S-EPA
             United States
             Environmental Protection
             Agency
             Office of
             Pesticides and Toxic Substances
             Washington DC 20460
September 1980
             Pesticides
5-Ethoxy-3-trichloromethyl
    -  1,2,4-thiadiazole
         Terrazole
Pesticide Registration
Standard

-------
                      Registration Standard
                               for
                     Prod in ts Containing the       R
                 Single Active Ingredient Terrazole
         Gregory A. Thies, project Manager  (SPRD)
         Hank Appleton, Environmental Chemist (HED, EFB)
         Diane Beavers, Predict Manager  (RD)
         William Boodee, Chemist (HED, RGB)
         Rodger Gardner, "lexicologist (HED, TB)
         Robert Hoist,  Plant Physiologist  (HED, EEB)
         John Tice, Wildlife Biologist (HED, EEB)
A special thanks is extended to Donna Peacher, Jerry Moore and
Juanita Wills for their assistance during this project.
                         September, 1980
            Office of Pesticides and Toxic Substances

                 Environmental Protection Agency
                 401 M Street, S.W.
                 Washington, D.C. 20460

-------
                               TABLE CF CONTENTS


                                                                   Page

Chapter 1 - Haw to Register Under a Registration Standard
    Organization of the Standard	    1
    Purpose of the Standard  	    1
    Requirements for Re-reg istration Under the Standard   	    3
    "Product specific" Data and "Generic" Data  	    3
    Data Compensation RequironentsqUnder FIFRA 3(c) (1)(D)   	    4
    Obtaining Data to Fill "Data Gaps;" FIFRA 3(c)  (2)(B)   	    5
    Amendments to the Standard  	    5

Chapter 2 - Regulatory Position
    Introduction
    Generic Data Requiranents  	    3
         Manufacturing-Use Terrazola	  12
         End-Use formulations of TerraaDle   	  13

Chapter 3 - Product Chemistry
    Topical Discussions
         Chemical Identity	  25
         Manufacturing Process  	  26
         Formation of Unintentional Ingredients  	  27
         Percentages of Active Ingredient  	  27
         Product Analytical Methods and Data  	  29
         Physical Chemical Properties	  29
    Disciplinary Review
         Chemistry Profile  	  31
         Gener ic Data Gaps  	  31
         Suggested Label ing  	  32
    Bibliography  	  33

Chaper 4 - Environmental Fate
    Usa Profile  	  34
    Topical Discussions
         Physico-Chemical Transformation  	  35
         Metabolian  	  3G
         Mobility  	  45
         Field Dissipation  	  47
         Accumulation  	  43
    Disciplinary Review
         Environmental Fate Profile  	  51
         Exposure Profile  	  53
         Generic Data Gaps  	  55
         Suggested Label ing  	  55
    Bibliography  	  55

-------
Chapter 5 - Toxicology
    Topical Discussions
         Metabolism and Fharmacodynamics   	   58
         /cute Effects and Neurotoxicity   	   62
         Subchronic Effects and Nsurotoxicity   	   69
         Chronic Effects  	   71
         Qncogenicity  	•	   72
         Mutagenicity	•••	   72
         Teratology	•	   73
         Reproductive Effects  	•	   75
         Emergency Treatment  	   75
    Disciplinary Review
         Toxicology Profile	   75
         Toxicology Hazard Assessment	   79
         Generic Data Gaps  	   79
                                                                    QOI
         Suggested Labeling  	   0lJ
    Bibliog raphy  	   32

Chapter 6 - Residue Chemistry
    Topcial Discussions
         Metabolism in Plants  	   85
         Metabolian in Animals  	   8°
         Analytical Methods  	   25
         Residue Data  	   ^7
         Present Tolerances  	   88
         Regulatory Incidents	   38
    Disciplinary Review
         Residue Chemistry Profile	   89
         Reassessment of Established Tolerances   	   39
         Generic Data Gaps	   90
    Bibliography	   91

Chapter 7 - Ecological Effects
    Topical Discussions
         Birds	   92
         Wild Mammals  	   92
         Aquatic Invertebrates  	   93
         Fish	   93
         Ecosystan Effects  	   93
    Disciplinary Review
         Ecological Effects Profile	   94
         Hazard Assessment  	   94
         Generic Data Gap  	>.	   94
         Suggested Labeling	   95
    Bibliography	   95

Chapter 8 - Regulatory Rationale
    Product Composition Standards   	   93
    Acute Tbxicity Limits  	„	   93
    Use Patterns  	   99
    Data Requiranents  	   99
    Required  Labeling  	   99

-------
Bibliography

    Guide to Use of This Bibliography  	  99
    Citations Considered to be Part of the Data Base
     Supporting Reg istration of This Standard  	 101
    Citations Judged to be Inappropriate for Use in
      Developing This Standard  	 109
    Standard Reference mterial  	 lib
                                        in

-------
                                   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 Requirements under FIFR^ 3(c) (1)(D)
Obtaining Data to Fill "Data Gaps"; FIFR^ 3(c) (2) (B)
Amendments to the St
Organization _of the Standard

This first chapter explains the purpose of a Registration Standard and
sumnarizes the legal principles involved in registering or re-register ing 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 re/lews 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 haying 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 can posit ion is such as to warrant the proposed claims for it;
     (B) its labeling and other material required to be submitted comply with
         the requiranents 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 vvhich
registrants are required to submit, and assesses the risks and benefits
associated with the use of the proposed pesticide.  But the established
approach to making these findings has been found to be defective on two counts:

First, I-, v\ and its predecessor agency, the United States Department of
Agriculture (USDA) , routinely reviewed registration applications on a 'pro-duct
by product' basis, evaluating each product-specific application  somewhat
independently.  In the review of products containing similar components, there

-------
was  little opportunity  for a retrospective review of the full range of
pertinent data  available  in Agency files and in the public literature.  Thus
the ^product by product'  approach was often inefficient and sometimes resulted
in  inconsistent or  incomplete regulatory judgments.
Second,  over the years, as a result of inevitable and continuing advancesin
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.  Mien EPA issued new requiranents 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  37335, August 22, 1978) , many products that had already been
registered for  years were being sold and used without the same assurances of
human and environmental safety as was being required for new products.  Because
of  this  inconsistency,  Congress directed EPA to re-register all previously
registered products, so as to bring their registrations and their data bases
into compliance with current requirements [See  FIFRA Section 3(g)].

Facing the enormous job of re-reviewing and calling-in new data for^the
approximately 35,003 current registrations, and realizing the inefficiencies of
the  'product by product'  approach, the Agency decided that a new, more
effective method of review was needed.

Anew 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
ba met to obtain or retain full registration or re-registration under Section
3 (c) (5)  of FIFRA., include the submission of needed scientific data -which the
Agency does not row have, compliance with standards of toxicity, composition,
labeling, and packaging, and satisfaction of the data compensation provisions
of FIFRA Section 3(c) (1) (D) .

The  Standard will also serve as a tool for product classification.  As part of
the  registration of a pesticide product,  SPA 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
anvironnsnt.  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  152.1] (c) (5)]  instead of, or in addition to, the certified applicator
requirement.   These other  ragulatory restrictions may include such actions as
seasonal or regional limitations on use,  or a requirement for the monitoring of
residue levels after use.   A pesticide classified  for "general  use,"  or  not
classified at all,  is available for  use by any  individual who is in compliance
with State or  local  regulations.   The  Registration Standard review compares
information about potential  adverse  effects of  specific  uses of the pesticide
with risk criteria  listed  in. 40 CFR  152.11 (c) ,  and thereby determines whether a

-------
product needs to be classified for "restricted use."  If the Standard does
classify a pesticide for "restricted use," this determination is stated in the
second chapter.


Requirement _to Re-register Under the Standard

FIFRA Section 3(g) , as amended in 1973, directs EPA to re-rejister 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 v/hich this Standa-;:!
applies, and who wishes to continue to sell or distribute his product in
commerce, must apply for re-regisration.  His application must contain proposed
labeling that can plies with this Standard.

EPA will issue a notice of intent to cancel the registration of any currently
registered product to which this Standard applies if the registrant fails to
caaply with the procedures for re-registration set forth in the Guidance
Package which accompanies this Standard.


^Prgduct Specific" Data and "Generic" Data

In the course of developing this Standard, EPA lias determined the types of aat£i
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 1973 (43
FR 23635, July 10, 1973, and 43 FR 37336, August 22, 1973), 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 uis actually
unnecessary to evaluate these products, the Standard indicates that the
requirement has been waived.  Qi 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 sucn data have been in
effect for sane time and are, the Agency believes, relatively familiar to
registrants.  Data which we have found are needed to evaluate the
registrability of same products covered by the Standard may not be needed for
the evaluation of other products, depending upon the composition, formulation
type, and intended uses of the product in question.  The Standard states which
data requirements apply to which product categories.  (See the second chapter.)

The various kinds of data normally required for registration of a pesticide
product can be divided into two basic groups:

    (A)   data that is "product specific," i.e., data that relates only to
         the properties or effects of a product with a particular composition
         (or a group of products with closely similar composition) ; and

-------
    (B)  "generic" data that pertains to the proparties or effects of a
         particular ingredient, and thus is relevant to an evaluation of the
         risks and benefits of all products containing that ingredient (or all
         such products having a certain use pattern) ,  regardless of any such
         product's unique composition.

The Agency requires certain "product specific" data for each product to
characterize the product's particular composition and  physical/chemical
properties (Product Chemistry), and to characterize the product's acute
toxicity (which is a function of its total composition) .  Trie applicant for
registration or re-registration of any product, whether it is a manufacturing-
use or end-use product, and without regard to its intended use pattern, must
submit or cite enough of this kind of data to allow EPA to evaluate the
product.  Ebr 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 e/aluating, 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 sane cases a pesticidally inactive, or "inert,"
ingredient) .  Some data in this "generic" category are required to evaluate the
properties and effects of all products containing that ingredient [e.g., the
acute LD-50 of the active ingredient in its technical  or purer grade; see
proposed 40 CFR 153.81-1 (a) , 43 FR 37355].

Other  "generic" data are required to evaluate all products which both contain a
particular ingredient and are intended for certain uses (see, e.g., proposed 40
CFR 163.32-1, 43 FR 37363, which requires subchronic oral testing of the active
ingredient with respect to certain use patterns only) .  Where a particular data
requirement is use-pattern dependent, it will apply to each end-use product
which  is to be labeled for that use pattern (except where such end-use product
is formulated from a registered manufacturing-use product permitting such
formulations)  and to each manufacturing-use product with labeling that allows
it to be used to make end-use products with that use pattern.  Thus, for
exanple, 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 pro-ducts not involving food/feed
use or repeated hunan exposure, that         subchronic oral study would not be
relevant to the evaluation of the manufacturing-use product either.

If a registrant of a currently registered manufacturing-use or end-use product
•wishes to avoid the costs of data compensation [under  FIFRA Section 3(c) (1) (D)]
or data generation [under  Section 3(c) (2) (B)]  for "generic" data that is
required only with respect to some use patterns, he may elect to delete those
use patterns  from his labeling at the time he re-registers his product.  .An
applicant for registration of a new product under this Standard may similarly
request approval  for only certain use patterns.

-------
Data Compensation Requirements under FIFRA 3(c)(1)(D)

Under FIFRA Section 3(c) (1) (D) , an applicant for registration, re-registration,
or anended 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 anendment 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 exanpted by
         FIFRA Section 3(c) (2) (D)  from the duty to offer  to pay compensation.
         (Tais exemption applies  to che "generic" data concerning the safety of
         an actwe ingredient of  the applicant's product, not to i; product
         specific" data.  The exemption is available only to applicants whose
         product is labeled for end-uses for which the active ingredient in
         question is  present in the applicant's product because of his use of
         another registered product containing that active ingredient which he
         purchases from another producer.)

An applicant for re-registration of an already registered product under this
Standard, or for registration of  a new product under this Standard, accordingly
must determine which of the data  used by EPA in developing the Standard must be
the subject of an offer to pay compensation, and must submit with his
application the appropriate statements evidencing his compliance with FIFRA
Section 3(c) (1) (D) .

An applicant would never be required to offer  to pay for ''product specific"
data submitted by another firm.    In many, if not in most cases, data which
arespecific to another  firm's product will not suffice to allow EPA to e/dluute
the applicant's product, that is, will not be  useful to the Agency in determin-
ing whether the applicant's product is registrable.   There may b3 cases, how-
eyer, 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, lie would have to
comply with the offer-to-pay requiranents 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 exanpted by FIFRA Section 3(c) (2) (D) , must ccnply with the
Section 3 (c) (1)(D) requirements with respect to each itati 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)

Sone 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
tiie Agency  (or, if submitted, have been found to have deficiencies rendering
them inadequate for making registrability decisions) and  ha/e not been located
in tne 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
CPA to require registrants to whom a data requirement applies to generate (or
other-wise produce) data  to fill such "gaps'1 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 mechanise 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 smrnary 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 sane 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 an all number of currently registered products will
attempt to state definitively the "product specific" data gaps on a 'product by
product' basis.   (Although the Standard will in some cases note which data that
EPA does possess would suffice to satisfy certain "product specific" data
requirements for a category of products with closely similar composition
characteristics.)

As part of the process of re-register ing 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 subnit (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  subnit data needed to
fill "generic"  data gaps.  (We  expect they will respond to this requirement by
entering  into cost-sharing  agreanents 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 cohered by the Standard, or which present product compositions,
product chemistry data, hazj. d 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 anendments 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 ttiat the proposed product vould cause unreasonable adverse effects to
the environment.  In the former case, when .additional data have been
satisfactorily supplied, and providing that the data do not indicate the
potential for unreasonable adverse effects, the Agency will then amend the
Standard to cover the new registration.

Each Registration Standard is based upon all data and information available to
the Agency's reviewers on a particular date prior to the publication date.
This "cut-off" date is stated at the beginning of the 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 pesticide ingredients.  Where the Agency has
identified inert ingredients of concern in a specific product to which the
Standard applies, these ingredients will be pointed out in the Guidance Package,

-------
Chapter 2

REGULATORY POSITION

This chapter presents the Agency's decision on what Standards of product
composition, toxicity, use, labeling  and  packaging  are  required  for  the
pesticide 5-ethoxy-3(trichloromethyl)-l,2,4-thiadiazole.   Eb£ ease of reading,
the Agency will refer to this active ingredient as  Terrazole , which is  the
technical producer's trade name for the  product.   Its use  in this docunent does
not constitute endorsement or recommendation of use by  this Agency.

This decision complies with the rules and regulations  (40_CFR 162) used  to
implement the Federal Insecticide, Fungicide and  Rodenticide Pet, as amended
(FIFRA) , and with the Agency's present regulatory policy.   This  Registration
Standard is based upon all data and information on  Terraaole available to the
Agency's reviews as of December 28, 1979.

Two companies have submitted data in support of their registrations  of
Terrazole products:  Olin Corporation of  Little Rock, Arkansas and
Mallinckrodt, Inc. of St. Louis, Missouri.  These data  may be cited  by other
registrants or applicants for registration, when  appropriate, to support the
registration(s)  of their own product(s) ,  provided they  have offered  and  agreed
to pay compensation, as required by FIFRA Sections  3(c) (1) (C)  and 3(c) (2) (D) .

Generic" Data Requirements

The following charts outline the data requirements  of each discipline for the
registration of any Terrazole product.  As discussed in the preceding chapter,
the "generic" data pertain to the properties or effects of the active
ingredient.  These studies are, therefore, relevant to  the evaluation of the
risks  and benefits of all products containing Terrazole, regardless  of the
product's unique composition.

All applicants for registration or rereg istration of any Terrazole  product who
are not exempted by FIFRA Section 3(c) (2)  (D)  must agree to cite  available data
and submit all of the information identified below as data gaps  as  provided  for
in Section 3(c) (2) (B)  .

A demonstration that a Terrazole product has a composition similar  to a product
for which the Agency already has acceptable acute toxicity data  will satisfy
acute  toxicity data requirements for the  former product.  Both active and
inert  ingredients will be considered in making determinations of similarity.
Studies such as avian reproduction, aquatic embryolarvae tests or invertebrate
life-cycle bests may be required if the  basic studies do not provide sufficient
information to assess the hazard associated with the chemical.  The  need for
these  studies is based on specific factors derived  from the intended use
pattern, chemistry data, hunan toxicology data, residue chemistry data and
basic  fish and wildlife data.  These studies go beyond  the initial  toxicity
question and examine reproductive impairment and food chain magnification and
other  chronic effects.  The specific triggers for these subsequent tests are
represented in Subpart E, 43 FR 132, 29696.

-------
 TOXICOLOGY

Guidelines Section

163.81-1
163.81-2
163.81-3
163.81-7
163.82-1
163.82-2
163.82-3
163.82-4
163.82-5
163.83-1
163.83-2
163.83-3
163.83-4
163.84-1
163.85-1

Generic Data
Requirement
Acute oral toxicity*
Acute dermal toxicity*
Acute inhalation toxicity*
Acute delayed neurotoxicity
Subchronic oral dosing
Subchronic 21-day dermal toxicity
Subchronic 90-day dermal toxicity
Subchronic inhalation toxicity
Subchronic neurotoxicity
Chronic feeding
Oncogenicity
Teratogenicity
Reproduction
Mutagenicity
Metabolism

Use Pattern

Ornamentals & Turf
Ornamentals (, Turf
Ornamentals & Turf
Ornamentals & Turf
Ornamentals & Turf
Ornamentals & Turf
Ornamentals & Turf
Ornamentals & Turf
Ornamentals & Turf
Ornamentals & Turf
Ornamentals & Turf
Ornamentals .& Turf
Ornamentals & Turf
Ornamentals & Turf
Ornamentals & Turf

Do We Need Data
in Column 12
yes
yes
yes
no
yes
yes
no
no
no
yes
yes
yes
yes
yes
yes

Do We Have
Any Data?
yes
yes
yes

yes
yes



yes
yes
yes
yes
yes
yes
Will We Ask
foe Data In
Column 12
no
no
yes

yes
yes



yes
yes
yes
no
yes
no
'*Required on Technical  Product

-------
ECOiJOGICAL EFFECTS
Guidelines Section
163.71-1
163.71-2


163.71-3
163.71-4

163.72-1


163.72-2
163.72-3

163.72-4

163.72-5

Generic Data
Raqui rement
Avian single-dose £!>,.«
Avian dietary LC - ,
—wild waterfowl^"3'
— upland game bird . .
Mammalian acute toxicity '
Avian reproduction.
—wild waterfowl1 '
— upland game bird.
Fish acute LC * '
— cold water fish
— warm water fish
Acute toxicity to. aquatic
invertebrates l '
Acute toxicity to estuarine
and marine organisms '
Embryolarvae and life cycle
studies/fish .and aquatic
vertebrates l '
Aquatic organism toxicity
and residue studies * '
Us® Pattern
Ornamentals
Ornamentals


Ornamentals
Ornamentals

Ornamentals


Ornamentals
Ornamentals

Ornamentals

Ornamentals


& Turf
& Turf


6 Turf
& Turf

& Turf


& Turf
& Turf

It Turf

& Turf

Eto We Mead Data Ba I*fe Have Par Data In
in Column §2 toy Dafc®? Column §2
yes yes no
yes no yes


no
no

yes yes no


yes no yes
no

no

no

(a)  Required on technical
                                                                  10

-------
ENVIRONMENTAL CHEMISTRY
Guidelines Section
163.62-7 (b)
163.62-7 (c)
163.62-8 (b)
163.62-8 (c)
163.62-8 (d)
163.62-8 (e)
163.62-8 (f) (2)
163.62-8 (f) (3)
163.62-8 (g)
163.62-9 (b)
163.62-9 (c)
163.62-9 (d)
163.62-9 (e)
163.62-10 (b)
163.62-10 (c)
163.62-10 (d)
163.62-10 (e)
163.62-10 (f)
163.62-11 (b)
163.62-11 (c)
163.62-11 (d)
163.62-11 (e)
Generic Data
Requirement
Hydrolysis
Photodegradation
Aerobic soil metabolism
Anaerobic soil metabolism
Anaerobic aquatic metabolism
Aerobic aquatic metabolism
Effects of microbes on pesticides
Effects of pesticides on microbes
Activated sludge metabolism
Leaching , .
Volatility ia;
Adsorption/desorption
Water dispersal , .
Terrestrial field dissipation (aj
Aquatic field dissipation ' '
Terrestrial/Aqua tic. ( forest j
ecosystem residue ' ' , .
Specialized aquatic uses
Combination and tank mixes
Rotational crops
Irrigated crops
Fish accumulation . .
Special study-aquatic non-crop * '
Use Pattern
Ornamentals & Turf
Ornamentals & Turf
Ornamentals & Turf
Ornamentals & Turf
Ornamentals & Turf
Ornamentals 6 Turf
Ornamentals & Turf
Ornamentals & Turf
Ornamentals & Turf
Ornamentals 6 Turf
Ornamentals & Turf
Ornamentals & Turf
Ornamentals & Turf
Ornamentals & Turf
Ornamentals & Turf
Ornamentals & Turf
Ornamentals & Turf
Ornamentals & Turf
Ornamentals 6 Turf
Ornamentals & Turf
Ornamentals & Turf
Ornamentals & Turf
Do We Need Data
in Column 12
yes
yes
yes
yes
no
no
yes
yes
yes
yes
yes
yes

yes
no
no
no
no
no
no
yes
no
Do We Have
Any Data?
yes
yes
yes
yes


yes
yes
yes
yes
no
no
no
yes





yes

Will We Ask
For Data In
Column f2
no
yes
yes
no


yes
no
no
yes
yes
yes

yes





y®s

                                                                   11

-------
Manufacturing-Use Terrazole

The Agency has reviewed all data available to it.  Although incomplete, these
data indicate that manufacturing-use Terrazole is suitable  for  registration
because it does not meet or exceed the risk criteria  leading  to a Ffebuttable
Presumption Against Registration (Chapter 40,  Section 162.11 (a)  of the  Code of
Federal Regulations) .  Data gaps have been identified; when these data  are
supplied, the Agency will again review the registration  status  of this
ccm pound.

