. (1977) Eight-day Dietary LC5Q-Bobwhite Quail
CGA-48988 Technical, Final Report: Project No. 108-147.
(Unpublished study received July 13, 1978 under 100-EUP-62; prepared
by Wildlife International Ltd. for Ciba-Geigy Corp., Greensboro, N.C. ,
CDL:234439-F)
:0053 Beavers, J.; Fink, R. (1977) Eight-day Dietary LC50-Mallard Duck,
CGA-48988, Final Report: Project No. 108-148. (Unpublished study
received July 13, 1978 under 100-EUP-62; prepared by Wildlife
International Ltd. for "Ciba-Geigy Corp., Greensboro, N.C., CDL:234439-
H)
:0076 Birkhard, N. (1976) Hydrolysis of CGA-48988 under Laboratory
Conditions: AC 2.52, Project Report 26/76. (Unpublished Study
received July 13 1978 under 100-EUP-62; preapced by Ciba-Geigy Ltd.,
Basle, Switzerland, CDL:234438-C)
:0077 Burkhard, N. (1977).Volatilization of CGA-43988 from Soil Under
Laboratory Conditions: AC 2.52, Project Report 29/77. (Unpublished
study received July 13, 1978 under 100-EUP-62; prepared by Ciba-
Geigy Ltd., Basle, Switzerland; CDL:234438-D)
:0100 Burkhard, N. (1978) Photolysis of CGA-48988 (Ridomil1" ' in Aqueous
Solution under Artifical Sunlight Conditions: AC 2.52, Project Report
12/79. (Unpublished study received April 26, 1979 under 100-600;
prepared by Ciba-Geigy Corp. Greensboro, N.C. ; CDL:238231-F)
:0078 Burkhard, N. (1978) Photolysis of CGA-48988 (Ridomil on Soil
Surfaces under Artificial Sunlight Conditions: AC 2.52, Project
Report 09/78. (Unpublished study received July 13, 1978 under 100-EUP-
62; prepared by Ciba-Geigy Ltd., Basle, Switzerland; CDL:234438-E)
:0160 Ciba-Geigy Corporation (1978) Ciba-Geigy Technical CGA-48938—Product
Chemistry Information. (Unpublished study received July 13, 1978
under 100-EUP-63; CDL:234427-A)
:0161 Ciba-Geigy Corporation (1978) CGA-48988 2EC—Product Chemistry
Information. (Unpublished study received July 13, 1978 under 100-EUP-
63; CDL:234427-A)
:0126 Ciba-Geigy Corporation (1978) Residue Reports of CGA-48988 on
Potatoes. (Unpublished study that includes AG-A 4903, AG-A 4903 2nd
Rept. , AG-A 4935, AG-A 4936, AG-A 4936 2nd Kept. , AG-A 4937, AG-A 4937
I-III 2nd Rept. , AG-A 4977, AG-A 4977 2nd Rept. , AG-A 4978, AG-A 4978
2nd Rept., AG-A 4979, AG-A 4979 2nd Rept., AG-A 4998, AG-A 4998 I-II,
2nd Rept., AG-A 6038, AG-A 6038 2nd Rept., 3rd Rept. , 4th Rept., 5th
Rept., AG-A 6039, AG-A 6039 2nd Rept. received September 5, 1978 under
100-EUP-l, 8G2121 submitted by Ciba-Geigy Corp., Greensboro, N.C. ,
CDL:097389-A)
-------
:0127 Ciba-Geigy Corporation (1978) Residue Reports - Metalaxyl Total
Analyses. (Unpublished study that includes NC AG-A 4732 II, IV 2nd
Rept., VA AG-A 4778 II, III 2nd Rept. , TO AG-A 4785 III 2nd Rept. , MD
AG-A 4789 II, III 2nd Rept., GA AG-A 4799 2nd Rept. , received October
31, 1979 under 100-607; CDL:241246-B)
:0128 Ciba-Geigy Corporation (1978) Residue Reports Tobacco - Metalaxyl
Parent Analyses. (Unpublished study that includes NC AG-A 4732 II,
IV; VA AG-A 4778 II, III; TN AG-A 4785 III; MD AG-A 4789 II, III; GA
AG-A 4799, received October 31, 1979 under 100-607; CDL:241246-A)
:0129 Ciba-Geigy Corporation (1979) Residue Reports—Rotational Studies.
(Unpublished study that includes [NY1 AG-A 5027 I, II, III A; AG-A
5118 I, IIA; AG-A 5119 I, II; AG-A 5131; [NC] AG-A 5146 I, II; AG-A
5209 I, II; AG-A 5210 I, II; AG-A 5211 I, II; AG-A 5342 received
October 31, 1979 under 100-607; CDL: 241.243)
:0107 Ciba-Geigy Corporation (1980) Interim Report: Fourth Metalaxyl Ground
Water Monitoring Project Status Report, Tobacco-Suwanee County,
Florida and the Tobacco Experimental Farm, MD. (Unpublished study
received November 14, 1980 under 100-607 prepared by Ciba-Geigy Corp.,
Greensboro, M.C. ; CDL:273743-A)
:0037 Coate, W. (1980) Final Report: Subacute Inhalation Toxicity Sturiy in
Rats, CGA-48988 (Metalaxyl)—Spiked Cigarettes: Rroject No. 483-187.