A manufacturing-use Terrazole product must comply with the  following
standards.  A manufacturing-use Terrazole product must contain  Terrazole [5-
ethoxy-3(trichloromethyl)-l,2,4-thiadiazole]  as the sole active ingredient.
Given current technical product grades and formulation methods, the Agency
expects that most manufacturing-use  material  will range  above 95% a.i.   Siould
an applicatnt desire to register a manufacturing-use  product that departs
greatly from the one currently registered, that applicant should contact the
Agency for specific directions on tow to  accomplish registration.   Because
Terrazole is corrosive to steel and  many  other metals, manufacturers of the
technical "material may not ship it in unlined  metal containers.   The acute
toxicology testing on a manufacturing-use Terrazole product must demonstrate
into which Toxicity Category (I through IV)  the product  falls  for  the following
acute effects:

    Acute Oral Toxicity;
    Acute Dermal Toxicity;
    Acute Inhalation Toxicity;
    Primary Eye irritation; and
    Primary Dermal Irritation

The label for the currently registered manufacturing-use Terrazole product must
include the following:

    1.  Ebr Formulation Into Bid-Use Fungicide Products

The intended end-use products formulated  from  manufacturing-use products
determines which data applicants for registration of  the manufacturing-use
product are required to submit or cite.   The  statement above obligates  the
manufacturer of the product to the complete battery of tests required by the
Agency.  This requirement could be lessened by restricting  the  use of the
product to such categories as:

         a.  Domestic Use Only
         b.  Nan-domestic Use Only
         c.  NDn-food Use Only
         d.  Outdoor Use Only

    2.  All manufacturing-use Terrazole products must carry the following
label, under the "Environmental Ffczards"  section:

         Do not contaminate water by cleaning  of equipment  or  disposal  of
         wastes.
                                     12

-------
    3.  All manufacturing-use Terrazole products must carry the following
warning on the label:

         This product is corrosive to steel and many other metals.  DD not
         transport or store in unlined metal containers.

    4.  Manufacturing-use product labels must comply with the requirements of
40 CFR 162.10 regarding label format, including placement of hazard warnings on
the label, type size and color, etc.

The following charts outline the data requirements of each discipline for the
registration of a manufacturing-use product.  All applicants for registration
or rereg istration of a similar manufacturing-use product must agree to cite
available data (and submit all of the information identified below as data
gaps)  in addition to the generic data above, in accordance with FIFRA Section
3(c) (2) (B)  .

A demonstration that a Terrazole product has a composition substantially
similar to a product for which the Agency already has acceptable acute toxicity
data  will  satisfy acute toxicity data requirements for the former product.
tfowever , both active and inert ingredients will be considered in making
determinations for similarity.

End-Use Formulations of Terrazole

An end-use formulation of Terrazole must contain Terrazole [5-ethoxy-
3(trichlorcmethyl)-l,2,4-thiadiazole]  as the sole active ingredient.   FIFRA
Section 162.11 (c)  lists the criteria for classifying pesticides for restricted,
non-dcmestic - or domestic use.  In addition, products intended for domestic use
with  Toxicity Category I or II ratings for primary eye or dermal irritation
must meet  the criteria for child-resistant packaging [see FR 44(48):   13019--
13024, March 9,  1979].

    Labels for currently registered Terrazole products must include the
    following :

         1.  If emulsifiable concentrate Terrazole products contain- patroleun
         distillates, the statement "Contains petroleum distillates'*  must
         appear on the label in close proximity to the ingredient statement.
         For example:

              Active Ingredient
               5-ethoxy-3 (trichlo rom ethyl) -1, 2,4- thi ad ia zole ....    %
              Inert Ingredients*                             ....~   %
              To tal                                          ...     %
                 *Contains Petroleum Distillates

         2.  The  following labeling must appear on all products Wiich contain
         greater  than 10%  (by weight)  petroletm distillates:

              "If  patient is unconscious, maintain breathing and heartbeat
              (CPR: cardiopulonmary resuscitation, if necessary).  Contact your
              local Poison Control Center, hospital or physician immediately."
                                      13

-------
PRODUCT CHEMISTRY
Guidelines Section
163.61-3

163.61-4

163.61-5

163.61-6

163.61-7

163.61-8 (1)
163.61-8 (2)
163.61-8 (3)
163.61-8 (4)
163.61-8 (5)
163.61-8 (6)
163.61 8 87)

163.61.8 (8)

163.61.8 (9)

163.61.8 (10)

163.61.8 (11)

163.61-8 (12)
163.61-8 (13)
163.61.8 (14)
163.61.8 (15)
Product Specific
Data Requirement for
Manufacturing-Use Products
Product identity and
disclosure of ingredients
Description of manufacturing
process
Discussion on formation of
unintentional ingredients
Declaration and certification
of ingredient limits
Product analytical methods
and data
Color
Odor
Melting point
Solubility
Stability
Octanol/water partition coefficient
Physical state

Density or specific gravity

Boiling point

Vapor pressure

pH

Storage stability
Flammability
Oxidizing or reducing action
Explosiveness
Composition
Characteristics
Manuf actur ing-Use
Product
Manuf actur ing-Use
Product
Manufacturing-Use
Product
Manufacturing-Use
Product
Manuf actur ing-Use
Product
Technical
Technical
Technical
Technical
Technical
Technical
Technical and
Manuf actur ing-Use
Technical and
Manufacturing-Use
Technical and
Manufacturing-Use
Technical and
Manuf actur ing-Use
Technical and
Manuf actur ing-Use
Manuf actur ing-Use
Manuf actur ing-Use
Manufacturing-Use
Manuf actupr ing -Use
Do We
Need It?
yes

yes

yes

yes

yes

yes
yes
no
yes
yes
yes
yes

yes

yes

yes

yes

yes
yes
yes
yes
Do We
Have It?
yes

yes

yes

yes

yes

yes
yes

yes
yes
yes
yes

yes

yes

yes

yes

yes
yes
yes
no
                                                                   14

-------
Product Chemistry  (continued)
Guidelines Section
163.61-8
163.61-8
163.61-8
(16)
(17)
(18)
Product Specific
Data Requirement for
Manufacturing-Use Products
Miscibility
Viscosity
Corrosion characteristics
Composition
Characteristics
Manuf actur ing-Use
Manuf actur ing-Use
Manufacturing-Use
Da We
Need It?
yes
yes
yes
Do We
Have It?
no
yes
yes

-------
TOXICOLOGY
Guidelines Section
Product Specific
Data Requirement for
Manufacturing-Use Products
                                                                    Composition
                                                                    Characteristics
                                Do We
                                Need It?
                   Do We
                   Have It?
163.81-1

163.81-2

163.81-3

163.81-4

163.81-5

163.81-6
Acute oral toxicity

Acute dermal toxicity

Acute inhalation toxicity

Primary eye irritation

Primary dermal irritation

Dermal sensitization
Hanufactur ing-Use
 Product
Manufacturing-Use
 Product
Manufacturing-Use
 Product
Manufactur ing-Use
 Product
Manufacturing-Use
 Product
Manufactur ing-Use
 Product
yes

yes

yes

yes

yes

yes
yes

yes

no

yes

no

no
                                                               16

-------
In addition, for all products which contain greater than (10% by
weight)  petroleum distillates, and are in Oral Tbxicity
Category I, the following statements must appear on the label.

     "If patient is conscious, induce vomiting (syrup of Ipecac;  if
     not available, stimulate back of throat with finger) .   Never give
     anything by mouth to an unconscious person]"

For all products which contain greater than 10% (by weight)  petroleum
distillates and are in Oral Tbxicity Category IV, the following
statements must appear on the label:

     "Do not induce vomiting"

Products in Oral Tbxicity Categories II and III will be dealt with on
a case-by-case basis at the time for registration.

3.  All currently registered EC Terrazole products containing 25%
a .i . must carry on the label the acute toxicity hazard warnings  and
first aid statements required for the following Tbxicity Categories
(see Appendix A) :

     Primary Eye Irritation - I

4.  All currently registered EC Terrazole products containing 4
Ibs/gal a.i. must carry on the label the acute toxicity hazard
warnings and first aid statements required for the following Tbxicity
Categories  (see Appendix A):

     Acute Dermal Tbxicity - II
     Acute Oral Tbxicity - III
     Primary Eye Irritation - I
     Primary Dermal Irritation - II

5.  All currently registered WP/t) Tterrazole products containing  30%
a.i. must carry on the label the acute toxicity hazard warnings  and
first aid statements required for the following Tbxicity Category (see
Appendix A)  .

     Acute Oral Tbxicity - III

6.  All currently registered granular Terrazole products containing 5%
a.i. must carry  on the label the acute toxicity hazard warnings and
first aid statements required for the following Tbxicity Categories
(see Appendix A) .

     Acute Oral Tbxicity - IV
     Acute Dermal Tbxicity - III
     Acute Inhalation Tbxicity - III
     Primary Eye Irritation _ III
     Primary Dermal Irritation - IV
                              17

-------
         7.  All Terra zole products must carry the  following  warning on  the
         label under the "Environmental  Hazards"  section:

              "Eto not apply directly  to  ponds  or  streans.   Do not contaminate
              water by cleaning  of equipment or disposal  of wastes."

         8.  All labels and labeling  intended  for agricultural  use  products
         must bear the statement "this product must  be  applied  in accordance
         with 40 CFR Part 170."   Registrants may  amplify  the  above  statement on
         labels or labeling by stating the  requirements of 40 CFR F&rt 170 or
         additions thereto, if they choose.

         9.  All product labels  must  comply with  the requirements of 40  CFR
         162.10 regarding label  format;  including placement of  hazard  warnings
         on the label, type size and  color,  etc.

The following charts outline the data requirements of each discipline  for the
registration of end-use products.  All. applicants for registration  or
reregistration of a similar end-use product  must agree  to  cite  available data
and submit all of the information identified below as data gaps.  For  those  not
exempted from generic gap requirsnents by FIFRA Section 3(c)2) (D) the  end-use
data and generic data apply and  must  be  cited  or submitted in accordance with
Section 3(c)2) (B) .

    A demonstration that a Terrazole  product has a composition  similar to a
    product for which the Agency already has acceptable acute toxicity data
    will satisfy acute toxicity  data  requiranents for the  former product.  Eo.th
    active and inert ingredients will  be considered  in making determinations of
    similarity.
                                      18

-------
PRODUCT CHEMISTW
Guidelines Section

163.61-3



163,61-4



163.61-5



163.61-6



163.61-7



163.61-8(1)



ProtJucDf Specific Data
Ke«,[u'lrement or End-Use Products
Product Identity and disclosure
of Ingredients


description of manufacturing
process


Discussion of formation of
un intentional ingredients


Declaration and certification
of ingredient limits


Product analytical methods
and data


Golor(a)



Composition
Characteristics
30% WP/D & 35% WP
25% EC
». io/gal EC
5% G
30% WP/D & 35% WP
25% EC
4 ib/gal EC
5% G
30% WP/D & 35% WP
25% EC
4 Ib/gal EC
5% G
30% WP/D & 35% WP
25% EC
4 Ib/gal EC
5^G
30% WP/D & 35% WP
25% EC
4 Ib/gal EC
5% G
30% WP/D & 35% WP
25% EC
4 Ib/gal EC
5% G
jj'"? "flQ
tieed It?
J"9S
ves
yes
yes
yes
yes
yes
yes
yes
yes
ves
yes
yes
yes
yes
ves
yes
yes
yes
yes
yes
yes
yes
yes
Do Wa
Have 'It?
J»
no
w
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
                                                                    19

-------
PRODUCT CHEMISTOY   (Continued)
Guidelines Section

163.61-8(2)



163.61-8(7)



163.61-8(8)



163.61-8(9)



163.61-8(10)



163.61-8(1)



Product Specific Data Composition
Requirement for End-Use Products Characteristics
Odor(a) 30% WP/D 6 35% WP
25% EC
4 Ib/gal EC
5% G
Physical state (a) 30% WP/D & 35% WP
25% EC
4 Ib/gal EC
5% G
Density or specific gravity'8' 30% WP/D & 35% WP
25% EC
4 Ib/gal EC
5% G
Boiling point'3* 30% WP/D & 35% WP
25% EC
4 Ib/gal EC
5% G
Vapor pressure'3' 30% WP/D & 35% WP
25% EC
4 Ib/gal EC
5% G
pH
-------
product Chemistry
Guidelines Section
163.61-0(12)
163.61-8(13)
163.61-8(14)
163.61-8(15)
163.61-8(16)
163.61-8(17)
(Continued)
Product Specific Data
Requirement for End-Use Products
Storage stability
Flammability
Oxidizing or reducing action
Explosiveness
Miscibility
Viscosity

Composition
Characteristics
30% WP/D & 35% WP
25% EC
4 Ib/gal EC
5% G
30% WP/D & 35% WP
25% EC
4 Ib/gal EC
5% G
30% WP/D £.' 35% WP
25% EC
4 Ib/gal EC
5% G
30% WP/D & 35% WP
25% EC
4 Ib/gal EC
5% G
30% WP/D & 35% WP
25% EC
4 Ib/gal EC
5% G
30% WP/D & 35% WP
25% EC
4 Ib/gal EC
5% G

Do We
Need It?
yes
yes
yes
yes
no
yes
yes
no
yes
yes
yes
yes
yes
yes
yes
yes
no
yes
yes
no
yes
yes
no

Do We
Have It?
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
21

-------
Product Chemistry (Continued)
Guidelines Section
163.61-8(18)
163.61-8(19)
Product Specific Data
Requirement End-Use Products
Corrosion characteristics
Dielectric breakdown
voltage

Composition
Characteristics
30% WP/t) & 35% WP
25% EC
4 Ib/gal EC
5% G
30% WP/D & 35% WP
25% EC
4 Ib/gal EC
5% G

Do We
Need It?
yes
yes
yes
yes
no
no
no
no

Do .We
Have It?
no
no
no
no

(a)
     Required on both formulated and technical product.
                                                                   22

-------
TOXICOLOGY
Guidelines Section

163.81-1



163.81-2



163.81-3



163.81-4



163.81-5



163.81-6



Product Specific Data
Requirement End-Use Products
Acute oral toxicity '



Acute dermal toxicity'3'



Acute inhalation toxicity'3'



Primary eye irritation



Primary dermal irritation '



Dermal sensitization '



Composition
Characteristics
30% WP/D & 35% WP
25% EC
4 Ib/gal EC
5% G
30% WP/D & 35% WP
25% EC
4 Ib/gal EC
5% G
30% WP/D & 35% WP
25% EC
4 Ib/gal EC
5% G
30% WP/D & 35% WP
25% EC
4 Ib/gal EC
5% G
30% WP/D & 35% WP
25% EC
4 Ib/gal EC
5% G
30% WP/D & 35% WP
25% EC
4 Ib/gal EC
5% G
Do We
Need It?
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
Do We
Have It?
yes
no
yes
yes
yes
no
yes
yes
no
no
no
yes
no
yes
yes
yes
no
no
yes
yes
no
no
no
no
                                                                    23

-------
ECOLOGICAL EFFECTS
Guidelines Section
163.71-5(1)
163.71-5(2)
163.72-1
163.72-2
163.72-3
163. 72-6 (a) (1)
163. 72-6 (a) (2)
Product Specific Data
Requirements End-Use Products
Cage of nen field test'8'
SUll-scale field tesfciaj
Fish acute LC -rainbow*3'
trout and blue gill
t~\
Acute toxicity to aquatic
invertebrates
Acute toxicity to estuarin and
marine organisms
Eliort term simulated field *a'
test
Long-term simulated field
test
Composition
Characteristics
30% WP/D & 351 WP
25% EC
4 Ib/gal EC
5% G
30% WP/D & 35% WP
25% EC
4 Ib/gal EC
5% G
30% WP/D & 35% WP
25% EC
4 Ib/gal EC
5% G
30% WP/t» & 35% WP
25% EC
4 Ib/gal EC
5% G
30% WP/D & 35% WP
25% EC
4 Ib/gal EC
5% G
30% WP/D & 35% WP
25% EC
4 Ib/gal EC
5% G
Do We Bo We
Need It? Have It?
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
(a)
     Test on typical  formulated product.
                                                                 24

-------
Chapter 3

PRODUCT CHEMISTRY

INTRODUCTION

FIFRA  3(c) (2) (A) requires the Agency to establish guidelines for registering
pesticides  in the Hiited States,  The Agency requires registrants to provide
quantitative data on all added  ingredients, active and  inert, which are equal
to or greater than  0.1 percent of the product by weight.

To establish the composition of products proposed for registration, the Agency
requires data and information not only on the manufacturing and formulation
processes,  but  also a discussion on the formation of manufacturing impurities
and other product ingredients,  intentional and unintentional.  Further, to
assure that the composition of the product as marketed  will not vary from the
composition evaluated at the time of registration, applicants are
required  to submit  a statement certifying upper and lower composition limits
for the added ingredients, and upper limits only for sane unintentional
ingredients.  Subpart D  (43 FR, No. 132, 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 also requires data
to establish the physical and chemical properties of both the pesticide active
ingredient  and  its  formulations.  Ebr example, data are needed concerning the
identity  and physical state of the active ingredient (e.g., melting and boiling
point data, vapor pressure and solubility).  Eata are also required on
the properties  of the formulated product to establish labeling cautions (e.cj.,
flaitmability, corrosivity or storage stability) .  The Agency uses these data to
characterize each pesticide and to determine its environmental and health
hazards."

TOPICAL DISCUSSION

The Topical Discussions listed below correspond to the  sections in the
"Proposed Guidelines for Registering Pesticides" of July 10, 1978 (43 FR,
No. 132,  29696).  These sections explain the minimum data the
Agency requires to assess Terrazole's Product Chemistry-

    Topical Discussions                       Guideline Sections

    Chemical Identity                            163.61-3
    Manufacturing Process                        163.61-4
    Formation of Unintentional Ingredients       163.61-5
    Percentage  of Active Ingredients             163.61-6
    Product Analytical Methods and Data          163.61-7
    Physical/Chemical Properties                 163.61-8

CHEMICAL IDENTITY

The trade name  "Terrazole"  will be routinely used in this Standard in
lieu of the chemical name,  5-ethoxy-3-trichloromethyl-l, 2,4-thiadiazole,
for convenience in writing  this Standard.  Use of the trade name implies
no endorsement of any specific product containing the active ingredient.


                                        25

-------
Other trade nanes ares   Ethazol,  Ethazole,  ETMT,,  Etridiazol,
Etridiazole, Koban, Truban and OM2424.

The technical chemical  nanes of Terrazole are as  follows:

Chemical Name:     5-Ettoxy-3-(trichloromethyl)-l, 2,4-thiadiazole
                   5-Ethoxy-3-tricKLoronethyl-l,2,4-thiadiazole
                   Trichloro methylethoxy thiadiazole

Type:  Fungicide

Shaughnessy ft 084701

C.A*S. #:  2593-15-9

Mo. Wt; 247.5

Chemical -Formula:  CnHcCl-jNpOS

Structural Formula:
CC13 - C - N

       N   C - OC2H5
MANUFACTURING PROCESS

Details of the procedures, equipment and manufacturing conditions required
for commercial production of the chemical will be discussed in Appendix h
which contains confidential information protected under Section 10 of
FIFRA.

According to the Farm Chemicals Handbook,, 1980, Terrazole is only
manufactured in th~e~ USA by Qiin CharflcaTs,  01 in Corporation, Little Rock,
Arkansas,,

In general, applicable U.S. Patent tfos. 3,825,581 and 3,389,338 describe
the manufacture of Terrazole as follows:  A mixture of trichloroacetami-
dine hydrochloride, trichioromethane sulfeny^chloride and methylene
chloride is kept at a temperature between -4 C and 1 C while stirring
and adding dropwise sodiun hydroxide in water,,  After two hours, the
methylene chloride layer is separated, washed with water then dried
over sodiun sulfate.   After evaporation of the solvent, the residue is
vacuum distilled to recover the intermediate, 3-trichloranethyl-5-chloro-
1,2,4-thiadiazole.  The intermediate (U.S.  Patent ND. 3,890,338) is
dissolved in ethanol and stirred with sodiun in anhydrous ethanol.  After
15 minutes, the reaction mixture becomes neutral and the precipitated
sodium chloride is removed by filtration.  Excess ethanol is evaporated
and the residue is vacuum distilled at 94*5 C and Iran Hg to recover the
                                  26

-------
product 5-ethoxy-3-(trichloronethyl)-l,2,4-thiadiazole.  (Pesticide
Process Ehcvclopedia, Noyes Data Cbrp., Park Ridge, New jersey,  1977
           "
FORMATION OF UNINTENTIAL INGREDIENTS

Potentially harmful impurities sometimes result during the production of
pesticides.  The main impurities during the production of  Terrazole are 5-
chlorc—3-trichloromethyl-l, 2,4-thiadiazole, and trichloroacetamide (Nfertin
et al., 1977, GS0009-035) .  Reporting of manufacturing impurities is
required by the proposed registration guidelines in the Federal  Register,
43_"(132) 29696  (issue of July 10, 1978), Section 163.61-7(2)  and (3).  The
presence of manufacturing impurities depends on the nature of the reaction
used.  Detailed information is available to Agency personnel  in  Appendix
A which contains confidential business information protected  under Section
10 of the  FIFRA.

PERCENTAGES OF ACTIVE INGREDIENT

The Registration Standard will describe the acceptable composition of the
technical  ingredient.  This information is needed to define the  acceptable
ranges of  active ingredient allowable in registered products, to
prescribe  appropriate test material concentrations in hazard  evaluation
testing and later, to estimate likely exposures to the active ingredient
resulting  fron the handling or use of the products in which it is
contained«

Technical  Terrazole
A confidential statement of formula as submitted by din Chemical  Corp*
states that their technical grade Terrazole contains 95% 5-ethoxy-3-
(tr ic hi o ran ethyl) -1,2,4-thiadiazole as the active ingredient.  The
remaining 5% consists of manufacturing impurities whose identifies are
available to Agency personnel in Appendix B as confidential  business
information,

Formulated Terrazole

Formulations of Terrazole are used as fungicides against a narrow range  of
fungal pests (Pythian and Phytophthora species) „  The four types of
formulations covered in this Standard are wettable powders,  emulsifiable
concentrates, wettable powder/dusts, and granular.  Table 1.1 surmarizes
the uses of these formulations and Appendix B (which contains confidential
business information protected under Section 10  of FIFRA)  presents the
ingredients of each formulation.  Terrazole formulations are applied by
ground equipment only including  broadcast spray, irrigation  systems,
mechanical mixing, drench methods and granular spreaders. Typical
application rates vary according to need and are shown in Table 1.1. A
detailed discussion of the use of Terrazole formulations is  presented in
the Use Profile contained in Chapter Three.
                                   27

-------
Table 1-1.  Summary of the Registered Uses of Terrazole2
Product .
Description
30 % UP
30% WP"-

30 % WP
25% EC
95% Technical

35%
35% WP
4 Ib/gal EC
5£ G
5? G
Registered
Sites
Turf
Ryegrass -Seed
Treatment
Ornamentals
"
For formulation
uses only
Turf
Ornamentals
Avocados
Avocados
Ornamentals
Application
Rate a.i.
0.1 to 0.2 lb/1000 sq. ft.
1.35 to 2.1 02/100 Ib seed

0.8 to 0.23 Ib/ilOO sq. ft.
0.8 to 0.2?, lb/400 sq. ft.
for manufacturing purposes

0.1 to 0.2 lb/1000 sq. ft
0.8 to 0.23 lb/400 sq. ft.
0.02 to 0.27 Ib/ tree
0.02 to 0.27 Ib/ tree
0.03 to 0.12 Ib/ cu. yd. soil
Method

Broadcast spray
Mechanical seed treater

Broadcast spray or through
t ii t



Broadcast spray or through
Broadcast spray or through
Drenching vessel to soil
Granular applicator
Mechanical soil mixer




irrigation
n


irrigation
irrigation



   Terrazole is a fungicide registered for1 use against a narrow range of
     fungal pests (Pythium and PhyLophthora species)

   WP = Wettable Powder;  D = Dust; EC - Emulsifiable  concentrate; G = Granular
     Adapted from Reference GS0009-036

   Wettable Powder used as a dust.
                                                     28

-------
PRODUCT ANALYTICAL l^ETHODS AND DATA

In order to ensure that products contain only those percentages of active
ingredients which they properly claim to contain, it is necessary to  have
analytical methods to determine the concentration of active ingredients
in each formulation.  In addition, the commercial production of pesticide
chemicals, reactions between pesticide ingredients, reactions with
packaging materials, as well as degradation during the long period over
which some products may be stored before use, can result in the formation
of chemical impurities.  Because of the potential toxicity of these
impurities, analytical methods must also be provided for their assessment,
both to improve the reliability of the Agency's hazard assessment and to
ensure  that marketed products conform to the standards of purity agreed
upon by the pesticide producer.

Analytical methods  for the  identification and quantification of Terrazole
in the  manufacturing-use and formulated end-use product have been
submitted.  Methods for  the analysis of impurities have also been
submitted and are considered to be adequate.  No infrared or ultraviolet
spectrophotometric  or mass  spectra methods which may be used in the
identification of Terrazole were reported.

PHYSICAL/CHEMICAL PROPERTIES

Physical/Chemical properties can serve as a means of chemical
identification or as a confirmation of the reliability of other
composition data.
 Technical

 The  following Physical/Chemical properties for technical Terrazole were
 reported by  01 in Chemical Corp. under references 00001553, 00001556,
 00001760,  and 00002232:

     Color:         pale  yellow

     Odor:          musty, mildy persistent
                                                                o
     Solubility:    practically insoluble in water. (50 ppm at 25 C)
                   Soluble  in acetone, ether, ethanol,
                   Skellysolve  and carbon tetrachloride

 Although the Guidelines  state that solubility should be determined at
 20°C,  the  Agency feels that since Terrazole is practically insoluble
 in water,  a 5°C temperature difference in the determination of
 Terrazole1 s  solubility would not make a significant difference and does
 not  constitute a data gap.
                             o
 Freezing Point:          20-22 C

 Stability;   Terrazole  is stable to light (including ultraviolet)  and
 prolonged  storage  in sealed containers of metal or glass.  Some loss will
 occur  in polyethylene over  prolonged storage of more than 3 years.
 Terrazole  hydrolyzes with acids and bases.


                                  29

-------
Octanol/Water partition Coefficient:

An octanol/v\ater partition coefficient of 405 was reported at 12.5 ppn and
300 at 18.7 ppn starting concentrations.  The temperature of the test was
25 C.

Physical State:  Liquid
                                         o
Density or Specific Gravity:  1.503 at 25 C
                  o
Boiling Point:  95 C at 1 mm mercury

Vapor Pressure:      1X10  mm Hg at 25QC
                     0.30mm Hg at 37.8 C
                     1mm Hg at 95°C
                     13.6mm Hg at 114.4 C

pH:  3-4 in saturated water solution

Storage Stability;  The technical material is stable to prolonged
storage in sealed containers.  Degradation occurs after three years of
storage in polyethylene containers.

Flammability:  Flash point 151 C (Tagged Closed Cup Method)

Oxidizing or Reducing Action:  May emit toxic funes of chloride, oxides
of sulfur and nitrogen under conditions of heat and moisture.

Explosiveness;  Nb data reported

Miscibility;  No data reported

Corrosion Characteristics:   The technical material reacts with steel and
many other metals, therefore, lined containers must be used.   According to
NACE TMH31-69, the corrosive action of Terraaole is as follows:   Steel SAE
1020, 0.14; Aluninum 7075-T6, 0.09.

Formulations:

Physical/chemical properties of Terrazole formulations ware not available
for this Standard; however, these data are required prior to  registration
under this Standard.
                                   30

-------
DISCIPLINARY REVIEW

Chemistry Profile
Generic EBta Gaps
Suggested Labeling

CHEMISTRY PROFILE

Terrazole contains a minimum of 95-97% of the active ingredient, 5-ethoxy-
3-trichloronethyl-l,2,4-thiadiazole.  Technical Terrazole is a pale
yellow to reddish brown liquid with a mildy persistent musty odor.  The
compound is stable when stored under normal conditions.  Technical
Terrazole is practically insoluble  in water but very soluble in acetone,
ether, ethanol, Skellysolve  , and carbon tetrachloride.  The spegific
gravity is 1.503 at 25 C and the vapor pressure is 1 mm Hg at 95 C.
Because it is  intended only  for re-formulation into an end-use pesticide,
technical Terrazole is a "manufacturing-use" product.

In order to be registrable under this Standard, a technical pesticide
product containing Terrazole must have at least 95-97% concentration of
active  ingredient, the same or less identifiable non 5-ethoxy-3-
trichlorcmethyl components,  and physical/chemical properties comparable  to
those described  in this chapter.
Generic Data Gaps

The  following  data gaps  in  the  Product  Chemistry data base  are  tests
needed to  adequately support  registration  for a product containing
Terrazole.  Following  each  data gap is  listed the  section  in  the  Proposed
Registration Guidelines  of  July 10,  1978  (FR 43, No. 132, 29695)  which
describes  the  type of  data  needed.

For  Technical  Terrazole  and/or manufacturing-use product:

     1.   Explosiveness                        163. 61-8 (c) - (15)
     2.   Miscibility                          163.61-8 (c)-(16)

For  formulated end-use Terrazole:

                                                 Guidelines Section

For  Emulsifiable  Cbncentrate  Terrazole:
     1) color	163.61-8 (c) (1)
     2) odor	163.61-8 (c) (2)
     3) Density or  Specific  Gravity	163.61-8 (c) (8)
     4) Boiling Point	163.61-3 (c) (9)
     5) Storage Stability	163. 61-8 (c) (12)
     6) Flarmability	163.61-3 (c) (13)
     7) Oxidizing  or  Reducing  Action	163. 61-8 (c) (14)
     8) Explosiveness	163.51-8 (c) (15)
     9) Miscibility	163. 61-3 (c) (16)
    10) Viscosity	163.61-8 (c) (17)
    11) Corrosion  Characteristics	163. 51-8 (c) (18)
                                     31

-------
 Ebr Granular and Pow3er Terrazole:
    1) Color	163.61-8(c) (1)
    2) Odor	163.61-8(c) (2)
    3) Density or Specific Gravity	163.61-8 (c) (8)
    4) Storage Stability		163.61-8 (c) (12)
    5) Oxidizing or Reducing Action	163.61-8 (c) (14)
    6) Explosiveness	163.61-8 (c) (15)
    7) Corrosion Characteristics	163.61-8 (c) (18)


 Chemical Identity (163.61-3):   (1) Complete identification of all
 impurities  and reaction compounds in the technical chanical.  (2)
 Identification of all substances appearing in the manufacturing-use and
 formulated  products.

 Manufacturing Process (163.61-4):   Complete information on the  present
 manufacturing process, including type of process, equipment and
 quality control measures.

 Formation of Unintentional Ingredients^(163.61-5):  Theoretical discussion
 of the formation of each substance, aside from the active ingredient and
 intentionally added inert ingredients, that might reasonably be identified
 as being present in the pesticide  product.

 Uider  the Proposed Policy for Pesticides con'tarn in a ted with N-nitroso
 compounds  (45 FR, 124, 42854)  applicants whose products contain at least
 1 ppm  N-nitroso compoinds are required to perform exposure analyses as
 prescribed  by the Agency -

 Percentages of Components in Pesticide Products  (163.61-6):

 Declaration or certification of limits for all active and inert
 ingredients.

 Product Analytical Methods and Data  (163.61-7):   Methods for analysis of
 formulations and submission of gas chrcmatography methods for the
 technical compound.

 Suggested Labeling

 Ingredient  Statement:  The ingredient statement will list the active
 ingredient, Terra zole as:

    5-ethoxy-3-trichloromethyl-l,2,4-thiadiazole	   %.
Physical Hazard Precautionary Labeling:  Precautionary labeling may become
necessary, depending on the nature of the physical/chemical properties
submitted by applicants for registration in response to requirements
listed in the sections of this chapter on Generic Data Gaps and
Registration Requirements.

Since the technical product is corrosive to steel and other metals, the
technical label must carry a warning against storage in unlined
metal containers.

-------
 Bibliography

GS0009-035— Martin, H., and C.R. Worthing, eds.  1977.  Pesticide Index:
    Basic information on the chemicals used as active components of
    pesticides, 5th ed. British Corp. Protection Cbi_ncil, Worcestershire,
    England.

00001760—01 in Ffethieson Chemical Corporation. 1964. Chemical and
    Physical Properties for Terrazole.   (Unpublished study received Dec
    16, 1964 under 1258-740; CDL: 119218-A)
                                                              p
00001556—01 in Corporation. 1966.  Technical Data:  Terrachlor  Super X:
      (Terraclor  + Terrazole)  .  (Unpublished study received Jan 1,
      1966?  under 1258-Q; CDL:  110045-A)
                                           n
00001553—01 in Corporation. 1977- Terrazole  Technical Grade—Data Sheet
     (Unpublished study  that includes data sheets A. 1-A.2, A.3, A.4,
    received Pab. 4, 1977 under 1258-812; CDL: 095799^)

GS0009-036— Pesticide  Chemical Use Pattern Profile for Terrazole
     (084701) .  U.S. Environmental Protection Agency, Office of Pesticide
    Programs, Benefits  and Field Studies Division, my 1979.

G30009-048—Pesticide  Process Encyclopedia, 1977. Isbyes Data Corp.  Park
    Ridge,  New Jersey.
                                                                  TD
00002232—Schingh, J.E. 1976.  Vapor Pressure Studies of Terrazole  (5-
    Ethoxy-3-trichloronethyl-l,2,4-thiadiazole) :  CASR-21-76.
     (Unpublished study received Cct 10,  1976 under 1258-812; submitted by
    Olin  Corp., Agricultural  Div., Little Rock, Ark.; CDL: 228143-
                                       33

-------
Chapter 4

ENVIRON MENTAL FATE

USE PROFILE

Use and Formulations

TerrazoleR  is a soil fungicide that is registered and used against a narrow
range of plant pathogenic fungi.  As a single active ingredient product, it is
registered  in the United States for use on turf (primarily for golf courses)
and ornamental crops (approximately 24 species of flowering bedding plants, 9
species of  container growi plants and 10 species of tropical foliage plants);
ornamental  use is limited to commercial growers.  Terrazole also has a state
registration  in California for use as a soil treatment around avocado trees.
It is formulated for turf and ornamental use as a 30 and 35% wettable powder
 (WP) , and for ornamental use only as a 25% emulsifiable concentrate (EC) .  The
5% Granular (G)  is used to treat soil prior to seeding or transplanting of
ornamentals.  For use on avocados it is formulated as a 4 Ib/gal EC and as a 5%
granular  (G) .  Terrazole has one use as a seed treatment; the 30% WP may be
used as a dust to treat ryegrass seed.
 For  turf  use, Terraaole WP formulations are applied as a broadcast spray by
 means of  tractor mounted, or motor scooter mounted boom sprayers or vehicle
 mounted hand- held spray wands.  The application rate is 0.1 to 0.2 Ib
 active ingredient (a.i)  in 100 gal of water per 1000 square feet (sq. ft.) .
 Frequency of application varies with disease incidence but as many as 15
 applications may be made at five to ten day intervals.  Terrazole is used in
 all  states but primarily in Southern states (Sparks, 1980, GS0009-070) .

 For  soil  treatment of bedding and tropical foliage plants the WP and EC
 formulations are applied through irrigation systems at 0.8 to 0.23 Ib. a.i. per
 400  sq. ft. or as a broadcast spray by means of a back pack or wheeled boom
 sprayer at the rate of 0.8 to 0.23 Ib a.i. in 100 gallons of water per 400 sq.
 ft.  Frequency of application varies with disease incidence but as many  as six
 applications may be made at one to three month intervals.  For treatment of
 soils prior to planting of ornamentals, Terrazole WP (as a dry powder) or 5
 percent G may be incorporated into soil by means of a mechanical mixer at the
 rate of 0.03 to 0.12 Ib a.i. per cubic yard (cu. yd.)  of soil.  It is used in
 most states but mainly in California, Florida, and Alabama (Sparks, 1980,
 GS0009-070) „

 For  treatment of container grown plants (including some tropical foliage
 plants)  the EC and the 30% WP are applied as a drench by means of sprinkling
 can  or drench dispensing vessel at the rate of 0.05 to 0.2 Ib a.i. per 100
gallons of water;  0.5 pint is used for a six inch diameter container.
 Frequency of application varies with disease incidence but as many as three
 applications may be made at two to three month intervals.  Usage is primarily
 in California, Florida and Alabama (Sparks, 1980,  GS0009-070) .

 For  soil   treatment of avocado the 5% G formulation is applied by means
of a granular spreader or the 4 Ib/gal EC formulation is applied by means of a
drenching vessel  at 0.02 to 0.27 Ib a.i. per tree (1.8  to 24.3 Ib per acre)  to
 a circular area surrounding the tree.  At the present time Terrazole is  not


                                     34

-------
extensively used in California but in the event of severe disease outbreak
applications would be made at monthly intervals for nine to ten months (Geonet,
1980, GS0009-021) .  For treatment of ryegrass seed the 30% WP is applied at the
rate of 1.35 to 21. oz. a.i. per 100 Ib of seed.

Usage

It has been estimated by Geomet that on an annual basis 20,000 to 132,000 Ib
a.i. of Terrazole are used for treatment of from 2,570 to 2,880 acres of turf
(Geomet, 1980, G30009-021) .  Personal communication with 01 in Corporation
indicates that turf grass usage is approximately 120,000 Ib (Sparks, 1980,
GS0009-071) .  The annual usage for treatment of greater than 3,760 acres of
ornamental crops has been estimated by Geonet to be approximately 98,000 Ib
a.i. hovvever, calculations based on acreage estimates and application rates
indicate usage at 51,000 Ib  (Geomet, 1980, GS0009-021) „  The manufacturer
suggests usage at 25,000 Ib  for ornamentals (Sparks, 1980, GS0009-071) .  It has
been reported that in 1979,  20 Ib of Terrazole were used for treatment of
avocado trees and that  in the event of a widespread disease out-break 72,000 to
1,224,000 Ib a.i. would be used to treat 51,200 acres  (Geomet, 1980, GS0009-
021) .  The estimated usage for avocados in 1979 was approximately 20 Ib a.i.
(Gecmet, 1980, GS0009-020) ;  however, communication with the manufacturer
indicates that the usage greatly exceeds this figure (Sparks, 1980, GS0009-071) ,
 Topical Discussions

The Topical Discussions listed below correspond to the sections in the
"Proposed Guidelines for Registration of Pesticides" of July 10, 1978 (43
CFR No. 163) .  These sections explain the minimum data the Agency
retires to assess Terrazole1 s  Environmental Fate,,

    Topical Discussions                   Guidelines Section

    Physico-chemical Transformation         163.62-7 (b) and (c)
    Metabolism
      Soil                                  163.62-8(b) and (c)
      Microbial                             163.62-8(f) 2 and 3
      Activated Sludge                      163o62-8(g)
    Mobility                                163.62-9 (b) , (c) ,  (d) , and (e)
    Field Dissipation                       163.62-10 (b) , (c) ,  (d)  , and  (e)
    Accumulation                            163.62-11 (b) , (c) , and (d)

PHYSICO-CHEMICAL TRANSFORMATION

Hydrolysis

Hydrolysis data are usually  required to support the registration of all
manufacturing-use products regardless of the  intended  end uses of  the
formulated products.

Two studies relating to the  hydrolysis of Terrazole were reviewed, and
both were considered valid.  Thomas,  (1975, 00001650)  determined the
rate of [3-  C] Terrazole hydrolysis in 0.01  M phosphate buffered
solutions at pH values of 5.1, 7.1, and 8.9 and in distilled water at room
temperature, in the dark.  Half-life values of 82, 83, 81,  and  85  days
                                      35

-------
were  reported under the respective experimental conditions.  The acid
metabolite  (3-carboxy-5-ethoxy-l, 2,4-thiadiazole) waj reported as
the only hydrolysis product.  The hydrolysis of  [3-  C] Terrazole was
also  studied at  25, 35, and 45 C at specified pH values  (Thomas, 1976,
00001652) .  The  data  in this study indicated that the rate of
Terrazole hydrolysis  increased with increasing temperature and pH  (Table
1) .   At  pH  6, half-life values of 103, 30, and 12 days were obtained at
25, 35,  and 45 C,  respectively.  The major hydrolysis product identified
was the  acid metabolite.

The results of the above studies demonstrate that Terrazole is hydrolyzed
in phosphate buffered solutions and in distilled water.  The rate of
Terrazole hydrolysis  increases with increasing temperature and pH.  The
major hydrolysis product is 3-carboxy-5-ethoxy-l,2,4-thiadiazole.

These studies fulfill the hydrolysis data requirements in Section 163.62-
7(b).

Photolysis

Photodegradation studies in water are required to support the
registration of  all formulated products intended for terrestrial (except
greenhouse  or domestic outdoors)  , aquatic, and terrestrial/aqua tic
(forest) uses.   These studies are not intended to assess potential
hazards  that may be associated with indirect pesticide discharges into
waste-water treatment systems.

In addition, studies  in soil are required to support the registration of
all formulated products intended for crop and terrestrial/aquatic (forest)
uses.
 Two  studies  relating  to the photolysis of Terrazole were reviewed and
 both were judged  invalid because dark controls were not employed.  Thus,
 all  data as  specified  in Section 163.62-7 (c) are needed to determine the
 effect of light on Terrazole degradation.

 METABOLISM

 Data on metabolism are required to determine the nature and availability
 of pesticide residues to rotational crops and to help in the assessment of
 potential disposal and re-entry hazards.

 Soil

 Aerobic metabolism studies are required to support the registration of all
 formulated products intended for terrestrial uses or terrestrial/aquatic
 (forest)  uses.  Anaerobic soil metabolism studies are required to support
 the  registration of all formulated products intended for field and
 vegetable crop uses.

 Four studies pertaining to soil metaboliaiji.ware reviewed and three were
 considered valid.  The degradation of [3-  C] Terrazole was studied
after application at 1.2 ppm to Tiak sandy loam and My silt loam soil
 incubated at either 25 or 38 C (Thomas, 1976, 00001657).  The
concentrations of Terrazole and its degradation products, the dichloro and
                                      36

-------
    Table 1.  Hydrolysis half-life data for Ll-C] Terrazole'
Temperature
(0
(ppm/day)
25






35





45





Buffer
PH
3.0
6.0
9'3b
5.2°
7 1°
8.9° b
Dist. water
3.0
6.0
9.3
3.0
6.0
9.3
3.0
6.0
-9.2
3.2
6.0
9.2
Initial
Terra zole
concentration
(ppm)
6.23
6.23
6.23
46.0
43.2
45.0
54.0
6.23
6.23
6.23
43.6
40.0
55.6
6.23
6.23
6.23
40.0
58.0
59.4
Half-life
(days)
112
103
109
32
33
81
35
30
30
20
31.5
30
28.5
10.3
12
5
9.5
12
7.5
Hydrolysis
rate
0.027
0.030
0.028
0.28
0.24
0.27
0.33
0.10
0. 10
0.15
0.70
0.65
0.94
0.30
0.26
0.61
2.16
2.38
3.87
a Adapted from Thomas (1976,  00001652).



b Adapted fron Thonas (1975,  00001650).
                                      37

-------
acid metabolites, after 10 days of incubation under aerobic and anaerobic
conditions are given in Table 2.  Ttoo other possible metabolites ware
CCL and oxalic acid (under aerobic or anaerobic conditions).  Generally,
after the first half-life an increase in soilboind radioactivity and
decrease in Terrazole and its metabolites occur under all conditions.
The half-life values of Terrazole ranged from 2 to 9.5 days under the
experimental conditions described in Table 3.  Metabolic pathways were
postulated for aerobic and anaerobic soil metabolism of Terrazole (Figure
1) .  Ercegovich (1976, 00001664) confirmed that C02 was a
metabolite of Terrazole by demonstrating that soil microorganisms released
more   CCL from soils treated with [3-  C] Terrazole than was
released from similarly treated sterile soils.

The degradation of Terrazole in sandy and silt loam soils planted with
green beans under greenhouse conditions was investigated (Kuchar, 1976,
00001662) .  No Terrazole residues remained in the silt loam soil
incubated for 71 days in a greenhouse following the application of [3-
  C]-Terrazole at 2 ppm.  In sandy soil, only 6 percent of the original
Terrazole remained after 71 days (Table 4) .  At the sane time, only 31 and
11 percent of the original radioactivity remained in the sandy and silt
loam soils, respectively.  Greater than 90 percent of the radioactivity
unaccounted for by Terrazole was in the form of the dichloro metabolite.
Concentrations of the acid metabolite and soilbound residues were less
than 2 percent in both soils.

In summary, these studies indicate that Terrazole can be rapidly metabolized
in sandy and silt loan soils under described anaerobic and aerobic
conditions.  The dichloro metabolite is the major metabolite formed under all
described experimental conditions.  The other two metabolites are CCu and the
acid metabolite.  No attempt was made to differentiate the effects or
hydrolysis, photolysis, and microbial metabolism on the degradation of
Terrazole.  tbwever, the formation of the dichloro metabolite and shorter half-
life of Terrazole in soil than  in distilled water suggest that Terrazole
degradation in soil was mainly due to microbiological processes.

Anaerobic soil metabolism data  requirements in Section 163.62-8 (c) are
fulfilled by the above studies.

Aerobic soil metabolism requirements are not fulfilled by the above
studies because, according to Section 163.62-8 (b) , a study using soil
other than sandy loam or silt loam is required to assess the fate of
Terrazole in soil, and the sandy and silt loan soil studies were too short
in duration.

Microbial Metabolism

Data on the effects of microbes on pesticide degradation and the effects
of pesticides on microbes are required to support the registration of all
formulated products intended for the following uses:  terrestrial noncrop,
tree fruit/nut crop, field/vegetable crop, terrestrial/aquatic  (forest) ,
and direct discharge aquatic impact.
                                      38

-------
                                     14,
Table 2.  Degradation products of [3-  Cj-Terrazole applied to soil
at 1.2 ppm.
Soil
Aerobic
25 C 36 C

25°C
Anaerobic
38 C
% of applied Terrazole remaining.
after 10 days
Terrazole
Sandy loam
Silt loam

Sandy loam
Silt loam
48 51
48 53
Dichloro
46 15
31 17
10
25
metabolite
43
48
0
5
a
13
22
Acid metabolite
Sandy loam
Silt loam
c
6
11
25
13
a 3-dichloromethyl-5-ethoxy-1,2,4-thiadiazole,
b 3-carboxy-5-ethoxy-1,2,4-thiadiazole.
c Mot detected.