(Unpublished study received April 29, 1980 under 100-607 prepared by
Hazleton Laboratories America for Ciba-Geigy Corp., Greensboro, M.C. ;
CDL:242398)
:0044 Cozens et al. (1930) Rat reproduction study (Unpublished study
received 1981; prepared by Huntington Research Centre for Ciba-Geigy
Corp., Greensboro, M.C. ; CDL: 070015)
:0045 de'ward et al. (1980) Subchronic oral toxicity in dogs (Unpublished
study received 1981; prepared by Elars Bioresearch Laboratories Inc. ,
for Ciba-Geigy Corp., Greensboro, II.C. ; CDL: 070016)
:0101 Doebbler, G. (1979) Investigation of the Metabolism by Activated-
Sludge of the Compound CGA-48988: 11506-96. (Unpublished study
received April 26, 1979 under 100-600; prepared by Union Carbide
Environmental Services, submitted bv Ciba-Geiqy Corp. , Greensboro,
N.C. , CDL:238231-G)
:0011 Drake, J. (1977) Three-Months Dietary Study in Rats with Conpounri CGA-
43988. (Unpublished study received July 13, 197C under 100-EUP-62
prepared by Geigy Pharmaceuticals, Wilmslow, Cheshire for Ciba-Geigy
Ltd., Basle, Switzerland; CDL.-234428-H)
-------
:0062 E.G. and G. Bionomics (1930) Metalaxyl life cycle test- Daphnia
maona (Unpublished study received Jan. 1981 under 100-607 prepared
for Ciba-Geigy Corp., Greensboro, H.C.; CDL: 244133)
:0063 E.G. and G. Bionomics (1980) Metalaxyl embryolarvae test-Fathead
minnow (Unpublished study received Jan. 1981 under 100-607 prepared
for Ciba Geigy Corp. , Greensboro, N.C. ; CDL: 244183)
:0079 Ellgehaysen, H. (1977) Distribution and Degradation of CGA-48988
Ridomil in a Field Soil: AC 2.52. Project Report 55/77.
(Unpublished study received July 13, 1978 under 100-EUP-62 prepared
by Ciba-Geigy Ltd., Basle, Switzerland; CDL:234438-F)
:0080 Ellgehausen, H. (1977) Distribution of the tton-Extractable
Radioactivity between Different Soil Organic Matter Fractions of a
Field Soil Treated with C-Labeled CGA-48988: Project Report 56/77,
Addendum to Project Report 55/77. (Unpublished study received July
13, 1978 under 100-EUP-62 prepared by Ciba-Geigy Ltd'., Basle,
Switzerland, CDL:234438-G)
:0081 Ellgehausen, H. (1978) Degradation of CGA-48988 Ridomil in Soil
Under Aerobic, Aerobic/Anaerobic and Sterile/Aerobic Conditions: AC
2.52, Project Report 08/78. (Unpublished study received July 13, 1978
under 100-EUP-62 prepared by Ciba-Geigy Ltd., Basle, Switzerland, CDL:
234438-H)
:0102 Ercegovich, C (1979?) The Effects of N-(2,6-Dimethylphenyl)-N-
(Methoxyacetyl)-Alanine Methyl Ester on Soil Miorcorganisms.
(Unpublished study received April 26, 1979 under 100-600 prepared by
Penn. State University; submitted by Ciba-Geigy Corp., Greensboro,
N.C. , CDL:238231-J)
:0103 Ercegovich, C.; Bogus, E. (1979?) Effects of [N-(2,6-dimethylphenyl)-
N-(mŁthoxyacetyl)-a^anine methyl esjer] (CGA-48988) on the Degradation
of C-cellulose, C-proteih, and C-starch in Soil.
(Unpublished study received April 26, 1979 under 100-600 prepared
by Penn. State University, submitted by Ciba-Geigy Corp., Greensboro,
N.C. , CDL:238231-K)
:0104 Ercegovich, C. ; Vallejo, R. , Bogus, E. (1979?) The Effects of 5,25,
and 125 ppm of CGA-48988 [N-(2,6-Dimethylphenyl)-N-(MethoxyacetyD-
Alanine methyl ester on Soil Nitrification. (Unpublished study
received April 26, 1979 under 100-600 prepared by Penn. State
University, submitted by Ciba-Geigy Corp. , Greensboro, !'.C. , CDL:
238231-L)
:0012 Finn, J. (1977) CGA-48988 Ninety-one Day Dietary Toxicity Study in
Beagle Dogs: Report No. 653/38014. (Unpublished study received
July 13,1978 under 100-EUP-62 prepared by Hazleton Laboratories
Europe Ltd. for Ciba-Geigy Ltd., Basle, Switzerland; CDL:234428-1)
-------
:00y9 Fischer, W. ; Cassidy, J. (1978) Balance annd Metabolism of 0- C-
CGA-48988 in Potatoes: Report ABR-78001. (Unpublished study received
July 13, 1978 under 100-EUP-62 prepared by Ciba-Geigy Corp.,
Greensboro, N.C., CDL: 234438-1)
:0083 Fischer, U, ; Cassidy, J. (1978) Uptake and Characterization of 0-
C-CGA-40988 and its Soil Metabolites in Rotation Lettuce: ABR-
78078. (Unpublished study received October 31, 1979 under 100-607
prepared by Ciba-Geigy Corp., Greensboro, N.C. , CDL:241243-G)
:0085 Fischer, U ; Cassidy, J. (1978) Uptake and Characterization of 0-
C - CGA-48938 and its Soil Metabolites in Rotation Winter Wheat:
ABR-78077. (Unpublished study received October 31, 1979 under 100-607
prepared by Ciba-Geiqy Corp. , Greensboro, N.C. , CDL:241243-F)
:0032 Fischer, W. ; Cassidy, J. (1979) Uptake and Characterization of 0-
C-CGA-48988 and its Soil Metabolites in Field Rotation Corn: A3R-
79004. (Unpublished study received October 31, 1979 under 100-607
prepared by Ciba-Geigy Corp., Greensboro, N.C. , CDL:241243-1)
:0084 Fischer, W. ; Cassidy, J. (1979) Uptake annd Characterization of 0-
C-CGA-48988 and its Soil Metabolites in Field Rotation Spring
Oats: ABR-79002. (Unpublished study received October 31, 1979 under
100-607; prepared by Ciba-Geigy Corp. , Greensboro, N.C. , CDL:241243-H)
:0131 Fischer, W. ; Foster, R. , Cassidy, J. (1978) Balance and Metabolism of
0- C-CGA-48988 in a Lactating Goat: ABR-78046. (Unpublished
study received September 5, 1978 under 100-EUP-l, 3G2J.21; prepared by
Ciba-Geigy Corp., Greensboro, N.C. , CDL:097388-D)
:0036 Foster, R. ; Fischer, W. , Cassidy, J. (1978) Uptake of 0-14C-CGA-
48988 in Potatoes Grown in a Field Plot-Preparation of Rotational
Plots: ABR-78013. (Unpublished study received October 31, 1979 under
100-607 prepared by Ciba-Geigy Corp., Greensboro, N.C. , CDL: 241243-J)
:0055 Fratus, G. ; Buccafusco, R, (1978) Acute Toxicity of CGA-48988
Technical to Bluegill (Lepomis macrochirus); Report Ł BU-78-12-
381. (Unpublished study received January 25, 1979 under 100-601,
prepared by EG & G Bionomics Laboratory for Ciba-Geigy Corp.,
Greensboro, N.C. , CDL:236854-A)
:0056 Fratus, G. ; Buccafusco, R. (1978) Acute Toxicity of CGA-48988
Technical to Rainbow Trout (Salmo gairdneri); Report 4 BW-78-12-
376. (Unpublished study received January 25, 1979 under 100-601,
prepared by EG & G Bionomics Laboratory for Ciba-Geigy Corp. ,
Greensboro, N.C., CDL:236854-B)
-------
:0013 Fritz, H. (1978) Dominant Lethal Study-CGA 48988 Tech. Mouse — Test
foe Cytotoxic or Mutagenic Effects on Male Germinal Cells: Experiment
No. 327761. (Unpublished study received July 13, 1978 under 100-EUP-
62; prepared by Ciba-Geigy Ltd., Basle, Switzerland, CDL:234428-L)
:0014 Fritz, II. (1978) Reproduction Study CGA-48988 Tech. Rat Seg. II—Test
foe Teratogenic or Embryotoxic Effects: Experiment No. 227716.
(Unpublished study received July 13, 1978 under 100-EUP-62; prepared
by Ciba-Geigy Ltd., Basle,-Switzerland; CDL:234428-J)
:0105 Glinski, D. (1978) Effects of CGA-48988 on the Performance of the
Activated Sludge Process. (Unpublished study received April 26, 1979
under 100-600 prepared by Union Carbide Environmental Services,
submitted by Ciba-Geigy Corp., Greensboro, N.C. , CDL:233231-0)
:0132 Gross, D. (1977) Metabolism of CGA-48988 in Field Grow Potato Plants:
AC 2.52, Rroject Report 30/77. (Unpublished study received September
5, 1978 under 100-EUP-l, 8G 2121; prepared by Ciba-Geigy Ltd., Basle,
Switzerland; CDL:097388-C)
:0087 Guth, J. (1976) Leaching Model Study with the Fungicide CGA-48988 in
Four Standard Soils: Project Report 30/76. (Unpublished study
received July 13, 1978 under 100-EUP-62 prepared by Ciba-Geigy Ltd. ,
Basle, Switzerland; CDL:234438-K)
-------
:0091 Hamilton, T. ; Fischer,,U. ; Cassidy, J. (1979) Uptake and
characterization of 91- C-CGA-43988 and its Soil Metabolites in
Field Rotation Sugar beets: ABR-79005. (Unpublished study received
October 31, 1979 under 100-607 prepared by Ciba-Geigy Corp.,
Greensboro, N.C., CDL:241243-L)
:0166 Heinrichs, L. (1978) Analysis of CGA-48988 in Formulations by Gas
Chromatograpny: Method No. PA-173-T. (Unpublished study received July
13, 1978 under 100-EUP-63; prepared by Ciba-Geigy Corp., Greensboro,
tl.C. ; CDL:234427-A)
:0164 Heinrichs, L. (1978) Analysis of CGA-48988 Technical and Related
Impurities by Gas Chromatography: Methods PA-172-T and PA-173-T.