Adapted from Thomas (1976,  00001657).
                                       39

-------
Table 3.  Half-lives of Terrazole in aerobic and  anaerobic  soils.
Metabolism
Aerobic



Anaerobic



Temperature (C)
25
38
25
38
25
38
25
38
Soil
Amy silt loam

Tiak sandy loam

Amy silt loam

Tiak sandy loam

Half-life (days)
9.5
6.5
9
9
3
2
D
2.5
Adapted from Thomas (1976, 00001657).
                                        40

-------
Table 4.  Analysis of soils for radiolabeled Terrazole and its
          metabolites after incubation under greenhouse conditions/
Terrazole


Soil type
.Sandy
Silt loam
Total
radioactivity
(% of applied)
31
11


(ppm)
0.135
0.0

(% of
applied)
6.3
0.0
Dichloro , Acid
metabolite metabolite


(ppm)
0.405
0.179

(% of
applied)
23.0
10.0

(% of
applied)
1.7
1.6
radioactivity

(% of
applied)
1
1
a Incubation for 71 days at 68 F; all analyses were run in duplicate
       and the results were averaged by the reviewer.

b Dichloro metabolite = 3-dichloro-5-ethoxy-1,2,4-thiadiazole.

c Acid metabolite = 3-carboxy-5-ethoxy-1,2,4-thiadiazole.

d Terrazole applied at 2 ppm.

Adapted from Kuchar (1976, 00001662).
                                               41

-------
Aerobic
        14
C1.,C —C —• N
       N     C-OC-H,
        \   /      '
          S
    Terrazole

Anaerobic

                                     Cl
                                            Dichloro metabolite
         ,14
   Cl   N     C-OC-Hc-
         \  /
           S
Ring fragments
                                      Cl
                                      i     14
                                  H — C — C   —
                                      Cl  N
               -OC-Hr
                  2
                             HO —C —C
                                       14
        Soilbound


            .14
->     COp™^ Atmosphe  r
                               Soilbound
                                   ^14
                              0   0
                              li   II
                         HO — C — C — OH
                                Acid metabolite

Figure 1.  Postulated metabolic pathways for aerobic and anaerobic soil
        metabolism of Terrazole (Thomas, 1976,  00001657).
                                       42

-------
Microbial - Effects of Microbes on Pesticides

Two studies relating to the effects of microbes on pesticides  were
reviev\ed and both were considered valid.  Some preliminary information on
the microbial metabolism of Terrazole is available in a report by
Ercegovich (1976, 00001664), who studied the effects of [   C]
Terra zole on populations of bacteria and fungi in silt loam and  sandy loam
soils.  Gradual evolution of   CCL from the soil samples indicated
that microbes were capable of degrading Terrazole.  The highest  level of
  CCL evolution was 6 percent of the applied radioactivity observed
over a 9-week period in soil containing Terrazole at 5 ppm, whereas  no
  CCL was evolved from sterile samples.  Kb attempt was made to
determine either the identity of the organisms that were responsible for
the degradation or the degradation pathway.  Kvien (1975,  00001567)  also
provided some preliminary evidence that microorganisms are capable of
utilizing Terrazole (formulation unspecified)  as a sole source of carbon.
tfe found 6 fungal and 5 bacterial species conmonly found in soil (8  and 17
tested, respectively)  that were able to grow on a median containing
Terrazole as the sole carbon source.  Two predominant soil organisms,
Micrococcus and Achromobacter, that were capable of growing on the medium
containing Terrazole were isolated from Tana silt loan soils by  enrichment
culture techniques.

Although the above studies are scientifically valid, they do not entirely
satisfy the requirement because both the degrading organisms and the
degradation pathways should be identified.

Microbial - Effects of Pesticides on Microbes

R)ur studies on the effects of Terrazole on microorganisms were
reviewed and three were judged valid.

Kvien  (1975, 00001567)  demonstrated that nitrification of urea and
ammonium sulfate (Ntt^)-SO^) fertilizers in soil was markedly
inhibited when they were coated with Terrazole  (reagent grade)  or when
liquid mixtures of (NH.)-SO* and Terrazole were used.  Complete
inhibition of nitrification for up to 3 weeks was observed with use  of.
Terrazole at concentrations as low as 1-2 ppm, indicating that the level
of nitrification inhibition by Terrazole was comparable to that obtained
with the commercial product N-Serve  (2-chloro-6-trichloromethyl  pyridine) .

Ercegovich (1976, 00001564) determined the effects of Terrazole on
pure cultures of bacteria and fungi chosen for their prevalence  and
special soil functions, as well as the effects of Terrazole on microbial
populations and their respiration and seven enzyme activities in silt and
sandy loam soils.  He found that technical Terrazole was not. bactericidal
at concentrations up to 30 ppn in pure cultures.  Most of the 23 bacterial
species tested wsre not profoundly affected at low concentrations (3»S~7«5
ppm)  of Terrazole.  Only 2 of 13 mycelial fungi were markedly inhibited by
Terrazole at 100 ppm.  Microorganisms that were not affected ware
protease, cellulase, and pectinase producers; wax and starch degraders;
and nitrogen fixers and denitrifiers.  In addition, Terraaale at 5 and 25
ppm in soils generally did not inhibit the growth of in situ populations
of fungi, actinomycetes, aerobic eubacteria, anaerobes, and spore-forming
bacteria.  At concentrations up to 125 ppm, [3-  C] Terrazole stimulated
rather than inhibited CCL evolution.  The enzyme activities in soils of


                                       43

-------
phosphatase, irwertase, protease, urease, and dehydrogenase were not
adversely affected over a 65-day period.  However, the alpha-amylase
activity was inhibited for at least 8 weeks in sandy loam soil containing
technical Terrazole at 25 and 125 ppm.  Catalase activity was slightly
inhibited for at least 21 weeks in this soil type containing technical
Terrazole at 5 and 25 ppm, but not in soil containing technical Terrazole
at 125 ppn.

In summary, Terrazole at field use doses markedly inhibits microbes
responsible for soil nitrification; however, no other soil microbes or
their function are significantly affected.

These studies fulfill the data requirements in Section 163.62-8 (f) (3)
pertaining to the effects of pesticides on microbes.

Activated Sludge

A laboratory study of the effects of pesticides on the wastewater treatment
process is required to support the registration of all manufacturing-use
products and all formulated products that are indirectly discharged into
wastewater treatment systems or are used as treatments in wastewater treatment
systems.

One activated sludge metabolism study was reviewed and considered valid
(lacoviello, 1979, GS0009-039) . [  C] Terrazole added to sludge at 3 and
80 ppn had no apparent effect on gross populations of microbes sampled 1 and 2
days after treatment.  Within 47 hours, unextractable radiolabeled  residues in
the solids accounted for 18 and 29 percent (8 and 80 ppn levels,  respectively)
of the applied radioactivity in the solids was extractable.  Terrazole and its
dichlorometabolite accounted for only about 0.05 percent of the extractable
residues; the maximum Terrazole concentration determined was 0.001  ppm 1 day
after treatment at 8 ppn.  The acid metabolite represented 1.8 percent of the
extractable residues obtained from the solids treated at 80 ppm but was
nondetectable in solids treated at 8 ppn.   A total of 48-54 percent of the
radioactivity was recovered from supernatant 47 hours after treatment, and the
combination of Terrazole and its acid and  dichlorometabolites in  solution
accounted for 15 percent of the Terrazole applied at 8 ppm and 43 percent of
the Terrazole applied at 80 ppn.  Terrazole was in the supernatant  at  0.1 and
19 ppm 1 day after treatment at 8 and 80 ppm, respectively, but no  detectable
anounts were found during the next 24 hours.   The acid metabolite was
undetectable in solution 1 and 2 days after treatment with Terrazole at 8 ppm,
and the rate of formation of the dichlorometabolite decreased during the second
day (1st day, 1.4 ppm;  2nd day, 0.8 ppm) .   However, the dichlorometabolite was
present at 4.7 ppm 1 day after treatment with Terrazole at 80 ppn and  17.9 ppn
was formed during the next day.  Similar results were obtained for  the acid
metabolite in the high treatment supernatant; respective values were 4 and 14.5
ppm.  Only 2-3 percent of the applied radioactivity was volatilized to
unidentified products during the 2-day incubation period.

In summary, this study sufficiently demonstrates that Terrazole is rapidly
transformed in activated sludge, despite the rate of treatment, and that the
compound has little, if any, effect on microorganisms in sludge.   The  study was
not conducted long enough to determine the fate and impact of excessive
metabolites formed from high concentrations of Terrazole added to sludge;
however, it is satifactory in spite of this minor shortcoming.
                                        44

-------
M3BILITY

Data on mobility are  required  to determine pesticide residue rnovanent
in  the environment.

Leaching

Leaching  data  are  required  to  support  registration of  formulated products
intended  for terrestrial noncrop,  tree  fruit/nut crop, field/vegetable
crop, and terrestrial/aquatic  (forest)  uses.

Two leaching studies  were reviewed and  are discussed below.

Data  from soil  colunn studies  (Thomas,  1976, 00001655) indicated that [3-
  C] Terrazole  (applied  at  6.23 ug/g and eluted with aqueous 0.01 M
CaSO. on  a 20-on colunn; three colunn volunes were collected) and its
dichloro  metabolite  (formed in the colunn)  readily leached from aged and
imaged Carnasaw silt  loam soils.   Greater than 60 percent of the added
 [   C]-Terrazole was  found in the leachate of an unaged silt loam soil
colunn; less than  5 percent of the added Terrazole was found in the
leachate  of Tiak sandy loam, 3nithdale  sandy loam, and My silt loam soils
 (Table 5) .   Comparison of leaching profiles of the aged versus the unaged
soils  indicated that  aged soils had a greater ability  to retain Terrazole
and its dichloro metabolite than did unaged soils.  These data indicated
that a decrease in sand  content and an  increase in organic matter content
increased the  leaching of Terrazole and its dichloro metabolite which
is  contrary to  the leaching behavior of most pesticides in soil.
Consequently,  further  investigation into the leaching behavior of
Terrazole in soil  is  warranted.  Belling et al. (1974, 05001190) reported
that technical  Terrazole was immobile  in Hagerstown silty clay loan, based
on  a soil thin-layer  chroma tog raphic  (TLC)  bioassay method.  These data
appear to contradict  the results of the above study.   However, the
procedure of sieving  the soil  to 250 urn removed some of the sand and
changed it  to a heavier  textured clay loam soil; therefore, the results do
not represent  those for  a typical  Hagerstown silty clay loam soil.
Nevertheless, the  data do contribute to an assessment of the mobility of
Terrazole in soil.

In  summary, Terrazole  and its  dichloro metabolite are mobile in coluvms
containing  silt loam,  sandy loam, loamy sand, and heavy silt loan soils, but
are immobile on silt clay loan soil TLC plates,

The behavior of Terrazole in the colunn systems is contrary to the usual
behavior  of organic pesticides.  Normally, less leaching occurs in soils
with higher amounts of organic matter.  Therefore, further assessment of
the mobility of Terrazole is needed as specified in Section 153.62-
9 (b) , in  order  to  adequately define the movement, via  leaching, of
Terrazole  in appropriate soils.

Volatility

Laboratory volatility studies  using nonradioisotopic analytical
techniques are required to support the registration of all formulated
products  intended  for greenhouse use.  ND data on the volatility of
Terrazole are available, thus all data as specified in Section 163.62-9 (c)
are needed.


                                       45

-------
Table 5.  Leaching  profiles of  [  C]-Terrazole  (6.25 ug/g)  from soil
columns
Soil
Tiak sandy loam
Amy silt loam
Staithdale sandy
loam
Carnasaw silt
loam
Aged Smithdale
sandy loam
Aged Carnasaw
silt loam
Organic Radioactivity
matter CEC pH recovered from
(%) (rag/100 g) (1:1) leachate (%)
1.5 8.3 4.8 1.2
2.0 18 5.0 5.0
0.9 11.5 5.7 0.9
2.5 25.4 4.7 65
1.3
23
Radioactivity recovered from
0-5 cm 5-10 cm
21 17
27 22
26 20
4 3
66 18
30 7
10-15 cm
18
25
17
3
9
8
soil of column (/&)
15-20 cm
20
16
16
4
5
7
20-25 cm
11
9
7
6.5
1.3
11
a Not reported.

Adapted from Thomas (1976, 00001655).
                                              46

-------
Adsorption/lDesorption

A laboratory study using radioisotopic or nonradioisotopic analytical
techniques is required to support the registration of all formulated
products intended for all terrestrial uses, terrestrial/aquatic (forest)
uses, aquatic uses, and aquatic impact uses (if the pesticides are
dicharged directly into the aquatic environment) . One study pertaining to
the adsorption/desorption of Terrazole was reviewed and considered
invalid.  Thus, all data specified in Section 163.62-9 (d)  are needed.

Water Dispersal

A field study tailored to one or more representative sites is required to
support the registration of all formulated products intended for aquatic
uses and aquatic  impact uses (if the pesticides are discharged directly
into aquatic sites) .

ND data on the water dispersal of Terrazole are available.

Terra zole formulations containing multiple active ingredients are used on
an aquatic food crop; however, this document deals only with the single
active ingredient formulations.  No data on the water dispersal of
Terrazole are required because the use pattern  indicates that introduction
of single active  ingredient formulations into the aquatic environment
would not occur.

FIELD DISSIPATION

A field dissipation study under actual use conditions is required to
support the registration of all formulated products intended for
terrestrial (except greenhouse) uses, aquatic uses, and
terrestrial/aquatic (forest) uses.  This document does not deal with
combinations or tank mixes of Terrazole that are used on field/vegetable
and aquatic food crops.

Terrestrial

Terrestrial field dissipation studies using the formulated product are
required to support the registration of representative pesticide
formulations intended for all terrestrial (except greenhouse)  uses.

Ebur studies were reviewed and considered valid.  Kuchar ( 1972, 00001763
applied a granular or dust form of Terrazole plus pentachloronitrobenzene
(PCNB)  to loam, clay, and sandy soils at rates of 0.125-2.5 Ib
Terrazole/Ac re.  Fran 2 to 3 months later, the author found no detectable
levels of Terrazole or its acid metabolite (sensitivity levels of 0.005
and 0.01 ppm, respectively)  except in sandy soil, in which Terrazole was
found at 0.09 ppn.  Kuchar  (1973, 00001661)  reported that no detectable
Terrazole was found in any soil sample from 1 week to 3 months after
application of Terrazole as a granular or emulsifiable concentrate alone
or with PCfcB to soil plots in Oklahoma (unspecified soil texture)  at 0.5-3
Ib ai/Acre.  Kuchar (1976, 00001659)  demonstrated that granular Terrazole
(applied at rates of 1 and 10 Ib ai/Acre)  and its dichloro metabolite
dissipated rapidly in silt clay loam and sandy loam soils.  The acid
metabolite dissipated at a slower rate but did not accumulate in these
                                     47

-------
soils.  All compounds were no nde tec table by 68 days after application of
Terrazole.  No further information was provided on the fate of Terrazole
or its metabolite.

Kuchar (1976, 00001660)  also reported that granular Terrazole
(applied at 1 and 10 Ib ai/Acre)  and its dichloro and acid metabolites
dissipated to nondetectable levels by 7 weeks after application to a fine
sandy loan soil.  A half-life of less than 1 week for Terrazole was
reported.  The mechanism of dissipation was not deduced.

These studies provided preliminary data showing the rapid field
dissipation of Terrazole and two of its metabolites (all compounds were
nondetectable from 1 week to 3 months).  If soil characteristics and
soil sampling depths data ware provided, the applicability of the studies
would be much greater.

Data in the following use areas are needed to assess the field
dissipation of Terrazole applied as a single active ingredient formulation;

    o  Domestic outdoor, ornamental, and turf uses - Section
       163.62-10 (b) (4)

Data are needed to determine the dissipation rate and the ultimate fate of
the following formulations of Terrazole:

       Emulsifiable concentrate      25% ai Terrazole
       Wattable powder               30 and 35% ai Terrazole
       Wettable powder/dust          30% ai Terrazole

ACCUMULATION

Data on accumulation are required to determine accimulation in food
webs.

Fish

A laboratory study employing radioisotopic or nonradioisotopic
analytical techniques is required to support the registration of all
formulated products intended for terrestrial noncrop, tree fruit/nut crop,
and field/vegetable crop uses; aquatic food crop and noncrop uses;
terrestrial/aquatic (forest) uses; and aquatic impact (direct discharge)
uses.

A single fish accumulation study was reviewed and considered.valid.  Iwan
(1976, 0001663)  investigated the possible accunulation of [  C]-
Terrazole residues and metabolites in the bottom-feed ing channel catfish
Ictalurus punctaj^s in a static system using silt loam soil.  The maximum
accunulation of   C radioactivity in the catfish tissue (0.3 and 0.04
ppn for high and low exposure concentrations, respectively)  was reached
within 3 days of exposure.  Cn. day 20,  the   C radioactivity had
declined to 0.09 and 0.009 ppn, respectively, for high and low exposure
concentrations (0.02 and 0.002 ppm, respectively) .  At both exposure
levels, the higher accunulation of Terrazole was found in the nonedible
portions (head and viscera)  .  The mean accunulation ratios for nonedible
and edible tissue were 3.7:1 and 4.6:1 at high and low exposure
concentrations,  respectively.  Approximately 50 percent of the   C that

                                    48

-------
accumulated in the catfish tissue by day 30 of exposure was eliminated by
day 30 of depuration.  The mean bioaccumulation factors for high and  low
exposure concentrations were 9.8 (range 4.7-24.5)  and 10.2  (range 4.2-21) ,
respectively,  in summary, Terrazole residues (parent plus  degradates)
accumulated in nontarget aquatic fish; the mean bio accumulation  factor was
10.

A fish accumulation study with a flow-through exposure system as
specified in Section 163.62-11 (d)  is needed to fully assess the  fish
accumulation properties of lerrazole under conditions of continuous
exposure to the parent material.
                                      49

-------
DISCIPLINARY REVIEW

Environmental Fate profile
Exposure Profile
Generic Data Gaps
Suggested Labeling

ENVIRON ffflMTAL FATE PROFILE

The environmental fate profile is designed to reflect the behavior of
Terrazole in the environment.  This behavior is closely associated with
the use pattern of the chemical.  Eventually, both Terrazole" s behavior in
nature and its use pattern will enable an assessment of any environmental
hazards that may be associated with this chemical or any of its uses.

Available data are insufficient to fully assess the environmental fate of
Terrazole.  Terrazole is hydrolyzed over the environmental pH range of 5-
9.  The rate of Terrazole hydrolysis was found to increase with jncreasing
temperature and pH.   For example, approximately 50 percent of [  C]-
Terrazole was degraded over a period of 85 days in distilled water at a
temperature of 25 C.  The acid metabolite (3-carboxy-5-ethoxy-l, 2,4-
thiadiazole)  was identified as the only hydrolysis product.

Radiolabeled Terrazole is rapidly metabolized in Tiak sandy and Any silt
loan soils under aerobic and anaerobic field and aerobic greenhouse
conditions.  The dichloro metabolite (3-dichloromethyl-5-ethoxy-l,2,4-
thiadiazole)  is the major metabolite; the other two metabolites are CCU
and the acid metabolite.  The aerobic and anaerobic soil metabolism of
Terrazole appear to proceed as follows:

 Aerobic         ^ Dichloro metabolite - - >  Soilbound
 -      /*         ^                      t
    Terrazole '       Ring fragments  ----- -*  C02 — - — ~> Atmosphere

  Anaerobic        Dichloro metabolite --  Soilbound
       Terrazole -- ± Acid metabolite - >  C&calic acid

The half-life values for Terrazole ranged from 2 to 9.5 days under
aerobic and anaerobic conditions in sandy and silt loam soils.  The half-
lives under aerobic conditions were two times longer than those under
anaerobic conditions.  Data also indicated that soilbound radioactivity
increased as Terrazole and its metabolites decreased after the first half-
life.  In the study of soil metabolism of [3-  C]-Terrazole in sandy
and silt loam soils planted with green beans under greenhouse conditions,
77-89 percent of the applied radioactivity had dissipated from the soil
after 71 days.   Only 1 percent of the applied radioactivity was
soilbouid.  Therefore, it is possible that observed dissipation of   c-
labeled material was due to the movement of Terrazole and its metabolites
away from application sites by volatilization, leaching, or trans-
location.  Soil metabolism appears to play a major role in the degradation
of Terrazole in the soil, since shorter Terrazole half-lives were observed
in soils than in water and two metabolites other than the acid metabolite
were obtained from soil  metabolism.
                                       50

-------
 Several cannon  soil organisns  (six fungal and five bacterial species)  can
grow on agar containing Terrazole as a sole carbon source.  These are
 species of Aspergillus, Candida, Geotrichum, Mucor,  Rhizopus,
Penicillium, Bacillus, Mycobacterium, and Micrococcus (Sarcina).
 Through the use of a Terrazole enriched culture technique, species of
 Micrococcus and Achromobacter were isolated on Terrazole containing agar
 fron,Tama  silt loam soils.  In addition, microbes are capable of degrading
 [3-  C] Terrazole to   C02 in Snithdale sandy loam soil.  The
highest level of   CCu evolution vas 6 percent of the applied
 radioactivity observed over a 9-week period in soil containing Terrazole
at 5 ppn.  Terrazole at field use doses markedly inhibits microbes
responsible for soil nitrification; however, no other soil microbes or
their functions will be significantly affected.

                                                       14
Data from  soil colunn leaching studies indicated that [   C]Terrazole
 and  its dichloro metabolites readily leached from aged and unaged Carnasaw
 silt loam  soil with 2.5 percent organic matter, but little leaching
occurred in Tiak sandy loan, Snithdale sandy loam, and Any silt loam soils
 having organic matter contents of 2 percent or less.  Data also showed
 that aged  Terrazole-treated soils appeared to have a greater binding
ability than maged treated soils.  Thus more Terrazole residues become
 soilbound  and less leaching occurs as the soils age.  Due to its
 relatively slow hydrolysis and its leaching characteristics, Terrazole
 residues may present potential hazards in the aquatic environment or with
 respect to ground water contamination.  Additional studies as outlined
 under Data Gaps will provide information that will help to define the
potential  and extent of groindwater contamination.  Ibwever, monitoring
 studies nay be required to adequately define the potential hazard.  The
chemical is persistent and does pose potential accumulation problems in
g ro urd we ter .