(Unpublished study received July 13, 1978 under 100-EUP-63; prepared
by Ciba-Geigy Corporation, Greensboro, N.C. , CDL:234427-A)
:0106 Honeycutt, R. ; Cassidy, J. (1973) Uptake and Balance of C-CGA-
48988 and its Metabolities in Greenhouse Grown Bright and Bur ley
Tobacco: ABR-78036. (Unpublished study received July 13, 1978 under
100-EUP-62; prepared by Ciba-Geigy Corp. , Greensboro, N.C. , CDL:
234438-N)
:0136 Honeycutt, R. ; Fischer, tv. , Cassidy, J. (1979) Uptake and Balance of
0- C-CGA-48988 and its Metabolites in Field Grown Bright Tobacco:
ABR-79100. (Unpublished study received October 31, 1979 under 100-607
prepared by Ciba-Geigy Corp., Greensboro, N'.C. , CDL:241245-B)
:0137 Honeycutt, R. ; Szolics, I., CassiHy, J. (1978\ Balance and
Characterization of Pyrolysis Products of 0- C-CGA-48988 and its
Metabolites in Cigarettes containing Bright and Bur ley Tobacco treated
with 0- C-CGA-48938: ABR-78040. (Unpublished study received
July 13, 1978 under 100-EUP-62; prepared by Ciba-Geigy Corp.,
Greensboro, II.C. , CDL:234431-B)
:0139 Honeycutt, R. ; Szolics, I., Simoneaux, B. , Cassidy, J. (1979)
Identification of the Major Aglycones of 0- C-CGA-48983
Conjugated Metabolites in Cured Greenhouse Grown Bright Tobacco: ABR-
79003. (Unpublished study received October 31, 1979 under 100-607
prepared by Ciba-Geigy Corp., Greensboro, N.C. , CDL.-241245-A)
:0017 Kapp, R. ; Piccirillo, V. (1973) Acute Dermal Toxicity Study in
Rabbits, CGA-48988 2EC, Final Report: Project No. 483-149.
(Unpublished study received July 13, 1978 under 100-EUP-62; prepared
by Hazleton Laboratories America, Inc. for Ciba-Geigy Corp. ,
Greensboro, N.C. , CDL:234429-C)
-------
:0018 Kapp, R.; Piccirillo, V. (1978) Acute Oral Toxicity Study in Male and
Female Albino Rats, CGA-48988 2EC, Final Report: Project No. 483-148.
(Unpublished study received July 13, 1978 under 100-EUP-62; prepared
by Hazleton Laboratories America, Inc. for Ciba-Geigy Corp.,
Greensboro, N.C., CDL:234429-B)
:0019 Kapp, R.; Piccirillo, V. (1978) Primary Skin Irritation Study in
Rabbits, CGA-48988 2EC, Final Report: Project No. 483-151.
(Unpublished study received July 13, 1978 under 100-EUP-62; prepared
by Hazleton Laboratories America, Inc. for Ciba-Geigy Corp.,
Greensboro, N.C., CDL:234429-E)
:0092 Lsdd, S.; Enos, J. (1979) Kinetics of (&-14C-CGA-48988 in a Model
Aquatic Ecosystem: Report 8BW-78-10-328. (Unpublished study received
April 26, 1979 under 100-600; prepared by EG&G, Bionomics for Ciba-
Geigy Corp.; Greensboro, N.C.; CDL:238232-G).
14
:0093 Ladd, S. ; Wilson, W. (1979) Accumulation and Elimination of C-
Residues by Bluegill Sunfish (Lepomis macrochirus) Exposed to 0-
C-CGA-48988. Report SBW-78-10-328. (Unpublished study received
April 26, 1979 under 100-600; preapred by EG&G, Bionomics for Ciba-
Geigy Corp., Greensboro, N.C.; CDL:23S232-E)
:0057 LeBlanc, G. (1977) Acute Tbxicity of CGA-48988 Technical to the Vteter
Flea (Daphnia maana). (Unpublished study received July 13, 1978
under 100-EUP-62; prepared by EGsG, Bionomics for Ciba-Geigy
Corporation, Greensboro, N.C.; CDL:234439-C)
:0058 LeBlanc, G.; Gary, G. (1978) Acute Ibxicity of CGA-48988 to the Water
Flea (Daphnia magna); Report #BW 78-12-364. (Unpublished study
received Jan. 25, 1979 under 100-601, prepared by EG&G Bionomics
Laboratory for Ciba-Geigy Corp., Greensboro, N.C. ; CDL:236854-C)
:0043 Life Science Research (1980) CGA-48988 Toxicity and Carcinogenicity
in Dietary Administration to Rats for 105 Weeks. (Unpublished report
prepared by Life Science Research, Suffolk, England, submitted by Ciba-
Geigy Corp., Greensboro, N.C.; CDL:241771-A)
:0067 McCann (1979) Acute LC50 of metalaxyl in rainbow trout and bluegill
sunfish (Unpublished study prepared by EPA Laboratories, Beltsville,
Maryland)
:0068 McCann (1979) 48-hour LC50 in Daphnia magna (Unpublished study
prepared by EPA Laboratories, Beltsville, Maryland)
:0064 McCann (1979) 96-hoir LC50 in bluegill sunfish of E.C. metalaxyl
(Unpublished study prepared by EPA Laboratories, Beltsville,
Maryland)
-------
:0065 McCann (1979) 96-hour LC50 in rainbow trout of E.G. metalaxyl
(Unpublished study prepared by EPA laboratories, Beltsville,
Maryland)
:00% Nixon, w. (1978) Gas Chroma tographic Method for the Determination of
Residues of CGA-48988 and its Acid Metabolite CGA-62826 in Soil:
Method AG-323. (Unpublished study received July 13, 1978 under 100-
EUP-62; prepared by Ciba-Geigy Corp., Gteensboro, N.C. ; CDL:234438-O)