 Field dissipation studies confirmed the potential for notable movanent of
 Terrazole  in the soil,  ito Terrazole residues were detected in sandy loam,
loan, or sandy soils 5 weeks after treatment with Terrazole in granular or
 emulsifiable concentrate formulations at rates up to 10  Ib a i/Acre.  The
dichloro and acid metabolites dissipated to negligible levels by 8 weeks
after application.  The overall half-life of Terrazole is approximately
 1 to 2 weeks.

The  available data do not indicate significant long-term accunulation of
 Terrazole,in fish.  Terrazole residues accunulated in catfish exposed to
aged [3-  C] Terrazole in a static systan.  The maximun  accunulation was
reached within 3 days of exposure.  By day 29 of exposure to the compound
at high and low concentrations (0.02 ad 0.002 ppm,, respectively)  in water,
 residue levels had declined to 0.09 and 0.009 ppm   C, respectively, and
stayed at these levels to the end of the exposure period.  Approximately
50 percent of the   C that accunulated in the catfish edible tissue by
day  30 of exposure was eliminated by day 30 of depuration.  The mean
bioaccunulation factor for radioactive residues was 10.

When Terrazole is added to sludge there is no effect on gross microbial
populations, and the compound is rapidly degraded to trace levels.  The
acid and dichloro metabolites can accunulate in solution to 40 percent of
the  applied Terrazole.  At low treatment levels (e.g., 8 pp^n) the acid
metabolite is undetectable for 2 days after treatment and the rate of
                                     51

-------
formation of the dichloro metabolite decreases about 50 percent from the
first to the second day post-treatment; the total amount representing
about 25 percent applied Terrazole.  Oily 2-3 percent of the applied
Terrazole is volatilized after 2 days in sludge.   About 50 percent of the
applied anoint becomes associated with the solids, half of which is
unextractable.

In  summary, although data deficiencies exist which prevent forming a
comprehensive profile of the fate of Terrazole in the environment, the
available information indicates that Tarrazole is hydrolyzed slowly under
environmental conditions and is metabolized rather rapidly in soil by
several soil/fungi and bacteria.  The overall half-life value in soil is
less than 10 days.  Major degradation products are its acid metabolite
(3-carboxy-5-ethoxy-l,2,4-thiadiazole)  and its dichloro metabolite (3-
dichloro-methyl-5-ethoxy-l,2,4-thiadiazole) .  The other product is OX,
under aerobic conditions.  Terrazole at field use doses has no  adverse
effects on soil microbes or their functions except for nitrification.
Terrazole and its dichloro metabolite can leach through most types of
soils.  Terrazole and its metabolites dissipate rapidly in soil by means
of  hydrolysis, microbial degradation, and leaching.   In addition,  once the
initial half-life is reached, soilboind residues rapidly accumulate.  The
potential for long-term accumulation of Terrazole and its metabolites in
catfish appears low and is further reduced by depuration.

EXPOSURE PROFILE

Introduction

Single active ingredient formulations of Terrazole are registered  for
control of Pythium on turf (35% WP; 30% WP/t>) , Pythium and Phytpphthpra
on  ornamentals (30% WP;  35%  WP; 25% EC, 5% G)  on avocados (California
only, 4 Ib/gal EC; 5% G) .  Application to turf (primarily golf  course
greens)  is by boon sprayers or from 400-500 gallon tanks with hand-held
spray wands.  Control of soil fungi on ornamentals is mainly through
irrigation systems, by soil drench, and to a lesser  extent, by  dry soil
incorporation.  Tarrazole appplication to avocado trees is by soil drench
with the EC formulation or by surface application and flushing  with the
granular formulation.

All Formulations

Single active ingredient formulations of Tarrazole are not applied
aerially, and are therefore not expected to result in direct contamina-
tion hazards (via spray drift)  to humans, livestock, or wildlife outside
the application sites.  The potential for exposure via spray drift is
further minimized by the use of boom type sprayers (as opposed  to  air
blast machines)  which direct the spray downward.   The greatest  potential
for direct exposure is to the mixers and applicators of these
formulations, but no quantitative data are available to estimate the
degree of sueh_exposure.  The low vapor pressure  of the manufacturing-use
product(l x 10   mm Hg at 25 C)  suggests a limited potential for
exposure by inhalation of volatilized Terrazole.
                                     52

-------
The relatively slow hydrolysis of Terrazole (t, /„  at about 103  days  at
pH 6 and 25°C), and the apparent leaching of Terrazole and its
dichloro metoblite, indicate a potential for groundwater contamination and
exposure of aquatic organisms.  An octanol/water  partition coefficient of
405 (at 12.5 ppm in water at 25 C) suggests the  possibility of
bio accumulation, but bioassay data do not stow long-term accumulation of
Terrazole in  the channel catfish, Ictalurus punctatus.  Under static test
conditions, a mean bio accumulation factor of approximately 10 was reported
for this fish, with maximum accumulation occurring within 3 days  of
exposure.  Exposure to terrestrial organisms is  expected to be  minimized
by rapid field dissipation.

Emulsifiable Concentrate Formulations

Emulsifiable  concentrates of Terrazole are registered for control of
Phytophthora  and Pythium on ornamentals, and Phytophthora on avocados.
The potential for dermal and ocular exposure is recognized from
splashing which may occur during dilution and tank-mix operations.  When
soil drench is accomplished by irrigation, exposure to Terrazole  can occur
when the EC containers are opened and the injector tubing is inserted.
Dermal  exposure can also occur during handling of treated plants, but
there  is no information as to the extent of such exposure.

Wettable Powder and Wettable Powder/bust Formulations

The greatest  human exposure resulting from the use of Terrazole is
expected  in persons involved  in  the mixing and application of formulations
registered for use on turf  (35% WP; 30% WP/D) .  This is due to  the
widespread use of these formulations, especially for control of Pythium on
golf courses, and because applications are repeated up to six times  per
year.   Respiratory exposure, from "puff" back during opening and  pouring
of these  formulations may represent the greatest exposure potential.
Dermal  or  inhalation exposure to  persons (golfers and groundskeepers)
following turf application is considered small.

The use of the 35% WP as a dry soil mix  for control of Phytophthora and
Pythium on ornamentals can result in dermal  exposure when workers handle
treated soil.  Such exposure would be limited, however , by the  use of
gloves, and because this use of  Terrazole  is a minor method of application
in large grower operations.

The use of WP and WP/D formulations  should not result  in  exposure to
wildlife or livestock during application, due to the use of directional
sprayers  which reduce  the potential  for  spray drift.   The potential for
human  exposure via contamination of drinking water cannot be ruled out.

Granular Formulations

The granular  formulation is  used  in very small quantities to control
root rot of avocados and as  a dry soil mix to control damping-off root
and stem  rot  in outdoor plantings of ornamental and  nursery stock.  These
uses will allow primarily dermal  exposure.   Dermal contact can be
essentially prevented  by the  use  of gloves  for workers while handling  the
fungicide  and the  treated soil.   Under  those conditions,  exposure to  the
granular  formulation would  be  insignificant.
                                      53

-------
A 5% granular formulation of Terrazole is registered for control of
Pythium and Phytophthora on ornamentals, and phytophthora on avocados
(California only) .

GENERIC DATA GAPS

The following are data gaps in the Environmental Fate data base.  These
date are needed to adequately support registration of Terrazole under
this Standard.

                                                 Guideline Sections

For Manufacturing-Use Terrazole:

    (1) Photolysis                               163. 62-7 (c)
    (2) Soil Metabolism
        - Aerobic                                163.62-8 (f) (2)
    (3) Microbial Metabolism
        - Effect of microbes on pesticides       163. 62-8 (f) (2)
    (4) Mobility
        - Leaching                               163.62-9(b)
        - volatility                             163.62-9(d)
    (5) Field Dissipation
        - Terrestrial: household and             163. 62-10 (b) (4)
          noncrop use for the following
          formulations: 25% ai EC; 30 and 35%
          ai WP; 30% ai D; 5% G
    (6) Accumulation
        - Fish: using a flow-through             163. 62-11 (d)
          exposure system

Suggested Labeling

There  are no environmental fate requirements for manufacturing-use
Terrazole labels and no label restrictions for end-use products with
Terrazole as the sole active ingredient.

-------
BIBLIOGRAPHY

00001664—Ercegovich, C.D. 1976.  Effects of 5-ethoxy-3- (trichlorom ethyl )-
    1,2,4-thiadiazole (Terrazole) on microorganisms and biochemical
    processes in soil:  Report No. E-l/1/76  (0).  (Unpublished study
    received Oct. 20, 1976, under 1258-812; prepared by PA. State Univ.,
    University Park, Pesticide Research Laboratory; sunbitted by 01 in
    Corp., Agricultural Div., Little Rock, Ark. CDL:  228143-AD.

GS0009-020—Geomet Technologies, Inc., Compilation of Data Related to Exposure
    to Terrazole, Geonet Technologies, Inc., Rockville, MD, my 14, 1980a.

GS0009-021—Geomet Technologies, Inc., Use Data for Exposure Analysis of
    Terrazole, Geomet Technologies, Inc., Rockville, MD, July 17, 1980b.

05001190—Helling, C.S., D.G. Dennison, and D.D. Kaufman, 1974.  Fungicide
    movement in soil.   Phytopath  64(8):  1091-1100.

GS0009-039— lacoviello, S.A. 1979.  Activated sludge test for Terrazole 3-
      C  (3-trichloromethyl-5-ethoxy-l,2,4-thiadiazole) .  (Olin Corp.
    report CASR-14-79,  prepared Apr. 12, 1979 by Olin Research Center,
    Analytical Department, New Haven, CN)  (CDL: 238774)
                                  14
00001663—Iwan, G.R. 1976.  Olin—  C Terrazole channel catfish
    (Ictalurus punctatus Rafinesque) , static bioaccunulation study.
    (Unpublished study  received Oct. 20, 1976, under 1258-812; prepared by
    Union Carbide Corp, Aquatic Environmental Sciences; submitted by Olin
    Corp., Agricultural Div., Little Rock, Ark. CDL:  228143-AB.)

00001763—Kuchar, E.J.  1972.  Residues of Terrachlor, Terrazole and
    metabolites in soil:  CASR-5-72.  (Unpublished study including letter
    dated Get. 12, 1972, from R.F. Ehilpitt to P.C. Williams, received
    Oct. 17, 1972, under 1258-Q; submitted by Olin Corp., New Haven , CN
    CDL:  120359-A) .

00001661—Kuchar, E.J.  1973.  Residues of Terrachlor and Terrazole in soil
    —1972 studies:  CASR-19-73.   (Unpublished study received Oct. 20,
    1976, under 1258-812; submitted by Olin Corp., Agricultural Div.,
    Little Rock, Ark CDL:  228143-X.)

00001659—Kuchar, E.J.  1976.  Field soil dissipation studies concerned
    with Terrazole (5-ethoxy-3-trichloronethyl-l, 2,4-thiadiazole :  CASR-6-
    76.  (Unpublished study received Oct. 20, 1978, under 1258-812;
    submitted by Olin Corp., Agricultural Div., Little Rock,  Ark.  CDL:
    223142-S.)

00001660—Kuchar, E.J.  1976.  Terrazole (5-ethoxy-3-trichloromethyl-
    1,2,4-thiadiazole)  greenhouse studies in soil:  CASR-24-76.
    (Unpublished study  received Oct. 20, 1976, under 1258-812; submitted
    by Olin Corp., Agricultural Div.,  Little Rock, Ark.  CDL:  228143-Y) .
                                          55

-------
00001567—Kvien, C. 1975. Nitrification inhibition in soils by Terrazole.
    Master's thesis, Southern Illinois University, Department of Plant and
    Soil Science.   (Unpublished study including report no. 3067, received
    Feb. 4, 1977, under 1258-812; submitted by CO-in Corp., Agricultural
    Div., Little Rock,  Ark. CDL-095799-J.)

GS0009-070—Sparks, D. , Sales Manager, Crop Protection Chemicals, Olin Cbrp.,
    Little Rock, Ark, personal communication to E.N.  Pelletier, BFSD, EPA,
    Washington, D.C. March 31, 1980a.

GS0009-071—Sparks, D. , Sales Manager, Crop Protection Chemicals, Olin Corp.,
    Little Rock, Ark, personal communication to E.N.  Pelletier, BFSD, EPA,
    Washington, D.C., Aug. 11, 19S0b,,

00001650—Thomas, R.j.  1975.  Analytical investigations concerned with the
    rate of hydrolysis  of Terrazole-C-14:  CASR-7-75.   (Unpublished study
    received Oct. 20, 1976, under 1258-812; submitted by CO.in Corp.,
    Agricultural Div.,  Little Rock,  Ark. CDL:228143-H.)

00001652—Thomas, R.j.  1975.  Analytical investigations concerned with the
    rate of hydrolysis  of Terrazole-C-14:  CASR-7-75.   Supplement #1.
    (Unpublished study received Oct. 20,  1975 under 1258-312; submitted by
    Olin Corp., Agricultural  Div.,  Little  Rock, Ark.  CDL: 228143-J.)

00001657—Thomas, R.j.  1976.  Laboratory soil metabolism studies concerned
    with Terrazole  (5-ethoxy-3-tr ichloronethyl-1, 2,4-thiadiazole) : CASR-7-
    76.  (Unpublished study received Oct.  20, 1976 under 1258-812;
    submitted by Olin Corp,,  Agricultural  Div., Little Rock,  Ark.
    CDL:228143-Q.)

00001655—Thomas, R.j.  1976.  Laboratory soil leaching studies concerned
    with Terrazole  (5-ethoxy-3-tr ichloromethyl-1, 2,4-thiadiazole) : CASR-4-
    76,  (Unpublished study received Oct.  20, 1976 under 1258-312;
    submitted by Olin Corp.,  Agricultural  Div., Little Rock,  Ark.
    CDL:228143-M.)
                                         56

-------
Chapter 5

TOXICOLOGY

TOPICAL DISCUSSIONS

The Tbpical Discussions listed below correspond to the number of the section in
the Proposed Guidelines (43 FR, No. 163, 37336) which explains the minimum
data that the Agency usually requires in order to  assess a pesticide' s
Toxicology.  Where no section nunber is listed a minimum requirement has not
been set for such information.
Metabolism and Pharmacodynamics
Acute Effects and Neurotoxicity
Subchronic Effects and Neurotoxicity
Sensitization
Chronic Effects
Cncogenicity
Mutagenicity
Teratology
Reproductive Effects
Emergency Treatment

.METABOLISM AND PHARMACODYNAMICS

Metabolism studies are required with a single dose of analytically pure,
radioactive Terrazole.
                                                  Guidelines  Section(2)

                                                 163.85-1
                                                 163.81-,  -2,  -3,  and -7
                                                 163.82-1,  -2  -4,  -5,
                                                 163.81-6
                                                 163.83-1
                                                 163.83-2
                                                 163.84-1,  -2,  -3, and  -4
                                                 163.83-3
                                                 163.83-4
 Technical
                                                                     rats,
A series of studies of Terrazole metabolism in DJtch rabbits, Wistar
and mongrel dogs was conducted by McKennis et al .  (1970,  00001599) .   Two  forms
of radiolabeled Terrazole were administered at doses of 0.87  to  6  mg/kg  in
single doses with or without pretreatment at 5.75  mg Terrazole per kg  body
weight.  Doses were administered in olive oil and  the   C label  was on the
thiadiazole ring (carbon 3)  or in the ethoxy group.   Urine and expired air were
analyzed for radioactivity and were also analyzed  chemically to  determine the
amount of the administered dose excreted and the chemical nature of metabolites
over various periods of time following treatment.

All three species metabolize Terrazole to a water  soluble carboxylic  acid (3-
carboxy-5-ethoxy-l, 2,4-thiadiazole)  which is rapidly excreted in the  urine.
Rats eliminated 69 percent of the administered dose  in 72 hours  while rabbits
excreted approximately 43 percent of a similar dose  (5.75 mg^'kg)  in the  same
amount of time.  A small fraction of the radioactivity from   C ethoxy
labeled Terrazole was eliminated in expired air which indicates that  de-
ethylation of Terrazole or its carboxylic acid metabolite does occur.
Pretreatment of animals with daily doses of 5.75 mg  Terrazole per  kg  body
weight for 3 to 18 days prior to administration of labeled Terrazole  had little
effect on excretion rates.

Fbur male and four female mongrel dogs were administered a single  oral dose of
32-54 mg/kg 01 in 2424 as a 5 percent solution in  corn oil  (01 in, 1965,
00001577).  Blood, urine and fecal samples were collected from six animals at
                                        57

-------
intervals up to 72 tours after dosing, and residues of Terrazole in various
organs were determined at necropsy (72 hours)  in two of six dogs.  Blood was
collected from two other dogs 2 and 4 hours after dosing, and  tissue residues
were determined at necropsy (4 hours) .  Terrazole residues found in blood at
various intervals ranged from 1 to 2.4 ppm 2 tours after treatment, and  0.8 to
1 = 3 ppm 6 hours after treatment.  Terrazole levels were measured in various
organs fron one dog of each sex both 4 and 72 tours after dosing.  The highest
"apparent residues" (no control samples)  were found in fat 4 hours after
treatment and ranged from 24 to 28 ppn.  Fat sanples were not analyzed at the
72-hour necropsy.,  No Terrazole was detected in any of the fecal samples, and
only very low levels were present in urine sanples „

Kuchar (1970a, 00001597) administered CM52424 (more than 95% Terrazole)  at
levels of 0P 10, 100P and 1,000 ppm in the diet to groups of four male and four
female beagle dogs for periods of up to 2 years.  Blood and urine samples were
taken at 1,3, and 12 months.  The dogs were sacrificed after 12  or 24 months.

HLood levels of animals at the 1,000 ppm level  were in the 0.25  to 0.55 ppm
range at the end of both 1 and 12 months.  However, at the end of 3 months, the
average blood level in these animals was only 00068 ppm (range 0.046 to 0.90).
The recovery of QM52424 fron blood averaged about 85 percent.

Urinary levels of CM52424 shoved no relationship with the anoint of test
compound ingested.  No CM52424 was detected at  the 0 ppn and 10  ppn
feeding levels throughout the first 12 months.   (No measurements were available
for the 2nd year) „  The highest levels were recorded in a female at the 100-
Pfm dose level after 6 months (0.042 Ppm) .  The percentage of recovery of
CM52424 from the urine averaged about 80 percent.

The highest concentration of CM52424 was present in fat tissue.   The average
tissue levels for controls and animals receiving 1,000 ppn are presented in
Table 3-1.   There was no chromatographic evidence of a metabolite of CM52424 in
any of the  tissues „

Kuchar (19705, 00001601)  conducted in vitro studies to determine if 3-carboxy-5-
ethoxy-l,2,4-thiadiazole and 3-carboxy-5-hydroxy-l,2,4-thiadiazole are formed
when 8.9 mg of Terrazole is added to 20 ml of simulated gastric  juice at pH
2,0, 5.5  or 9o5.   The  quantities of these compounds formed (based on the amount
of Terrazole reacted)  showed 'that 3-carboxylic  acid is the only  product
found after 4 hours (see Table 3-2) .   The 3-carboxy-5-hydroxy product was found
to accoun.t  for 2  percent of the Terrazole reacted after 24 hours.
                                     58

-------
TABLE 3-1—Tissue  Residues in Dogs Given Diets Containing Terrazole

Tissue  type                            '""    OF52424
(% recovery)   	12 months    	24 months
Kidney  (85%)

        0
    1,000

Brain (90%)

        0
    1,000

Liver (77%)

        0
    1,000

Muscle  (84%)

        0
    1,000

Fat (85%)

        0
    1,000

Spleen

        0
    1,000

Heart (89%)

        0
    1,000  (total)
    1,000  (fat)
Not detected  (M)
0.60  (M)        0.59  (F)
Not detected
0.30  (M)        0.22  (F)
Not detected
0.02  (M)        0.02  (F)
Not detected
21.6  (M)
Not detected
0.14  (M)
12.4 (F)
0.10 (F)
               Not detected
               0.46  (M)       0.37  (F)
               Not detected
               Not detected
                              Not detected
                              4.66  (M)        0.64  (F)
Not detected
17.7 (M)       9.8 (M)
Not detected
1.8 (M)        1.7  (F)
7.3 (M)        6.3  (F)
                                      59

-------
TABLE 3-2—Terrazole Reactions in Simulated  Gastric  Juice at 37 C
           based on mg Terrazole consumed)
ph
2.0
5.5
9.5
2.0
5.5
Hours
4
4
4
24
24
% Terrazole
reacted
3
13
11
6
6
11
13
1
3-carboxy
26
4
5
7
10
2
7
65
                                    60

-------
This study  indicates that Terrazole is susceptible to chemical breakdown in
gastric ju^ce.  The trichioromethyl group of Terrazole is cleaved in acid or
base at 37 C to yield the 3-carboxy acid product.  Tne enol ether group is
also cleaved within 24 hours at pH 2.0 and 37 C, leading to the 3-carboxy-5-
hydroxy product.  These polar acid products derived from Terrazole are
probably less readily absorbed from the gut.

Terrazole (purity unspecified)  was found to be an inhibitor of the microsomal
enzyme system in a study by Calvi and I-fowell (1977,- 05004729).  Liver
microscmes were prepared from mice 24 hours after administration of a single
intraperitoneal dose of 2.0 moles/kg (495 mg/kg)  of Terrazole.

Concentrations of cytochrone p-450 in microscmes from livers of these mice
were decreased to one-third of control values.  Both benzyphetamine demethylase
and aniline hydroxylase activities were also markedly decreased.  Pre-incuba-
tion of Terrazole (with and without NADPH)  with cytochrome P-450 from mice with
pretreated phenobarbitol produced decreased cytochrome P-450 only when both
Terrazole and NADPH were present in the incubation medium, indicating that
Terrazole may require metabolism to produce a toxic effect in the liver.

The effect of Terrazole on NADPH stimulated lipid peroxidase activity in
phenobarbitol induced mouse liver microscmes was investigated.  Mixtures of
NADPH and the mouse liver microsomes ware incubated with EDTA (an inhibitor of
this type of lipid peroxidase activity) , with Terrazole (1 mM in EMSO) , or
with nothing added.  Activity was determined by the amount of malonaldehyde
formed.  Results showed that EDTA completely inhibited lipid peroxidase
activity and Terrazole inhibited activity by 30 to 40 percent when compared to
the NADPH-microsome mixture alone.

In summary, a single water-soluble urinary metabolite of Terrazole (3-carboxy-5-
ethoxy-l,2,4-thiadiazole)  has been detected in the rabbit, rat, and dog
(K;Kennis et al . 1970, 00001599).  Terrazole is rapidly metabolized in rat and
rabbit to this mono-acid and de-athylated metabolites and  eliminated in urine
at a rate of 69% in rats and 43% in rabbits within 72 hours.  The highest
Terrazole residues in the tissue of the dog, after both acute and subchronic
dosing, were found in fat (01 in 1965,  00001547; Kuchar 1970a, 00001597).  No
metabolites were identified in tissues analyzed by gas chromatography (electron
capture detector) .  In the gut, the trie hi orom ethyl group breaks down to give
the mono-acid, and the enol ether group degrades to the 3-carboxy-5-hydroxy
product.  Terrazole or a metabolite inhibits the mitochondrial oxidative
metabolism in mouse liver.  These data adequately characterize Terrazole's
metabolism.

ACUTE EFFECTS AND NEUROTOXICITY

Oral Toxicity

The minimum data requirements for testing acute oral toxicity are as follows:
one test (LD,-,,)  for the technical formulation and one test for each end-use
formulation, preferably using the laboratory rat.

Technical

In male rats, the acute oral LEU™ of technical Terrazole (95.2% active
ingredient)  as a 10 percent solution in corn oil was estimated to be 1,077 -
                                6]

-------
78 mg/kg (Larson and Borzelleca,  1967,  00001555).   The only  reported  clinical
sign of toxicity before death was severe depression.  Perianal  staining  (but no
frank diarrhea)  was observed  in most of the  animals dosed.   No  obvious
pathological changes were seen on necropsy.   The data place  technical Terrazole
in Tbxicity Category III (See Appendix)  for  acute oral toxicity.

The following two studies represent supplemental  information on Terrazole1 s
toxicity.  In male albino rabbits the LE^0 of technical  Terrazole
(95.2% active ingredient)  dissolved in  corn  oil was 779  - 532 mg/kg  (Larson
and Borzelleca,  1970, 00001792).   Evidence of diarrhea was observed.  Yellow
livers ware observed at necropsy  in several  animals that had received 1,000 or
3,000 mg/kg of Terra zole.

in female mice, the LD   for  technical  Terrazole  (purity unspecified) at a
concentration of 10 percent in a  0.25%  agar  emulsion was 2,000  - 290  mg/kg
(Miller, 1961, 00001586).  Four of the  50 mice had  impaired  motor  activity^on
the day of treatment, and weight  loss was noted during the 10-day  observation
period.  Hswever, dose levels, necropsies, number of deaths, and statistical
methods were not reported.

Wettable Powder Formulations

One study is available on a wsttable powder  formulation  containing 30%
Terrazole (MDUlton, 1970a, 00001592).  The acute oral LE^0 in male and
female rats  (when this formulation was  administered in an aqueous  solution) was
4.70 g/kg.  No adverse clinical signs ware observed in animals  receiving the
lowest dose  (1.26 g/kg) .  Signs of toxicity  in animals receiving the  higher
dose levels  included malaise, ataxia, body tremors, diarrhea, pallor,
piloerection, lacrimation, weakness, arched  back,  inactivity, belligerence, and
hypersensitivity to touch.  The severity of  the clinical signs  was related  to
the dose.  The major proportion (nunber unspecified) of  survivors  appeared
normal by the end of the 14-day observation  period. Necropsy of the  animals
that died during the study stowed that  the majority (nunber  unspecified)  had
moderate-to-severe congestion of the gastrointestinal tract, adrenals, lings,
and kidneys, and speckled livers.  Cne  to five hemorrhages were observed in the
stomach linings of four of these  animals. Necropsy of the survivors  revealed
liver damage in five animals, thickening of  the stomach  wall in two animals,
and pitted kidney surface in  two  animals. The data indicate that  this
formulation  should be placed  in Category III (See Appendix)  for acute oral
toxicity.

No data exist concerning the  acute oral toxicity of the  wettable powder
formulation containing 35% Terrazole.  Fbwever, since the confidential
statement of formulation indicates that it  is similar  in composition  to  the
30% WP product the acute oral LDt0 is expected to be  similar and therefore
further testing is not required.

Emulsifiable Concentrate Formulations

Cne study is available for the 4  Ibs/gallon  emulsifiable concentrate
formulation of Terrazole (Palanker and  Coldhamer,  1973,  00001828).  In male and
female rats, the acute oral ID™  °f this formulation  was 1.3 ml/kg with  a 95
percent confidence interval or 0.8 to 2.1 ml/kg.   Depression was noted  in most
animals during the first 4 days of observation; survivors appeared normal by
                                 62

-------
the 7th day ard remained so through the end  of the  studyO  Necropsies  were  not
performed.  These results place the 4 Ibs/gallon formulation in  Category III
with respect to its acute oral toxicity.

No acute oral toxicity studies vvere available for the 25% emulsifiable
concentrate formulation.

Wettable Powder/Dust and Granular Formulations

There are no acute oral toxicity data on the 30% wettable powder/dust  products
containing Terrazole.  Fbwever , since the confidential statement of
formulation indicates that this product has a similar composition to  the
vvettable powder formulations, its acute oral LCu™ is expected to be similar
and therefore further testing is not required.

In an acute oral toxicity study, (Nham, Ean, et a,  1977,  GS0009-034)  rats were
given various doses of the 5% granular as a 40 percent (w/v)  corn oil
suspension.  The results indicated that the acute oral ID™ for  these  animals
was greater than 15,380 mg/kg since only one male died at this dose and  no
other mortalities were reported.  Tbxic signs observed during the 9 day
observation period included hypoactivity, diarrhea, muscular weakness, nasal
discharge, emaciation and high stance.  Necropsy of the animal that died during
the test revealed depletion of body fat, 3 hemorrhaged areas on  the pyloric
stomach lining, pale and mottled liver, purple testes and slight post mortem
autolysis.  Survivors showed no gross pathological  alterations.   The 5%
granular formulation is in Category IV with respect to its acute oral  toxicity.

Dermal Toxicity

The minimun data requirement  for acute dermal toxicity (LE^0) is one test for
the technical  formulation and one test for each end-use formulation, preferably
using the albino rabbit.

Technical

In male albino rabbits  (strain unspecified),  the acute dermal LD^g of
technical Terrazole was found to be 1,366  544 mg/kg  (Larson and
Borzelleca, 1964a, 00002227) .  The skin was not erythematous after the first
day.  Deaths were preceded by signs suggesting depression of the central
nervous system.  No histopathological examinations were conducted, but the
gross necropsies were essentially negative.   The data  indicate  that this
formulation should be placed  in Category II  (See Appendix) with respect to its
acute dermal toxicity.

Wettable Powder Formulations

Moulton  (1970b, 00001593)  studied  the acute dermal  toxicity of a wettable
powder  formulation containing 30%  Terrazole.  He determined the minimun Lethal
Dose of the formulation to be 2 g/kg  for male and  female New  Zealand albino
rabbits, when  applied as a 50% aqueous solution.   Dermal signs  included slight-
to-moderate erythema and siight-to-severe edema, with three of  the eight
treated animals  (sex and dose unspecified)  showing  scattered  yellowish lesions
at the  site of application 24-48 hours after  exposure.   Systemic signs of
toxicity were  weakness, anorexia, hypothermia,  and muscular  uncoordination of
the limbs.  At the highest dose  level, 4 g/kg;  both animals died; one died at
the next lowest level,  2 g/kg; the  rest of  the  treated animals  survived.


                                  63

-------
Necropsies revealed liver damage in animals that died during the treatment
period; no pathologic changes were observed in the survivors, except a small
sized liver in one animal.  Three of the five survivors also sufferred moderate
weight loss over the 4-day observation period.  These results are sufficient to
place  this formulation in Category II (See Appendix)  since the LD5g is
expected to be approximately 2gAg.

There are no data concerning the acute dermal toxicity of the wettable powder
formulation containing 35% Terrazole.  Fbwever, since the confidential
statement of formulation  indicates that it is similar in composition to the 30%
WP product the acute dermal LQ-j, is expected to be similar and therefore
further testing is not required.

Emulsifiable Concentrate Formulations

The only acute dermal toxicity study on an emulsifiable concentrate formulation
was performed by Duhamel and Paa (1978,  00001831)  with 4 Ib/gallon EC
Terrazole.  In young adult New Zealand albino rabbits, the acute dermal LD50
of this formulation, when administered undiluted, was 1.3 g/kg with a 95%
confidence interval of 0.8-2.1 g/kg.  Skin irritation ranged from moderate at
lower dose levels to severe at higher levels.  At the lower levels the animals
had pale erythema, mild edema, and moderate desquamation.  At the higher
levels, the animals had well-defined erythema, severe edema, second-degree
burns, and escharosis.  At middle dose levels and above, brief initial
hyper activity was followed by hypoactivity that persisted until death, or,
for 1-5 days in survivors.  Also, at high doses the majority of the animals
suffered muscular weakness frcrn the first day.  At the highest doses muscular
weakness was accompanied by ataxia and tremors.  Animals in the middle dose
groups snowed analgesia and mydriasis from day 1 until death, or until day 5 in
the case of the only survivor.  Ebr the  animals that died, 12 or 18 necropsies
were obscured by autolysis; of the 6 ranaining animals, some were reported to
have discolored livers or kidneys.  Three of these six animals had red or
hemorrhagic lungs, two had enlarged gall bladders, and one showed a depletion
of body fat.  No lesions were reported in any of the animals sacrificed at the
end of the study.  The data indicate that this formulation is in Tbxicity
Category II (See Appendix) with respect to its acute dermal toxicity.

No acute dermal toxicity studies were available for the 25 % emulsifiable
concentrate formulations.

Wettable Powder/bust and Granular Formulations

There are no acute dermal toxicity data  on the 30% wettable powder/dust
product containing Terrazole.  tfowever,  since the confidential statement of
formulation indicates that this product  has a similar composition to the
wettable powder formulations its acute dermal LD\-~ is expected to be similar
and therefore further testing is not required ana this formulaltion is placed
in Tbxicity Category II for acute dermal toxicity.

An acute dermal toxicity study with the 5% Granular formulation indicated that
the dermal LEV™ is greater than 16,000 mg/kg when the 5% G was administered
to New Zealand albino rabbits.  In this study two male and two female rabbits
were administered 16,000 mg/kg of the 5% G under an occlusive wrap (one half
of the animals had abraded skin and one  half had non-abraded skin) .  No
mortalities or pharmacotoxic symptoms were observed.   Slight edana and barely
perceptible erythema were reported at 24  hours and slight desquamation of the
skin was noted at 7 and 14 days.  At necropsy no gross pathological alterations

                                 64

-------
were seen.  The granular formulation has been placed  in Toxicity  Category  III
for acute dermal toxicity.

Inhalation

The minimum data requirement for testing acute inhalation toxicity (LC^)  is
one test for the technical formulation and one test for each end-use
formulation that produces a respirable vapor, or that have 20 percent or more
of their aerodynamic equivalent composed of particles not larger  than 10
microns.  Use of the laboratory rat is preferred.

Technical

The only study is one by Carson (1964, 00001591) , reporting no deaths among a
group of 10 FDRL albino rats exposed to 01 in 2424 at a level of 200  mg/liter of
air (length of exposure not specified) .  No details were provided on the
methods used in generating the test atmosphere, aerosol size distribution, or
sex of the animal.  This study is not completely reported and therefore does
not describe inhaltion toxicity adequately.

Wettable Powder Formulations

There are no data on acute inhalation toxicity on the two wettable powder
formulations.  An acute inhalation study is required  with either  one of these
products or with the wettable powder/dust formulation.

Emulsifiable Concentrate Formulation

Drier et al. (1978, 0000182)  exposed male and female rats for 4 hours to a
nominal concentration of 60.40 mg/liter of Terrazole  Fungicide 4  Ib/gallon
Bnulsifiable.  Curing exposure, several of the animals exhibited  signs of
ataxia, paralysis, hypoactivity, and squinting.  Subsequently, three of five
males and one of five females died, all within 4 days.  Gross pathologic
examination revealed diffuse redness throughout the lungs of the  animals that
died.  Because of the brief description of the methods used in generating  the
test atmosphere and the lack of information on particle size, this study is
judged to be insufficient  to satisfy the Proposed Guidelines Ffequirements.
No acute inhalation toxicity studies were available for the 25% emulsifiable
concentrate formulations.

Wettable Powder/TJust and Granular Formulations

No acute inhalation toxicity data exist for the 30% wettable powder/dust
formulation (see testing requirements under the wattable powder formulations) .

Pn acute dust inhalation study (Weaver, Grade and Sullivan, 1977, GS009-035)
indicated that the L£,-0 for Terrazole 5G is greater than 2.33 mg/1.  In  this
study, five male and live  female rats were given whole body exposure to  a
gravimetrically determined concentration of 2.33 mg/1 of the dust for four
hours.  Microscopic determination of the particle size distribution revealed
that 20.9 percent were 6 to 10 microns and 0.8 percent were 1 to  5 microns in
size.  No mortalities ware observed and the only toxic sign reported was a red
nasal discharge in six of  the animals observed at 60 minutes post exposure and
persisting  for up to 17 hours in some of the animals.  Necropsy revealed  no
abnormal gross pathological alterations.  The formulation has been placed  in
Toxicity Category  III with respect to its acute inhalation  toxicity.


                                65

-------
Eye Irritation

The minimum data requirement for primary eye irritation is one test on the
technical formulation and one test for each end-use formulation product,
preferrably using the Albino rabbit.

Technical

Technical Terrazole was not irritating to the eyes of rabbits (Larson and
Borzelleca, 1964, 00001590).  Instillation of either Olin 2424-9-0 or a 50
percent aqueous suspension of Olin 2424-9-0 produced no damage to the cornea or
iris.  The blood vessels of the conjunctivae stowed slight dilatation but not
enough for a Draize score of 1.  No testing was conducted on eyes washed after
treatment.  The results place technical Terrazole in Toxicity Category IV,
indicating a low potential for eye irritation.

Wettable Powder Formulations

There are no data for primary eye irritation for the two wattable powder
formulations.  A primary eye irritation study is required with either one of
these products or with the wettable powder/dust formulation.

EmulsjLfJ.jable_ ConcentrateJTormulat ions

Scibor (1978, 00001830) found that Terrazole Fungicide 4 Ib/gallon Emulsifiable
caused persistait irritation when administered undiluted into the conjuctival
sac of rabbits.  Damage to the conjunctiva (redness, chemosis, hemorrhaging,
and chanical burns) , iris (congestion, swelling, folds above normal) , and the
cornea (opacity) was noted.  The reaction to Terrazole treatment in the
unwashed ayes was more severe than in the washed eyes.  The maximum mean
irritation scores were 23.4/110 for washed eyes and 34.8/110 for unwashed
eyes.  In both washed and unwashed eyes,  the signs were most severe at the
24-hour examination and then gradually subsided.  However, after 14 days,
damage to the conjunctiva and cornea was still apparent.  These results plac@
this formulation of Terrazole into Toxicity Category I (See Appendix)
indicating a considerable potential for eye damage as the result of corneal
opacities.

In another study conducted by Scientific  Associates, Inc (1979, (S0009-031) it
was shown that an Experimental 25 EC produced corneal opacity and conjuncti-
val irritation that persisted for at least seven days in three out of nine
treated eyes.  In this study, the undiluted chemical was placed into one eye of
each of nine New Zealand wnite rabbits.  The treated eyes of 3 of the rabbits
were washed with lukewarm tap water.   All eyes were washed with isotonic saline
after the 24 hour examination.  The 25 EC has been placed in Toxicity Category
I for primary eye irritation because of corneal opacities resulting from
experimental treatment of animals.

Wettable Powder/Dust and Granular Formulations

No data on primary eye irritation exist for the 30% wettable powder/dust
formulation (see testing requiranents under the wettable powder formulations) .

In a primary eye irritation study, (Nham, Dan, et al 1977, CS0009-034)  the 5 G
instilled into the conjunctival sac of the right eye of 9 rabbits.  ND corneal
                                 66

-------
opacity or iris irritation was observed in any of the treated eyes.
Cbnjinctival irritation was observed in all of the treated eyes.  In the cashed
eyes  (3/9) the irritation cleared by 48 hours and in the unwashed eyes (6/9)  it
cleared by day 7.  The chemical has been placed in Tbxicity Category III
because of its moderate primary eye irritation.

Dermal Irritation

The minimun data requirement for primary dermal irritation is one test on the
technical formulation and one test on each end-use formulation product,
preferably using the albino rabbit.

Technical

Mi 11 stein (1961, 00001593) reported on acute dermal toxicity after testing
Terrazole (purity unspecified)  on rabbits (strain unspecified)  at 200  mg/kg  and
at 750 mg/kg.  Cnly one rabbit of 3 at the highest dose died.  This death was
not considered to be con pound-related.   No necropsies were performed.   All
animals had slight erythema, which abated within 72 hours at the lower dose  and
was accompanied by dry skin at the higher dose.  This information is not
sufficient to assign a Toxicity Category.

Wettable Powder Formulations

There are no data on primary dermal irritation for either of the two wettable
powder formulations.  A primary dermal  irritation study is required with the
wettable powder/dust formulation.

Emulsifiable Concentrate Formulations

New Zealand albino rabbits received a single application of 0.5 ml of Terrazole
4 Ib/gallon Emulsifiable Concentrate on each of two areas of skin, one intact
and one abraded (Palanker and Goldhammer, 1973, 00001828).  The material caused
slight erythana at both sites that disappeared in 75 percent of the cases
within 72 hours of application.  These results place the emulsifiable
concentrate in Tbxicity Category IV, indicating a very low potential for dermal
irritation.

No primary dermal irritation studies were available for the 25% emulsifiable
concentrate formulations.

Wettable Powder/Dust and Granular Formulations

There are no data on primary dermal irritation for the 30% wettable powder
formulation (see testing requirements under the wettable powder formulations) .

A study  (Nham, Dan, et al, 1977, GS0009-034) stowed that the 5% G is
minimally irritating when 500 mg are applied to the abraded and intact skin of
six New Zealand albino rabbits.  In this study rabbits exhibited minimally
irritating erythema that cleared at 72 hours; no edema was observed.  The
formulation has been placed in Tbxicity Category IV because of its low primary
dermal irritation.
                                      67

-------
Dermal Sensitization

The minimum data requirement for dermal  sensitization  is an  intradermal  test
for technical formulations and  for  each  end-use  formualtion,  preferably  using
the guinea pig.

A dermal sensitization study with Terrazole technical  was  conducted  (Anon,
1978, GS0009-030) .   Validation  of this study (SPRD 4/16/80)  indicated that
there was a significant amount  of missing  data,  therefore, the  study cannot be
considered to fulfill the minimun data requirements.   Dermal  sensitization
studies must be performed on Terrazole technical  and all of  its formulations.

Acute Delayed Neurotoxicity

The minimun data requirement for acute delayed neurotoxicity is one  test  for
the technical formulation using the adult  hen.   These  data are  required  if the
active ingredient or any of its metabolites, degradation products, or
impurities cause esterase depression, or are structurally  related  to a
substance that induces delayed  neurotoxicity.

Terrazole does not meet these criteria,  so data  on acute delayed neurotoxicity
are not needed.  The signs of neurological effects reported  in  many  of the
acute toxicity studies occurred shortly  before death and within a  few days of
treatment.  They are not characteristic  of delayed neurotoxicity.

SUBCHRONIC EFFECTS AND NEUROTOXICITY

Subchronic Oral Toxicity

The minimun data requirement for subchronic oral  toxicity  is one test on  the
technical formulation in two mammalian species,  preferably the  rat and the dog.

Technical

In a range-find ing study, male  and  female  albino  rats  were given 01 in 2424
(95.3% Terrazole active ingredient)  in the diet  at 0,  78,  312,  1,250, 5,000,
or 20,000 ppm for 3 weeks (Msdical  College of Virginia, 1963, 00001589).  At
the two highest dose levels, the rate of growth  for rats of  both sexes was
markedly depressed.  With the exception  of one male rat at the  5,000 ppm
level, all rats at these two dose levels died during the 3-week study period.
The growth rate of male rats at the 1,250  pp^ level also was depressed.   No
other differences from the controls in survival  or rate of growth were observed
at the 'three lower dose levels.  Both  sexes showed dose-related increases in
liver-to-body weight ratios. No significant com pound-related differences were
observed in hematological parameters at  2  weeks.

In a subchronic study, male and female Wistar rats were fed  diets containing 0,
78, 156, 312, 625,  or 1,250 ppm (active  ingredient) of QM-2424  for a period of
3 months (Larson, 1963a, 00001600).  Throughout  the study, a moderate
depression was observed in the  rate of growth for animals  of both  sexes at the
highest dose level.  At the lower levels,  no reduction in  body  weight was noted
until the final month, when the average  body weight of animals  receiving  625
ppn was slightly depressed.  No dose-related differences in  survival, food
consumption, hematologic parameters, or  urinary  proteins and reducing
substances were observed.  Dose-related  increases were observed in the liver-to-
body weight and kidney-to-body  weight  ratios in  both male  and female rats.
                                  68

-------
Histopathologic examination revealed no lesions that could be related to the
ingestion of CM-2424.  Although there are statistically significant increases
in the kidney-to-body weight ratios at four out of five dose levels (including
the low dose) , a NOEL is considered to be 312 ppn since there were no effects
on clinical chemistry or hi sto pathology in the liver or kidneys of treated
animals to confirm toxic effects which ware suggested by organ-to-body weight
ratios.

Subchronic oral toxicity studies have been conducted on CM-2424 with dogs.

A range- find ing study was conducted with four male or female mongrel dogs
(alternating sexes) .  The dogs ware fed diets containing 312, 1,250, 5,000 or
20,000 ppm (active ingredient)  of CM-2424 for 4 weeks (Larson, 1963c,
00001588).  The female dog at the 5,000-ppm level died during the 4th week.
All dogs receiving the three highest doses lost weight during the study, but
their  food consumption was also reduced.  Ebcal periportal fatty changes were
observed in the 20,000 ppm male.

Groups of two male and two female beagle dogs were provided diets containing
0, 100, 400, or 1,600 ppm (active ingredient) CM-2424 for 3 months (Larson,
1963b, 00001650) .  No deaths occurred during the study.  Three of the four dogs
at the 1,600 ppn level lost weight during the study; this loss of weight was
attributed to a reduction in food consumption.  No dose-related differences in
hematology, urine analysis, liver function, or clinical signs were observed
during the 13-week test.  Spleen-to-body weight ratios were depressed at all
three  treatment levels.  Congestion of the spleen was observed in one low-dose
male dog.  Liver-to-body weight ratios were elevated in high-dose dogs.