:0103 Nixon, VI. (1980) Protocol: Ridomil Mobility Study—Fort Pierce
Research Station, Florida. (Unpublished study received November 14,
1980 under 100-607 prepared by Ciba-Geigy Corp., Greensboro, N.C. ;
CDL:243743-B)
:0020 Piccirillo, V. (1978) Acute Eye Irritation Study in Rabbits, CGA-48933
2EC, Final Report: Project No. 483-150. (Unpublished study received
July 13, 1978 under 100-EUP-62; prepared by Hazleton Laboratories
America, Inc. for Ciba-Geiqy Corp. , Greensboro, N.C; CDL:234429-D)
:0021 Piccirillo, V. (1978) Acute Inhalation Tbxicity Study in Rats, CGA-
48988 2EC, Final Report: Project No. 483-152. (Unpublished study
received July 13, 1978 under 100-EUP-62; prepared by Hazleton
Laboratories America, Inc. for Ciba-Geigy Corp., Greensboro, N.C. ;
CDL:234429-F)
:0023 Sachsse, K. ; Cathe, R. (1976) Acute Dermal LD5Q in the Rat of
Technical CGA-48988: Project No. Siss 5388. Tunpublished study
received July 13, 1978 under 100-EUP-62; prepared by Ciba-Geigy Ltd.,
Basle, Sv/itzerland; CDL:234428-D)
:0026 Sachsse, K; Bathe, R. (1976) Acute Oral LD5Q in the Rat of Technical
CGA-48988: Project No. Siss 5338. (Unpublished study received July
13, 1978 under 100-CUP-62; prepared by Ciba-Geigy, Ltd., Basle,
Switzerland; CDL:234428-B)
-.0059 Sacnsse, K. ; Bathe, R. (1976) Acute Ibxicity to Rainbow 'Irout, Carp,
Catfish, Bluegill and Guppy of Technical CGA-48988: Project No. Siss
5388. (Unpublished study received July 13, 1978 under 100-EUP-62;
prepared by Ciba-Geigy Ltd., Basle, Switzerland; CDL:234439-B)
:0029 Sachsse, K. ; Ullmann, L. (1976) Acute Dermal LD50 in the Rabbit of
Technical CGA-48988: Project No. 408378, Siss 6547. (Unpublished
study received July 13, 1978 under 100-EUP-62; prepared by Ciba-Geigv,
Ltd., Basle, Switzerland; CDL:234439-L)
:0061 Sachsse, K., Ullmann, L. (1976) Eight-day Feeding Tbxicity in the
Japanese- Quail of Technical CGA-48988: Project No. Siss 5388.
(Unpublished study received July 13, 1978 under 100-EUP-62; prepared
by Ciba-Geigy, Ltd.; Basle, Switzerland; CDL:234439-G)
-------
:0031 Sachsse, K., Ullmann, L. (1976) Eye Irritation in'the Rabbit of
Technical CGA-48988: PC eject No. 5388. (Unpublished study received
July 13, 1978 under 100-EUP-62; prepared by Ciba-Geigy, Ltd., Basle,
Switzerland; CDL:234428-F)
:0032 Sachsse, K. , Ullmann, L. (1976) Eye Irritation in the Rabbit after
Single Application of Technical CGA-48988: Project No. 5388.
(Unpublished study received July 13, 1978 under 100-EUP-62; prepared
by Ciba-Geigy, Ltd., Basle, Switzerland; CDL:234428-E)
:0033 Sachsse, K. ; Ullmann, L. (1976) Skin Sensitizing (Contact Allergenic)
Effect in Guinea Pigs of Technical CGA-48988: Project No. Siss 5388.
(Unpublished study received July 13, 1978 under 100-EUP-62; prepared
by Ciba-Geigy, Ltd., Basle, Switzerland; CDL:234428-G)
:0143 Seim, V. (1978) Biological Report for the Metabolism of 0-14C-CGA-
48988 in a Lactating Goat: BIOL-78002. (Unpublished study received
Sept. 5, 1978 under 100-EUP-l, 8G2121; prepared by Ciba-Geigy Corp.;
Vero Beach, Fla.; CDL:097388-E)
:0041 Toxigenics (1980) Metalaxyl 21-day dermal toxicity test (Unpublished
study received Jan. 1981 under 100-607; submitted by Ciba Geigy Corp.,
Greensboro, N.C.; CDL: 244182)
-------
OFFICE OF PESTICIDE PROGRAMS
PESTICIDE DOCUMEtn1 MANAGEMENT SYSTEM
CASE BIBLIOGRAPHY
Section 2: Citations Examined and Judaed to be Citations Inappropriate
for Use in Developing the Standard
GS-0081:
-.0116 Balasubremanian, K. ; Nixon, W. (1978) The Determination of CGA-48938
and its Metabolites in Tobacco as 2,6-Dimethylaniline using Phosphoric
Acid Reflux. Method AG-330. (Unpublished study received October 31,
1979 under 100-607 prepared by Ciba-Geigy Corp., Greensboro, N.C.;
CDL:241243-E)
:0118 Balasubrairwnian, K. ; Nixon, W; Ross, J. (1978) Validation of Method
AG-325 for the Determination of CGA-48988 Residues in Tobacco: ABR-
78039. (Unpublished study received July 13, 1978 under 100-EUP-62
prepared by Ciba-Geigy Corp., Greensboro, N.C., CDL:234432-B)
:0122 Balasubramanian, K. ; Ross, J. (1979) Validation of Method AG-330 for
the Determination of CGA-43988 and its Metabolites containing the 2,6-
Dimethy Ian lime Caramon Moiety in Tobacco: ABR-79016. (Unpublished
study received October 31, 1979 under 100-607; prepared by Ciba-Geigy
Corp., Greensboro, N.C. , CDL:241246-C)
:0074 Ballantine, L. (1979) CGA-48988: Environmental Impact Statement—
Summary of Environmental Chemistry Information: ABR-79041.
(Unpublished report received October 31, 1979 under 100-607 prepared
by Ciba-Geigy Corp. , Greensboro, N.C. , CDL:241243-B)
:0075 Ballantine, L. (1979) Rotational Qrog Data Submitted in Support of
Conditional Registration for Ridonil (Metalnxyl) Use on Tobacco:
ABP-79099. (Unpublished study received October 31, 1979 under 100-
607 prepared by Ciba-Geigy Corp., Greensboro, N.C. , CDL:241243-A)
:0072 Ballantine.^L.; Fischer, W. (1978) Environmental Investigations
Protocol, C-Fish Residue Bioaccumulation Study Soil-Water-Fish
tlodel Aquatic Ecosystem. (Unpublished study received April 26, 1979
under 100-600; prepared by Ciba-Geigy Corp. , Greensboro, N.C. , CDL:
238232-H)
:0073 Ballantine, L. ; Fisher,^'. (1978) Environmental Investigations
Protocol; Flow-Through C-Fish Residue Accumulation Study.
(Unpublished study received April 26, 1979 under 100-600 prepared by
Ciba-Geigy Corp., Greensboro, N.C. , CDL:238232-F)
-------
:0002 Bathe R. (1978) Acute Oral LD,-n in the Rat of CGA-48988 35 VJP (A-
6038 A): 785188 GU 2.1. (Unpublished study received August 30, 1979
under 100-608; prepared by Ciba-Geigy Ltd., Basle, Switzerland;
CDL:241049-B)
:0003 Cannelongo, B. (1978) Rabbit Eye Irritation, CGA-48988 2E-G: Project
No. 973-78. (Unpublished study received March 1979 under 100-EUP-63;
prepared by Stillmeadow, Inc. for Ciba-Geigy Corp., Greensboro, N.C.,
CDL:237807-D)
:0004 Cannelongo, B. (1978) Rabbit Primary Skin Irritation, CGA-48988 2E-G:
Project No. 974-78. (Unpublished study received March 1979 under 100-
EUP-63; prepared bv Stillmeadow, Inc. for Ciba-Geigy Corp.,
Greensboro, N.C.; CDL:237807-E)
:0005 Cannelongo, B. (1979) Rabbit Acute Dermal Toxicity, CGA-48988 2E-G:
Project No. 972-78. (Unpublished study received March 1979 under 100-
EUP-63; prepared by Stillmeadow, Inc. for Ciba-Geigy Corp.,
Greensboro, N.C., CDL:237807-C)
:0123 Cassidy, J. ; Ross, J. (1978) Summary of Section D CGA-48988—Tobacco;
Results of Tests on the Amounts and Nature of Residues in Tobacco and
its Smoke: ABR-78045. (Unpublished report received July 13, 1978
under 100-EUP-62 prepared by Ciba-Geigy Corp., Greensboro, N.C., CDL:
234430)
:0124 Cassidy, J. ; Ross, J. (1979) Summary of Section D, Metalaxyl (CGA-
48988) - Tobacco—Results of Tests on the Amounts and Nature of
Metalaxyl Residues in Tobacco and its Smoke: ABR-79103. (Unpublished
study received October 31, 1979 under 100-607; prepared by Ciba-Geigy
Corp., Greensboro, N.C. , CDL:241244)
:0141 Ciba-Geigy Corporation (197-7) Residues in Soil—CGA-48988 SOW Applied
to Tobacco. (Unpublished study that includes AG-A 4604 I, II, III,
IV, V, VI-A received April 26, 1979 under 100-600; prepared by North
Carolina State Univ. Tobacco Research Station, Reidsville, w.C. for
Ciba-Goigy Corp., Greensboro, N.C. ; CDL.-238232-J)
:0162 Ciba-Geigy Corporation (1978) CGA-48988 5W Chemical Data. (Unpublished
study received September 5, 1978 under 100-600; CDL: 235063-A)
:0006 Ciba-Geigy Corporation (1978) Full Reports of Investigation§ made
with respect to the Safety of Pesticide CGA-48988 (Ridiomil 2E—
Sunraary of Acute Toxicology Information, ('inpublished study received
July 13, 1978 under 100-EUP-62; CDL:234429-A)
:0007 Ciba-Geigy Corporation (1973) Full Reports of Investigations Made with
Respect to the Safety of the Pesticide CGA-48988 Technical—Summary of
Toxicology Information. (Unpublished report received July 13, 1978
under 100-EUP-62; CDL:234428-A)
-------
:0054 Ciba-Geigy Ccrpcration (1978) Reports of Investigations Made with
Respect to the Safety of CGA-48988 Technical to Representative
Wildlife Species—Environmental Safety Summary. (Unpublished report
received July 13, 1978 under 100-EUP-62; CDL:234439-A)
:0125 Ciba-Geigy Corporation (1978) Residues in Soil-Soil Dissipation.
(Unpublished study that includes AG-A 4813 I, II, III, IV received
April 26, 1979 under 100-600; CDL:238232-L)
:0149 Ciba-Geigy Corporation (1978) Residues in Soil—CGA-48'J88 SOW Applied
to Tobacco. (Unpublished study that includes AG-A 4604 VII received
April 26, 1979 under 100-600 prepared by North Carolina State Univ.