In a 2-year study (Larson and Borzelleca, 1968a, 00001697) , male and female
beagle dogs were fed 01 in 2424  (95.3% Terrazole)  in the diet at 0, 10,  100, and
1,000  ppm (active ingredient) .   The body weights of the high-dose dogs  were
depressed throughout the study, particularly during the first 13 weeks, but
food consumption at this level  was also reduced.  During the first year, all
blood  chemistry values were normal.  However, during the second year, serun
levels of alkaline phosphatase and cholinesterase were significantly elevated
in dogs of both sexes at 1,000 ppm.  Bromosulphthalein retention times ware
increased for males at 1,000 ppn at 18 and 24 months.  At 24 months,
significant increases ware seen in serun level of glutamic-oxaloacetic
transaminase in 100-ppm females.  Hematologic and urinalysis determinations
revealed no treatment-related effects.  Liver weights and liver-to-body weight
ratios were significantly elevated in male and female dogs at the 1,000 ppm
level.  Male dogs at the 1,000  ppm level also exhibited increased kidney-to-
body weight ratios at 24 months.  Hi sto pathologic examination revealed
cholestatic hepatosis with secondary bile nephrosis in 1,000-ppn treated males
and females.   This effect is not considered to be compound related because an
increase in transaminase was not observed in the 100 ppm gap and no abnormal
hi sto pathology was observed in  their liver.  Administration of Terrazole did
not cause any other hi sto pathological lesions.  Therefore, the "no-observed
effect level"  (NOEL)  for this study is considered to be 10o ppm.

21-Day Dermal Toxicity

The minimun data for the subchronic 21-day dermal toxicity requirement is one
study  for the technical formulation, preferably using the albino rat.
                                  69

-------
Technical

Groups of six male and six female albino rabbits received application of
technical Terrazole (OLin 2424-9-0)  5 days a week for 3 weeks on abraded skin
at doses of 0, 94, 188, 375, or 750 mg/kg/day (Larson and Borzelleca, 1965,
00001571) .  It was not stated if measures were taken to prevent ingestion of
the test substance, so the observed effects cannot definitely be attributed to
dermal absorption.  The dose levels of 375 and 750 mg/kg/day caused 100 percent
mortality; 188 mg/kg/day caused 25 percent mortality; no death was reported at
the 94-mg/kg/day  level.  Weight losses were seen in the three high-dose
groups.  Unspecified toxic signs suggestive of central nervous system
depression were observed before death.  Erythema of the treated areas of skin
was observed at all dose levels after one or two applications; the skin became
hard and crustlike after three to five applications.  Henatological parameters
 (hematocrit, hemoglobin, and white blood cell counts)  were lower for treated
rabbits of both sexes than for controls.  Gross and histopathological
examinations showed dose-related effects for lesions of the liver, kidney,
myocardium, and skin.

 Inhalation

The minimim data requirement for subchronic inhalation toxicity is one test for
the technical formulation preferably using the albino rabbit.  This test is not
required for Terrazole since repeated inhalation exposure is not expected for
hunans.

Neurotoxicity

The minimim data requirement for subchronic neurotoxicity is one test for the
 technical formulation, preferably using the adult hen.  A subchronic
neurotoxicity evaluation is not required because Terrazole does not depress
esterase activity, and it is not structurally related to a compound that
 induces neuropathy or delayed neurotoxicity.

CHRONIC EFFECTS

Feeding

The minimtm data requiranent for chronic toxicity is one test for the technical
 formulation preferably using the laboratory rat.

 Technical

Male and female CD-strain rats were fed diets containing 0, 10, 80, or 640 ppm
of Olin 2424 (95.3% Terrazole)  for 2 years  (Larson, 1968, 00001696).  Except
for a slight early retardation in growth in males at the 640 ppm level, no
treatment-related differences in survival, growth rate, or food consumption
were noted between treated and control groups.  At the end of 6 months, the
following organ-to-body weight ratios were significantly elevated above that of
untreated controls: kidney and liver for 640 ppm 'treated females and spleen and
testes for 640 ppn treated males.  After 2 years, liver-to-body weight ratios
in the 640 ppn treated males were significantly increased.  Except for a dose-
related increase in white blood cell counts in female rats at 6 months, no
abnormalities were detected by hematological or clinical biochemistry,
urinalysis, and gross pathologic evaluations.   In male rats, the incidences of
glonerulonephrosis and testicular atrophy were seen to increase with increasing


                                    70

-------
dose levels of Terrazole but statistical significance was not noted.  The NOEL
for this study was 80 ppm.  The snail nunber of animals undergoing complete
histopathological examination limit the value of this study for assessing the
chronic toxicity and oncogenic potential of Terrazole.

ONCOGENICITY

The minimum data requiranent for oncogenic ity is one test in each of two
mammalian species the for technical formulation.  The rat and mouse are
preferred test species.  The rat study discussed under "Technical" above is not
sufficient to satisfy this requirement, and there is no available long-term
feeding study in mice.

MUTAGENICITY

The following studies represent only the minimum requirements for data on the
potential heritable effects of Terrazole.

    1.  A mammalian in-vitro point mutation test.
    2.  A sensitive sub-mammalian point mutation test (Bacteria, fungi, insect) .
    3.  A primary ENA damage test (i.e., sister chromatid exchange or
    unscheduled DNA synthesis) .
    4.  A mammalian in-vitro cytogenetics test.  If this test suggests a
    positive result, a dominant lethal or heritable translocation test may be
    required.

After results from these test systems and other toxicology disciplines have
been considered, additional testing may be required to further characterize or
quantify the potential genetic risks.

Although the Agency's mutagenic testing requirements are not final, the
standards for these tests should be based on the principles set forth therein
(43 FR, ISb. 163).  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.

These requirements should be considered as an interim guide and not final
Agency policy.  Kbwever, the Agency does consider the above testing scheme to
be a reasonable minimum requirement.

Bacterial assays were conducted with technical grade Terrazole in Salmonella
typhimurium strains TA 100, TA 1535, TA 98, TA 1537, TA 1538, and TA 1978 as
well as Escherichia coli strains WP2, 14/P2WRA, WP67, WP6, M611, CM571, W3110,
and P3478 (Ercegovich and Kashid, 1977, GS0009-032) .  The assays detect reverse
mutations resulting from base pair substitution or frameshift events.  These
assays also detect effects on CNA repair (in Ej_. coli strains W3110 and P3478) .
Effects of liver microsomal activation have also been investigated  (Ercegovich
and Kashid, 1977, GS0009-032) .  Terrazole had no mutagenic activity in these
bacterial systems although the doses were sufficiently high to produce toxicity
in some of the strains.  (High doses ranged from 1000 to 5000 mg per disc) .

This study satisfies the requirements for sub-mammalian point mutation test as
outlined in Section 163.84-l(b) (2)(i) (A).
                             71

-------
TERATOGENICITY

The minimum data requiranent for teratogenicity testing is two mammalian
species using the technical formulation.

In a study conducted by Knickerbocker and Re (1979,  GS0009-033)  groups of at
least 15 pregnant Dutch-belted rabbits were given daily doses of 0,  1.5, 5,  15
or 45 mg Terraaole in corn oil per kg body weight.  Doses ware administered  by
gavage on days 6 through 18 of gestation.  A 2  mg/kg dose of 6-anino-
nicotinamide was given by gavage to a group of pregnant rabbits as the positive
controlc  ND effects on material body weights or  the incidence of soft tissue
and skeletal anomalies in fetuses from the 1.7, 5, or 15 mg/kg/day group were
seen when they were compared with the untreated control group.   However, the
highest dose caused three deaths or abortions in  the 17 rabbits tested.   The
mean maternal body weight for the 45 mg/kg does was  also decreased below that
for untreated dams at gestation day 18 (see table III) .  The number  of live
fetuses per doe and the percentage of does with resorptions  was increased above
that for the lower dose and untreated control groups.  The highest dose  also
reduced fetal weights and increased the number  of litters with anomalies. The
anomalies observed included missing sternebrae, tail defects, crossed hind
legs, and open eyes.   These effects cannot conclusively be attributed to
Terrazole since maternal toxicity was also indicated by the  three deaths and
weight loss in the does given the highest dose.   This experiment does not
distinguish between fetal effects caused  by Terraaole and fetal  effects
resulting from poor health of the dams in the high dose group.   The  NOEL in
this study is considered to be 15 mg/kg/day.
                               72

-------
TABLE III-3  Surcnary of Results of the Rabbit Teratology Study

 Finding                     Control              45_ mg/kg/day group

Mean maternal                                          ,
  body weight                 2.38 - 0.06 kg      2.12 - 0.09 kg

Live fetuses/does             5.3                 3.5

Percentage of does
  with resorptions           29.4%               57.1%

Mean fetal weights           41.7 g              32.8 g

Number of litters with
  ancmal ie s/ to tal
  nunber of litters
Skeletal
  Tail defects               0/17                5/9
  Missing sternebrae         0/17                3/9

Soft tissue
  Hind legs crossed          0/17                2/9
  Eyes open                  0/17                2/9
                                   73

-------
REPRODUCTIVE EFFECTS

The minimim data requiranent for reproductive effects is testing in one
marrmalian species, preferably the laboratory rat, using the technical
formulation and lasting for at least two generations.

Technical

For Terrazole, a three-generation reproduction study with two litters par
generation was conducted on rats (Larson and Borzelleca, 1968b, 00001698) .
Technical Terrazole (01 in, 2424) was administered in the diet at concentrations
of 0, 10, 80, or 640 ppn.  At the high dose, reductions in weanling weights and
adult weights were seen in both males and females at the time of the first  and
second matings.  The no-observed effect level with respect to pup weight
decreases is considered to be 80 ppn.

EMERGENCY TREATMENT

No information on the prevention and treatment of Terrazole intoxication is
available.
                                  74

-------
DISCIPLINARY REVIEW

Toxicology Profile
Tbxicity Ifezard Assessment
Generic Data Gaps
Suggested Labeling

TOXICOLOGY PROFILE

Manufacturing-Use Terrazole

Sufficient data are available bo show that Terrazole has moderate acute oral
toxicity.  The oral ID™ values are 1,077 (+78)  mg/kg/body weight in male
rats, 779 (+532) mg/kg in male rabbits, and 2,000 (+290)  mg/kg in
fanale mice.  The latter two values were reported without sufficient detail to
completely evaluate their adequacy.  Signs of toxicity observed were depression
in rats receiving relatively high doses, diarrhea and yellow livers in rabbits
receiving doses greater than the LDt0, and weight loss in mice 10 days after
dosing.

The data are sufficient to demonstrate a relatively high degree of acute dermal
toxicity.  The acute dermal LD50 value is 1,366   ( 544)  mg/kg.  Signs of
depression were reported.

Insufficient data are available to completely assess the acute inhalation
toxicity.  However, rats exposed to air containing 200 rag/liter for an unknown
period of time showed no mortality.

There are sufficient data indicating that Terrazole causes little primary eye
irritation.

There are insufficient data to completely assess the primary skin irritation
potential of Terrazole.  Hawever, skin of rabbits exposed to 200 mg/kg body
weight for 24 hours had erythema while that of rabbits exposed to 750 mg/kg
for 24 hours had erythema with dryness.  These signs disappeared within 72
hours after exposure.  There are no data available on skin sensitization.

There is insufficient data on the subchronic toxicity since there is only one
full study in dogs.  The no-observed effect level with respect to effects on
blood chemistry was 10 ppn in the diet of dogs for two years.  Another
study conducted in rats was stated to be a range finding study and cannot be
used in the evaluation of subchronic toxicity.

A 21-day dermal toxicity study in rabbits did not demonstrate a no-effect
level.  There was no indication that steps were  taken to prevent the ingestion
of the test material, so that the observed results cannot be definitely
attributed to dermal absorption.

One study in rats reported a no-effect level of 80 ppm in the diet for two
years.  Ibwever, since a less than adequate nunber of animals were examined
microscopically, the study's value in evaluating chronic toxicity and
oncogenicity is limited and additional testing is required.

A three generation reproduction study in rats demonstrated a no effect-level  of
80 ppm with respect to pup body weight decreases.

-------
A teratogenicity study in rabbits showed  that  15 mg/kg/day had  no  fetotoxic
or teratogenic effects.  At 45 mg/kg, maternal toxicity was noted  along  with
fetal effects.  A teratology study in a  second species (preferably rats)  is
required.

Terrazole had no mutagenic activity in  two species of bacteria  with or without
microscmal activation.

Sufficient data is available to satisfy the mutagenicity requirements for a
bacterial assay as stated in Sections 163.84-1 (b) (2) (i) (A) .  Studies done in
various strains of Salmonella typhimarium and  Escherichia coli_ , showed  that
Terrazole technical is not mutagenic.   However, mammalian in vitro point
mutation, in vitro cytogenics and heritable translocation or dominant lethal,
and primary~DNA damage assays are needed.  The last requirement can be
satisfied by sister chromatid exchange  or unscheduled  DMA synthesis studies.

There are sufficient data on the metabolism of Terrazole in the rat, rabbit and
dog.  The primary metabolite is 3-carboxy-5-ethoxy-l, 2,4-thiadiazole which is
excreted  in the urine.  In the rat an average  of 69 percent of  the 5.75  mg/kg
dose was  excreted  in 72 hours.  Ebr the rabbit this amount was  43  percent for
the same dose.  The greatest amount of  residues were found in the  fat of dogs
(no metabolites ware identified in tissues) .

Wettable  Powder Formulations

There are sufficient data on the acute  oral toxicity of the 30% Wettable Powder
formulation  to show that it has moderate toxicity.  The LDt0 value in male
and female rats is 4.70 g/kg body  weight.  Signs  of toxicity in animals
receiving the highest doses included  ataxia, tremors,  diarrhea, pallor,
piloerection, lacrimation, arched back, inactivity, and hypersensitivity to
touch.  Survivors appeared normal by the end of the 14-day observation period.
Congestion of the gastrointestinal tract, adrenals, and kidneys was noted.
Liver damage and thickening of the stomach wall was seen in survivors.

Sufficient data are available on the  acute dermal  toxicity of the  wettable
powder  formulations.  The minimun lethal dose  for  albino rabbits  is 2.0
g/kg.   Signs of dermal toxicity included erythema, edema.  Other  signs included
weakness, anorexia, hypothermia, and  lack of muscular  coordination in the
limbs.  Both animals died after 4 g/kg  was applied to  their skin  while one of
the  two died after receiving an application of 2 g/kg.

There are no data on the inhalation toxicity,  primary eye irritation primary
dermal  irritation, and dermal sensitization for both the 30 and 35% WP.   Since
the confidential statement of formulation indicates that these  two products and
the wattable powder/dust formulation have similar  compositions  and thus are
expected  to have similar acute toxicities and  irritation potentials, testing of
at least  one of the products in the above outlined studies will fulfill the
data requirement.

Emsulfiable Concentrate Formulations

Sufficient data are available to show that the acute oral LEu  for the
4 Ib/gallon emulsifiable concentrate containing 48 percent Terrazole is
1.3 ml/kg/body/weight (0.08 to 2.1, 95% confidence limits.)  Depression is the
only sign of toxicity reported.
                                      76

-------
There are sufficient data to show that the acute dermal LDu_ of Terrazole
4 Ib/gallon EC is 1.3 g/kg/body weight (95% confidence limits are 0.8  to 2.1
<3/kg) .  Skin irritation in this study ranged from moderate at the lower levels
 (0.27 to 0.7 g/kg) to severe at the higher dose levels (0.6 to 16 g/kg) .

Insufficient data are available to completely assess the  acute inhalation
toxicity of the 4 Ib/gallon emulsifiable concentrate.   A concentration of
50.50 mg/liter of air when breathed by male and female rats for four tours
caused ataxia, paralysis,  hypoactivity and squinting.   Three of five males and
one of five females died within 4 days after exposure.  A complete evaluation
cannot be made without further details regarding the methods and  results in
this test.

There are sufficient data  to classify the 4 Ib/gal emulsifiable concentrate as
a severe eye irritant.  It caused redness, cheraosis, and  hemorrhaging  of the
conjunctiva; congestion, swelling and greater than normal folding in the iris;
and corneal opacity in the eyes of treated rabbits.   Conjunctival and  corneal
damage persisted until the final observation 14 days after treatment.

There are sufficient data  showing that the 4 Ib/gal  EC formulation is  a  slight
primary skin irritant in Albino rabbits.

There are no data on dermal  sensitization for this 4 Ib/gal EC formulation.

There are sufficient data  to show that the 25% EC is a primary eye
irritant.  In a study done with rabbits three out of nine animals had  corneal
opacity and conjunctival irritation that persisted for at least seven  days.
Fbwever , there are no data available to assess the acute  oral, acute dermal
and acute inhalation toxicity as well as the primary skin irritation and skin
sensitization of this formulation.

Wettable Powder/lDust Formulation

See data gaps identified for the wettable powder products.

Granular Formulation

Sufficient data are available to show that the acute oral LDu,, for Terrazole
5% G is greater than 15,380  mg/kg.  Signs of toxicity  in  animals  receiving  the
higher doses included hypoactivity, diarrhea, muscular weakness,  nasal
discharge, diuresis, emaciation and high stance.  Minor pathological changes
were observed in the animal  that died during the study while the  survivors
showed no gross pathological alterations.

There are sufficient data  to show that the acute dermal LDb,, for  the
Terrazole 5% G is greater  than 16,000 mg/kg.  No mortalities were observed
when rabbits were administered this dose on abraded and non-abraded skin.
Barely perceptible erythema and slight edema were observed at 24  hours and
slight desquamation was reported at 7 and 14 days.  Necropsy revealed  no gross
pathologic alterations.

Sufficient data are available to assess the acute inhalation toxicity  of the
Terrazole 5% G.  In a study testing five male and five female rats exposed  for
four hours to a dust concentration of 2.33 mg/k of the test material,  no deaths
were reported.
                                   77

-------
There are sufficient data to show that the 5% G formulation is not a
primary skin irritant.  Oily minimally irritating erythema was observed when
the test material was applied to the abraded and non-abraded skin of  rabbits.
This irritation cleared by 72 hours.

Sufficient data are also available to show that the 5% G produces mild
eye irritation when instilled into the eyes rabbits.  In this study,
conjinctival irritation was observed in the washed and unwashed eyes  of
rabbits.  This irritation cleared by 48 hours in washed eyes and by 7 days in
unwashed eyes.

There are no data on dermal sensitization for this formulation.
TOXICITY HAZARD ASSESSMENT

Manufacturing-Use

The  technical material has moderate acute oral toxicity.  No effects on
reproduction or growth and development have been observed experimentally.  No
teratogenic effects have been reported, but one of two studies requires
validation by the Agency.  No mutagenic activity was noted in bacteria exposed
to Terrazole, and sufficient data are not available to assess the oncogenic
potential of the fungicide.

Emulsifiable Concentrate

These  formulations have moderate acute oral and high acute dermal toxicity.
The  high percentage of petroleun distillates in these formulations makes them
irritating to the eyes and skin.  If oral ingestion should occur the attending
physician should be advised of the petroleun distillate content of these
formulations prior to administration of emergency treatment.

Wettable Powder Formulation

These  formulations have moderate acute oral toxicity and high acute dermal
toxicity.  There are no data available on primary eye or skin irritation and
skin sensitization for these formulations.  However, skin and eye contact
should be avoided.

Granular Formulations

The  granular formulation has low acute oral toxicity and moderate acute dermal
toxicity.  Its acute inhalation toxicity is moderate.  This formulation is
moderately irritating to the eyes and slightly irritating to the skin.

GENERIC DATA GAPS

Manufacturing-Use Terrazole                            Guideline Sections

     Acute Inhalation Toxicity                                163.81-3
     Primary Dermal Irritation                                163.83-5
     Subchronic 21-day Dermal Toxicity                        163.82-2
     Dermal Sensitization                                     163.81-6
     Oncogenicity Studies (Pats and Mice)                     163.83-2
     Teratology in Second Species                             153.83-3
                                  78

-------
    Mutagenicity Studies (mamalian in vitro                 163.84-1
      cytogenetics and heritable tr an si oca t ion
      or dominant lethal and primary ENA
      damage assays are needed - the last
      requirenent can be satisfied by sister
      chromatid exchange or unscheduled DNA
      synthesis studies

Wettable Powder and Wettable Powder/Dust Formulations

    /cute Inhalation Toxicity                                163.81-3
    Primary Eye Irritation                                   163.81-4
    Primary Dermal Irritation                                163.81-5
    Dermal Sensitization                                     163.81-5

Granular Formulation
    Dermal Sensi tization                                     168.81-6

Emulsifiable Concentrate Formulations

    Terrazole 4 Ib/gal

    Acute  Inhalation Tbxicity                                163.81-3
    Dermal Sensitization                                     163.81-6

    Terrazole 25 EC

    Acute  Oral Toxicity                                      163.81-1
    Acute  Dermal Tbxicity                                    163.81-2
    Acute  Inhalation Tbxicity                                163.81-3
    Primary Dermal  Irritation                                163.81-5
    Dermal Sensitization                                     163.81-6


SUGGESTED  LABELING
    The  v>erning  statement on  the label  for Terrazole 25%
    Wettable  Powder  should be rewrittai to conform with that on
    the  labels of  the other formulation.  It should read as
    follovvs:

          WARNING-
          KEEP OUT  OF REACH OF CHILDREN

          Harmful if  swallowed.  Do not  inhale spray mist.  Do
          not  get on  skin or in  eyes.  Do  not take  internally.
          my  cause skin  irritation.  Wash thoroughly all exposed
          skin.  In case  of eye  contact  flush with  plenty of
          water.  Repeated contact may be  harmful.  Wash
          thoroughly  all  contaminated clothing before reuse.  Do
          not  store near  heat  or open flame.  Use with  adequate
          ventilation.   Keep container closed.   Co  not
          contaminate feed or  foodstuffs.
                                     79

-------
                            Appendix
Hazard Indicators
Oral UD50
Inhalation ECca
50
Dermal LDL
Eye Effects
I
Up to and
including
50 mg/kg
Up to and
including
0.2 mg/liter
Up to and
including
200 mg/kg
Corrosive;
corneal
opacity not
reversible
Toxic ity Categories
II III
From From
50-500 500-5000
mg/kg mg/kg
From From
0.2-2 2-20
mg/liter mg/liter
From From
200-2000 2,200-20,000
mg/kg mg/kg
Corneal No corneal
opacity opacity;
revers- irritation
ible reversible
within within 7
7 days days
IV
Greater than
5000/mg/kg
Greater than
20 mg/liter
Greater than
20,000 mg/kg
No irritation
Skin Effects
Corrosive      Severe    Moderate
               irrita-   irritation
               tion  at   at 72 hours
               72  hours
Mild or slight
irritation at
72 hours or
no effect
                                     80

-------
                                 BIBLIOGRAPHY

GS009-030—Anon,  1978.   Skin  sensitization  Test  with  Terrazole  Techncal  in
    Guinea Pigs;  IBT #8530-10903.

GS009-031—Anon,  1979,  Eye  Irritation  lest  in Rabbits.   Scientific Associates,
    Inc.;  6200 S.  Lindebergh St, St. Louis, MO 63123.