Tobacco Research Station, Reidsville, N.C.; CDL:238232-K)
:0163 Ciba-Geigy Corporation (1979) Apron 35 SD; Chemical Data Section.
(Unpublished study received August 30, 1979 under 100-608; CDL-241048)
:0008 Ciba-Geigy Corporation (1979) Full Repcrts^of Investigations made with
Respect to the Safety of Pesticide Ridomil (CGA-48988) 2E-G—
Summary of Acute Toxicology Information. (Unpublished study received
March 1979 under 100-EUP-63; CDL:237807-A)
:0009 Ciba-Geigy Corporation (1979) Summary-Reports on Investigations Made
with Respect to the Safety of the Pesticide CGA-48988 Ridomil 35 SD
(Apron 35 SD). (Unpublished study received August 30, 1979 under 100-
608; CDL: 241049-A)
:0010 Coate, W. (1978) Revised Final Report Four-Hour Acute Inhalation
Toxicity in Rats CGA-48988 2E-C: Project No. 483-167. (Unpublished
study received March 1979 under 100-EUP-63; prepared by Hazleton
Laboratories America, Inc. for Ciba-Geigy Corp. Greensboro, N.C. , CDL:
237807-F)
:0038 Elm Farm Laboratories (1979) CGA-48988—Potential Oncogcnicity in
Dietary Administration to Mice for a Period of 104 weeks: Summary 0-92
Weeks. (Unpublished report prepared by Elm Farm Laboratcries, Life
Science Research, Suffolk, England, submitted by Ciba-Geigy Corp. ,
Greensboro, N.C. ; CDL:241771-B)
:0133 Hermes, P. (1972) Biphasic Extraction of Radioactive Metabolites from
Treated Biological Material: Method AG-214 dated August 15, 1972.
(Unpublished study received September 5, 1978 under 100-EUP-L, 8G
2121; prepared by Ciba-Geigy Corp., Ardsley, NY; CDL:097390-A)
14
:0134 Hermes, P. (1973) Radioassay of C in Biological Materials by
Combustion using the Harvey Biological Material Oxidizcr (BMO):
Method AG-252 dated August 8, 1973. (Unpublished study received
September 5, 1978 under 100-EUP-l, 8G2121 prepared by Ciba-Geigy
Corp., Greensboro, N.C. , CDL:097390-D)
-------
:0138 Honeycutt, R.; Simoneaux, B., Szolics, I., Cgssidy, J. (1978)
Characterization of Polar Metabolites of 0- "C-CGA-48988 in
Greenhouse Grown Bright Tobacco: ABR-78044. (Unpublished study
received July 13, 1978 under 100-EUP-62; prepared by Ciba-Geigy Corp.,
Greensboro, N.C., CDL:234431-C)
:0165 Hoppe, T. (1978) Chemical Hazards Testing — Drying, Grinding and
Thermal Stability of CGA-48988-5W: CUT Ref: 62-78-09. (Unpublished
study received September 5, 1973 under 100-600; prepared by Ciba-
Geigy Corp., Tons River, N.J.; CDL:235063-B) •
:0040 Huntingdon Research Centre (1979) Summary of CGA-48988—
Multigeneration [Reproduction] Study: Test No. 77 0023. (Unpublished
report prepared by Huntingdon Research Centre, Huntingdon, England;
submitted by Ciba-Geigy Corp., Greensboro, N.C. ; CDL:241771-C)
:0094 Laskowski, D. (1979) Effects of Pesticides on Soil Microorganisms.
(Unpublished study received April 26, 1979 under 100-600; prepared by
Residue/Environniental/Metabolism Research, Agricultural Products
Dept., Dow Chemical U.S.A. Midland, MI; presented at lieed Science
Society Annual Meeting, San Francisco, 1979; CDL:238232-1)
:0147 Martin, G.; Boka, G.; Secrest, W.; Ryskiewich, D. (1978) Potassium
Hydroxide Fusion of CGA-48988 Derivatives and Treated Biological
Samples: ABR-78047. (Unpublished study received Oct. 31, 1979 under
100-607, prepared by Ciba-Geigy Corp., Greensboro, N.C.; CDL:241247-B)
:0095 Newby, L. (1978) CGA-48988: Environmental Impact Statement: ABR-
78054. (Unpublished study received July 13, 1978 under 100-EUP-62
prepared by Ciba-Geigy Corp., Greensboro, N.C.; CDL:234438-A)
:f)148 Ramsteiner, K. (1978) Status Report: Method Development of CGA-43'J88,
January 1, 1978 — Mass Spectrometric Fragmentation of CGA-48988, Its
Metabolites and/or Reference Compounds. (Unpublished report received
Oct. 31, 1979 under 100-607 submitted by Ciba-Geigy Corp., Greensboro,
N.C. ; CDL:241247-C)
14
:0140 Roger, J. (19??) Radioassay of C 0_ by Acid Neutralization and
Subsequent Counting by Liquid Scintillation: Method AG-250 super cedes
AG-112. (Unpublished study received Sept. 5, 1978 under 100-EUP-l,
8G2121 prepared by Ciba-Geigy Corp., Greensboro, N.C.; CDL:097390-C)
:0022 Sabol, R. (1979) Rat Acute Oral Toxicity, CGA-48988 2E-G: Project Ito.
971-78. (Unpublished study received March 1979 under 100-EUP-63;
prepared by Stillmeadow, Inc. for Ciba-Geigy Corp., Greensboro, M.C. ;
CDL:237807-B)
-------
:0024 Sachsso, K. ; Bathe, R. (1976) Acute Intraper itoneal LD5Q in the Rat
of Technical CGA-48988: Project to. Siss 5388. (Unpublished study
received July 13, 1978 under 100-EUP-62; prepared by Ciba-Geigy, Ltd.,
Basle, Switzerland; CDL:234429-G)
:0025 Sachsse, K.; Bathe, R. (1976) Acute Oral LD5Q in the Mouse of
Technical CGA-48988: Project to. Siss 5388. (Unpublished study
received July 13, 1978 under 100-EUP-62; prepared by Ciba-Geigy, Ltd.,
Basle, Switzerland; CDL:234439-J)
:0027 Sachsse, K. ; Bathe, R, (1977) Acute Dermal LD™ in the Rat of CGA-
48988 liP 50 (A-55150A): Siss 5907 PH 2.635. TOnpublished study
received Aug. 30, 1979 under 100-608; prepared by Ciba-Geigy, Ltd. ,
Basle, Switzerland; CDL:241049-D)
:0028 Sachsse, K. ; Bathe, R. (1977) Acute Oral LD,n in the Rat of CGA-
48988 WP 50 (A-5514 A): Siss 5907 PH 2.635. (Unpublished study
received Aug. 30, 1979 under 100-608; prepared by Ciba-Geigy, Ltd.,
Basle, Switzerland; CDL:241049-C)
:0060 Sachsse, K. , Ullnann, L. (1976) Acute Oral LD,-n in the Japanese
Quail of Technical CGA-48988: Project Mo. Sisl 5388. (Unpublished
study received July 13, 1978 under 100-EUP-62; prepared by Ciba-Geigy,
Ltd.; Basle, Switzerland; CDL:234439-E)
:0030 Sachsse, K. , Ullmann, L. (1976) Acute Cral LD™ in the Rabbit of
Technical CGA-48988: Project to. Siss 5338. Tunpublished study
received July 13, 1978 under 100-EUP-62; prepared by Ciba-Geigy, Ltd. ,
Basle, Switzerland; CDL:234439-K)
:0034 Sachsse, K., Ullmann, L. (1977) Acute Dust Inhalation Toxicity in the
Rat of CGA-48988 WP 50 (A-55140A): Siss 5907 PH 2.635. (Unpublished
study received Aug. 30, 1979 under 100-608; prepared by Ciba-Geigy,
Ltd., Basle, Switzerland; CDL:241049-E)
i
:0035 Sachsse, K. ; Ullmann, L. (1977) Eye Irritation in the Rabbit of CGA-
48988 WP 50 (A-55140A): Siss 5907 PH 2.635. (Unpublished study
received Aug. 30, 1979 under 100-603; prepared by Ciba-Geigy, Ltd.,
Basle, Switzerland; CDL.-241049-F)
:0036 Sachsse, K.; Ullmann, L. (1977) Skin Irritation in the Rabbit after
Single Application of CGA 48988 t.P 50. (A-55140A): Siss 5907 PH
2.635. (Unpublished study received Aug. 30, 1979 under 100-608;
prepared by Ciba-Geigy, Ltd., Basle, Switzerland; CDL:241049-G)
:0142 Secrest, W. ; Honeycutt, R. (1977) Material Balance Determination on
Cigarettes Containing Tobacco with C Compounds: Method AG-318
dated September 9, 1977. (Unpublished study received July 13, 1978
under 100-EUP-62 submitted by Ciba-Geigy, Corp., Greensboro, N. C. ;
CDL:234433-G)
-------
:0144 Seim, V. (1978) Biological Report for the Metabolism of 0-14C-CGA-
48988 in Greenhouse Grown Tobacco When Applied as a Drench to Bright
Tobacco and Preplant Incorporated to Bur ley Tobacco: BIOL-78003.
(Unpublished study received July 13, 1978 under 100-EUP-62;pre-
pared by Ciba-Geigy Corp.; Vero Beach, Fla.; CDL:234431-D)
:0097 Simoneaux, B.; Hermes, P. (1973) Extraction of CGA-10832 Residues from
Soil: Method AG-254 dated August 10, 1973 supercedcs AG-219.
(Unpublished study received Sept. 5, 1978 under 100-EUP-l, 8G2121
prepared by Ciba-Geigy Corp.; Ardsley, NY; CDL:097390-E)
:0098 Simoneaux, B.; Roger, J. (1972) Blending.of Soils and Homogenization
of Biological Materials for Radioassay and Extraction: Method AG-223
dated Oct. 5, 1972. (Unpublished study received Sept. 5, 1978 under
100-EUP-l, 8G2121 prepared by Ciba-Geigy, Corp., Ardsley, NY;
CDL:097390-B)
:0145 Thomas, R. ; Hermes, P. (19??) High Voltage Electrophoresis for
Characterization of Charged Radioactive Metabolites: Method AG-300.
(Unpublished study received Sept. 5, 1978 under 100-EUP-l, 8G2121
prepared by Ciba-Geigy Corp.; Ardsley, NY; CDL:097390-G)
:0146 Wolf, M, ; Sumner, D. (1974) Statistical Methods in the Measurement of
Radioactivity: Method AG-276 dated Jan. 1, 1974. (Unpublished study
received Sept. 5, 1978 under 100-EUP-l, 8G2121 prepared by Ciba-Geigy,
Corp.; Ardsley, NY; CDL.-097390-F)
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