00001591—Carson, S. 1964.  lest for Acute  Inhalation Ibxicity  in Rats.  Report
    (unpublished study received 12/16/64 under 1258-740, prepared by Food and
    Drug Research Labs,  Inc.  for Squibb Institute; submitted by Olin Mathieson
    Chanical Gbrp., Stamford, Conn.

05004729—Dalvi, R.R. and Howell, C.D. 1977.  Ibxic Effects of a Fungicide,
    (Terrazole)  on the Hepatic Drug Metabolizing Enzyme Systan  in Mice.
    Bulletin Environ. Oontam. Ibxicol. 17-225-232  (MRID 05004729).

0000182—Dreir, H. Horath,  L. L., and Lindberg, D.C. 1978.  Aerosol Inhalation
    Study with Terrazole Fungicide 4 lb., Bnulsifiable in Albino Rats.  IBT
    #8562-10907. unpublished  study received 11/15/78; under 6E1747 prepared by
    IBT Labs, Inc. submitted  by Olin Corp., Stamford, CN.

00001831—Duhanel, C.G. and Poa, H. 1978.  Report  to  Olin Corp.  Acute Dermal
    Toxicity Study with Terrazole Fungicide (4 lb. Emulsifiable) in Albino
    Rabbits, P.O. # RC-38830.  IBT # 8530-10906.   (unpublished study received
    11/15/78, under 6E1747, prepared by IBT Labs,  Inc.

GS0009-032—Ercegovich, C.D., and K.A. Rashid 1977.   The Mutagenic Evaluation
    of Terrazole for Mitagenic Effects in Bacterial Test Systems.  Unpublished
    data from Pesticide Research Laboratory, PA, State University,  University
    Park, PA.  EPA Accession  if240890.

GS0009-033—Knickerbocker,  M. and Re,  T.A. 1979.   Teratologic Evaluation of
    Terrazole Tech. in Dutch-belted Rabbits (Unpublished).   No F/MID#.   Lab
    #5845 received 7/6/78.

00001597	Kuchar , E.J. 1970a.  Determination of  Terrazole Residues in Beagle
    Dog Tissues, CASR-2-70.   Includes method date 2/13/70.  (Unpublished study
    received 3/28/70)

00001601	Kuchar, E.J. 1970b.  Analytical Studies—Terrazole  ( )  in Simulated
    Gastric Juice CASR-2-70.  (Unpublished study received 5/28/70 under OF0997,
    submitted by Olin Corp.,  Stamford, Conn.

00001600—Larson,  P.S 1963 (a)  Toxicology Studies on the Effect of Adding OM-2424
    to the Diet of Albino Rats.  (Unpublished study including letter dated
    9/3/63 from P.S.  Larson to Sylvan  I. Cohen, received 12/16/64 under 1258-
    740, prepared by Medical  College of Va., Dspt of  Pharmacology, submitted by
    Olin Mathieson Chemical Corp.,  Stamford, CN.

00001605—Larson, P.S.  1963 (b) Toxicolog ical Studies  on the Effect of Adding
    OM-2424 to the Diet of  Beagle Dogs:  Three Month  Study.  (Unpublished study
    received Dec. 16, 1964, under 1258-741); prepared by Medical College of
    VA.; Dept. of Pharm, Olin Mathieson Chem. Corp.   Stamford, CN.; CDL:
    050922.
                                     81

-------
00001588—Larson, P.S. 1963(c) Tbxicologic Studies on the Effect of Aiding 01 in
    2424 to the Diet of IXbngrel Dogs:  Range Finding Studies (4 weeks) „
     (unpublished study including addendum and letter dated June 17, 1963P from
    1258-740; prepared by Medical Cbllege of VA.; Dept. of Pharm., submitted
    by 01 in Mathieson Chan. Corp.  Stamford, CN.

00002227—Larson, P.S. and Borzelleca, J.F. 1964 (a)  Acute Percutaneous Toxicity
    of 01 in 2424 in Albino Rabbits (01 in 2424-9-0, Technical) .  (Unpublished
    study including letter to Sylvan I. Cohen, received Dec. 16, 1964, under
    1258-740; prepared by Medical College of VA, Dept. of Pharm., submitted by
    01 in Mathieson Chemical Co., Stamford, CN.

00001590—Larson, P.S. and Borzelleca, J.F. 1964(b)  Eye Irritation Properties
    of 01 in 2424 in Rabbits (01 in 2424-9-0, Technical) .  (Unpublished study
    including letter dated Nov. 17, 1964, under 1258-740; prepared by Medical
    College of VA, Dept. of Pharm, submitted by 01 in Mathieson Chem. Corp.,
    Stamford, CN.

00001571—Larson, P.S. and Borzelleca, J.F. 1965  The Percutaneous Ibxicity to
    Rabbits (Abraded skin)  of 01 in Conpound 2424  (01 in 2424-9-0, Technical) .
     (Unpublished study including letter dated Jan. 11, 1961, under 1258-Q;
    Prepared by Medical College of VA., Dept. of Pharm., submitted by 01 in
    Mathieson Chemical Corp., Stamford, CN.

00001555—Larson, P.S. and Borzelleca, J.F. 1967.  Acute Oral  Toxicities and
    Potentiation Studies of Terrachlor and Terrazole in Male Albino Rats.
     (Unpublished study prepared by Medical College of VA.,  Dept. of Pharm.,
    submitted by 01 in Mathieson Chemical Corp., Stamford, CN.

00001697—Larson, P.S. and Borzelleca, J.F. 1968 (a)  Toxicological Study on the
    Effect of Adding Terrazole to the Diet of Beagle Dogs for a Period of TWo
    Years.  (Lhpublished study received Nov- 18, 1968, under 0F0997;prepared by
    Medical College of VA., Dapt. of Pharm., submitted by 01 in Mathieson
    Chemical Corp., Stamford, CN.

00001698—Larson, P.S. and Borzelleca, J.F. 1968 (b) . Three Generation
    Reproduction Study on Rats Receiving Terrazole in Their Diet.  (Unpublished
    study received June 9,  1970, under 0F0997;  prepared by Medical College of
    VA., Dapt. of Pharm., submitted by 01 in Mathieson Chemical  Corp., Stanford,
    CN.

00001792—Larson, P.S. and Borzelleca, J.F. 1970.  Acute Oral  Ibxicity of
    Terrazole in Male Albino Rabbits. (Unpublished study received June 9, 1970,
    under 0F0907; prepared by Medical College of Virginia, Dept. of Pharm„,
    submitted by 01 in Mathieson Chemical Corp., Stamford, CN.

00001599-H^IcKenn is, H., Jr., Bownan, E.R. and Dar , M.S.  1970.   Studies on the
    Physiological Disposition of Terrazole-  C.  (Unpublished study received
    May 28,  1970, under 0F0997; prepared by Medical  College of VA., Dept „ of
    Pharm.,  submitted by 01 in Corp.,  Stamford, CN.

00001589—Medical College of Virginia,  Department of Pharmacology. 1963«
    Toxicologic Studies on the Effect of Adding Olin-2424 to the Diet of Albino
    Rats:   Range-Finding  Studies (3 weeks) . from P.S.  Larson to Sylvan I.
    Cohen, received Dae.  16,  1964,  under 1258-740; submitted by Olin Mathieson
    Chemical  Corp.,  Stamford,  CN.


                                   82

-------
00001586—Miller, M. 1961. A^ute Oral Toxic ity in Mice:  Fh. 425/B.
     (Unpublished study received Cec. 16, 1964, under 1258-740; submitted by
    01 in Mathieson Chemical Corp.,  Stamford, CN.

00001593—Millstein, L. 1961 Experimental Pesticides 1306 and 2424  (SQ542424):
    Acute Dermal Tbxicity in Rabbits:  TH. 08/B.   (Unpublished study  including
    letter dated Oct. 26, 1961, from L. Millstein to J.W. Poutsiaka,  received
    Dec. 16, 1964, under 1248-70, submitted by Olin Mathieson Chemical Corp.,
    Stamford, CN.

00001592—Moulton, R. H. 1970 (a) Acute Oral Tbxicity (LD™) Study in Rats.
    Truban 30% W.P.:  S.A. No. R-5719a .  (Unpublished study received  Get.  ,
    1970 under 372-43;  prepared by  Scientific Associates, Inc.  Submitted by
    Mallinckrodt Chemical V\brks, St. Louis, MO.

00001593—Moulton, R.H. 1970 (b) .  Acute Dermal Tbxicity  (MLD) in Rabbits;
    'Iruban 30% W.P.:  S.A. No. R-5719b.  (Unpublished study received  Oct. 1970
    under 372-43; prepared by Scientific Associates, Inc., submitted  by
    Mallinckrodt Chemical Works, St. Louis, MO.

GS0009-034—!Nham, Dan, et al. 10/27/77.  Acute Oral Tbxicity of 5G in Rats.
    Acute Dermal, Eye Irritation and Primary Skin Irritation Tests of Terrazole
    5G in Rabbits.

00001557—Olin Corporation. 1965.   Metabol ism of Olin 2424 in Mongrel Dogs:
    CASR-10-65.  Includes method dated Nov. 17, 1965.  (Unpublished study
    received Nov. 17, 1965  (?) , under 1258-Q.

00001828—Palanker, A. L., and Goldhamer, R. E. 1973.  Acute Oral LD50  in Rats
    Primary Dermal Irritation in Rabbits:  Terrazole:  A-851.  (Unpublished
    st:jdy received Nov. 15, 1978, under 6E1747; prepared by Biometric Testing,
    Inc.. submitted by Olin Corp.,  Stanford, CN.

00001830—Scibor, G. 1973.  Report  to Olin Corporation:  Eye Irritation Studies
    Irritation Studies with Terrazole Fungicide in Albino Rabbits:  P.O.  No.
    38830;  IBTNo. 8530-10906.  (Unpublished study received Nov. 15, 1978,
    under 6E1747; prepared by Industrial Bio-Test Laboratories, Inc., submitted
    by Olin Corp.. Stamford, CN.

GS0009-035—Weaver 7 J.  and John W.  Grade and D.J. Sullivan 11/2/77.   Acute Dust
    Inhalation Tbxicity Study of Terrazole 5G in Rats.

GS0009-036—Webig, J.H. , Kennedy, G. L. , Jr., Knickerbocker, M., and Smith, S.
    1980 Teratologic Eva! nation of  Etridiazol in Rats and Rabbits.
     (Unpublished)
                                       83

-------
Chapter 6

RESIDUE CHEMISTRY

The Proposed Guidelines for Residue Chemistry have not been finalized thus
there are no citations for the types of data normally required to assess the
Ffesidue Chemistry for Terrazole.  However , the Agency must have enough data for
each product to assure that the residues of the technical formulation and its
metabolites have been adequately identified.

Topical Discussions

Metabolism in Plants
Metabolism in Animals
Analytical Methods
Residue Data
Present Tolerances
Regulatory incidents

Tne only formulations used on food crops are Terrazole 5% G and
Terrazole 4 Ib/gal Bnulsif iable.

Metabolism in Plants

The absorption, distribution and metabolic fate of Terrazole was investigated
thoroughly.  In a study by Dr. McKennis, Jr.,  (1974, 00001689)  cotton plants
were grown for periods up to 44 days in soil treated with Terrazole-3-  C at
levels up to 260 ppn.   (This latter level is more than 100 times the level
expected  in actual agricultural practice) .  This study also included laboratory
investigations on hanogenates of fre^, young cotton plants grown in untreated
soil and  incubated with Terrazole-3-  C.

Isotopic dilution studies were conducted on cotton plant extracts.  Radio-
activity determinations were made by scintillation counting and residues were
identified by paper chromatography and/or thin layer chromatography  (TIC) .
Residues of Terrazole per se, were further determined by gas liquid
chroma tography.  Distribution of radioactivity in samples taken at 26 and 44
days indicates the presence of Terrazole, trichloroacetic acid, and  trace
amounts of oxalic acid as metabolites in the plant.  Radioactive CCU was also
detected thus indicating cleavage of the thiadiazole ring.  No other
metabolites contained the thiadiazole ring.

Another metabolism study by Dr. McKennis  (1970, 0000^599) with lettuce and
potato plants was made using  radioactive Terrazole-  C labeled either in the
3-position in the thiadiazole ring or in the 1 position of the ethoxy group.

In both studies, the aqueous  plant homogenate  was incubated for 24 hours with
the labeled compound.  Extracts were treated with propanol, filtered, and the
reaction  product identified by T.L.C.   Terrazole per se  and the mono-acid were
found; the presence of the di-acid as a minor metabolite was also  indicated.

In other  studies  (Kuchar, 1971, 00002255),  technical Terraaole was added  to  the
soil, mixed well and allowed  to renain  at  rocm temperature  for three weeks.
Tne soil  was then extracted with  acidified  water, the  residue partitioned  into
chloroform, the chloroform extract evaporated  to dryness and the  residue
examined  by mass and/or  infrared  spectroscopy. Again, the  predominant


                                     84

-------
metabolite  found was the mono-acid and a an all amount of the di-acid (i.e., 3-
carboxy-5-hydroxy-l, 2,4-thiadiazole)  was found.   Another compound present at a
low levels  was 3-carbethoxy-5-ethoxy-l, 2,3-thiadiazole.  The researchers
believed, however, that the latter compound could have been formed either
during the  extraction process or by rearrangement during mass spectroscopy and
may not have been a true metabolite.

In addition, the hydrolytic stability of the mono- and di-acid metabolites was
studied (Kuchar, 1970,  GS0009-003) .  Both confounds decomposed completely in
one hour in either dilute acid or base at 100 C.  The odor of H9S,
indicative of cleavage of the thiadiazole ring, was noted.  No identification
of the decomposition products was made.

Soil  treated at the time of planting of cotton produced no detectable residues
of Terrazole per se in the various portions (except leaves)  of the mature
plant.  No detectable residues were found in  roots, stems, or bolls at 86  and
158 days after treatment.  Residues of 0.1 ppm or less were found in the
leaves,  No analysis of the metabolites was made in these studies.

The mono-acid is found to be the  primary metabolite formed during the
degradation of Terrazole in cotton, with the possible formation of the di-
acid.  Trichloroacetic acid, oxalic acid and carbon dioxide are final
degradation products.  The metabolism and pathways of degradation for Terrazole
in the cotton plant and/or similar agricultural crops are considered adequately
defined.  The predominant residues in cotton plants which are open to
toxicological consideration are Terrazole per _se and its mono-acid.

With regard to the residues of Terrazole and its mono-acid metabolite,  there
are no data available on the fate of Terrazole in avocados or avocado trees.
The Agency does have data on the  fate of Terrazole in cotton plants and since
the Agency does not usually require residue studies on such minor crops as
avocados, it is concluded that Terrazole per se  and its mono-acid metabolite
and also residues in avocados.

Metabolism  in Animals

No   C-radiotracer study involving the ingestion of Terrazole by large
runinants (cows, goats)  was submitted.  From various feeding studies with rats,
rabbits and dogs using  radio-labeled material, it was indicated that the
metabolism of Terrazole in animals apparently proceeds in a manner similar  to
that in plants, with conversion to the mono-acid metabolite.

There is also evidence of a minor de-ethylation reaction which leads to the
elimination of respiratory radioactive CCU.  The cleavage and fragmentation
of the thiadiazole ring to one carbon components appears to occur as a  minor
metabolic route.  Since the registered avocado use has no animal feeding
implications (i.e., no  likelihood of residues in meat, milk, poultry and eggs) ,
feeding studies are presently not required.

Analytical Methods

The residue data submitted for avocados were obtained by the use of methods CAM-
23-73.  (Griffith,  1976,  00001645; 1973,  00001570),  Qlin method CM-23-75,
"Determination of Terrazole by blending with hexane."  After filtering, the
extract is cleaned  up on  a Florisil colunn  and a determination of the compound
                                   85

-------
is made by electron capture gas chronatography.   The sensitivity is claimed
to be 0.005 ppn, however, only two recovery values of 74  percent and 104
percent at fortification levels of 0.06 ppn and  0.3 ppn Terrazole are
reported.  This method was validated in EPA laboratories  for Terrazole on
cottonseed at 0.1 ppn and 0.2 ppn.  Recoveries ranged from 76 percent to  83
percent.  The sensitivity of the method is 0.02  ppm.

Residues of the mono-acid were determined  by a liquid chronatographic method
(CAM-37-75)  (Thomas, 1975, -03-0009-005; Kuchar,  1975, GS-0009-006).  Tnis_
method, however, is intended for the analysis of mono-acid residues in soils
and involves extraction of the residue  with methanolic ammoniun  hydroxide.
Terrazole is extracted from this solution  with hexane.  Chloroform  is used  to
extract the mono-acid.  After the chloroform is  evaporated, the  residue is
taken up in water and determined by liquid chronatography with a ultra violet
detector.  Cnly one recovery value is reported for the mono-acid added to
avocados.  This value is 80 percent at  a fortification level of  0.2 ppn.  The
sensitivity of the method is regarded as 0.05 ppm.

A polorgraphic method is available that determines residues of the  mono-acid
(CAM-10-70) .  This method was subjected to a method trial in EPA laboratories
on cottonseed.  Levels of fortification were 0.20 ppn and 0.40 ppn  of mono-acid
with recoveries reportedly ranging from 66 percent to 83  percent.  The
sensitivity of the method involves extraction of the residue from the crop  with
acetone by blending.  After filtering of the extract, 5%  HCl is  added to  the
acetone filtrate and it is shaken in a  separatory funnel.   The HCl  extract  is
collected and extracted twice with chloroform which is then discarded. Sodiun
sulfate is added to the HCl extract and it is extracted five times  with
chloroform.  Chloroform portions are combined and evaporated to  dryness.  The
residue is transferred with chloroform  to  a Florisil column for  final clean-
up.  Tne colunn is eluted with methanol and evaporated to dryness.   Tne final
residue is taken up in 3N HCl and the concentration of mono-acid determined by
polarography.

In conclusion, the above available methods have  adequate  specificity and  are
judged satisfactory for enforcement purposes and for data gathering.

Residue Data

Field residue data for avocados should  reflect the proposed use  with respect  to
dosage rate, mode of application, number and timing of treatments,  formulations
used and geographic areas represented.

For the control of avocado root rot Terrazole is to be applied evenly to  the
soil surface surrounding the trees, in  a circular area extending out to the
drip line.  Tne amount of material applied to each tree will be  governed  by the
area covered.  The application rate for the E.G. formulation is  0.25 oz.  for  a
5' diameter, 1 oz. for 10', 25 ozs. for 15' and  4.3 oz. for 20'  diameter
dripline.  The granular formulation is  applied at essentially the same rates
for the various tree sizes.

Following application of either EC or the granular formulation,  water is
applied to the treated area at the rate of one gallon/square foot.   Applica-
tions are made once a month for 9-10 months during the growing season.

The label also indicates that the use of Terrazole is intended for distribution
and use in California only,  isb treatments are to be made within 30 days  of


                                   86

-------
harvest; and, during application, care should be exercised so that the
pesticide does not cone in contact with the fruit.

Residue data have been submitted for California grown avocados for the 1974  and
1975 crop years.  These data reflect multiple treatments over a 2-4 year
period.  For the 5% granular formulation, 49 ozs. covering 176 square feet
within a 15 foot diameter drip line were applied once each month for 9-10
months during the growing season.  Following each application, one gallon of
water per square foot of area was applied.  For the Terrazole 4 E.G.
formulation, 5.0 ozs. covering 176 square feet for a 15 foot diameter drip line
were applied once each month for 9-10 months.  Fbllowing each application, one
gallon of water per square foot of area treated was applied.  The size of the
trees treated ranged from 66-77 an in diameter of trunk at the base and 18-20
feet in height.  The trees were fully mature and fully branched.

The residue studies (Kuchar, 1975, GS0009-007) show no detectable residues in
the avocados.  These studies also show that there is build-up of residues in
avocado trees over the 2-3 year treatment period.  It is indicated that if (1)
Terrazole is applied to the soil according to label recommendations and
does not come in contact with the fruit or foliage of the trees, (2) the skirt
of limbs is 3-5 feet above the ground, (3)  ripe avocados are harvested by hand
or by using a hand pruning-type harvester and (4) the normal time period
between the last application and harvest is about 30 days, then the resulting
combined residues of Terrazole and its mono-acid metabolite will not exceed  the
0.15 ppn established tolerance.   (The tolerance is based on method sensitivity
which is 0.15 ppm) .

Residues in Meat, Milk, Poultry and Eggs

The registered use of Terrazole on avocados does not result in residues of
Terrazole or its mono-acid metabolite in meat, milk, poultry or eggs.

Present Tolerances

According to 40 CFR 180.370, a tolerance has been established for combined
residues of the fungicide 5-ethoxy-3- (tr ichlorcmethyl) -1, 2,4-thiadiazole and
its mono-acid metabolite, 3-carboxy-5-ethoxy-l, 2,4-thiadiazole in or on
avocados at 0.15 ppm.

There is an interim tolerance (40 CFR 180.319) of 0.3 ppm in or on cottonseed
for residues resulting from the use of formulations with multiple active
ingredients, one being Terrazole.  This Registration Standard only includes
formulations with Terrazole as a single active ingredient, consequently the
interim tolerance on cottonseed is excluded from this Standard.

Regulatory Incidents

No report was made on any regulatory action taken by FEA with regard to the
registered use of Terrazole.
                                     87

-------
DISCIPLINARY REVIEW:

Residue Chanistry Profile
Reassessment of Established Tolerances
Generic Data Gaps

RESIDUE CHEMISTRY PROFILE

Terrazole is marketed in the US as a soil-fung icide primarily for
prevention fron root rot.  The metabolic  fate of  Terrazole  in plants through
absorption, distribution and,degradation  was investigated  thoroughly in the
cotton plant.  Studies with   C radioactive ring  labeled material indicate
Terrazole (5-ethoxy-3-[trichloromethyl]-l, 2,4-thiadiazole)  evolves through
decnlorination into a mono-acid metabolite  3-carboxy-5-ethoxy-l, 2,4-thiadiazole
which in turn, through de-ethoxylation, evolves into a di-acid metabolite (3-
carboxy-S-hydroxy-l^^^hiadiazole.  It  is concluded  that  some uptake of
Terrazole into the plant exists and that  Terrazole per jse  and the mono-acid
metabolite are the predominant residues in  cottonseed.  The hydrolytic
stability of the mono-acid and di-acid metabolites was studied.  Both compounds
decomposed completely in one hour in either dilute acid or base at 100 C.
The odor of HUS present was indicative of cleavage of the  ^iadiazole ring.
Other products of degradation found and identified in the    C radioactive
ring labeled Terrazole studies with cotton  plants were trichloroacetic acid,
oxalic acid and C0?.
   14
No   C-radiotracer study involving the ingestion of Terrazole by large
runinants (cows, goats)  was reported.   From various feeding studies with rats,
rabbits and dogs using radiolabeled material, it was indicated that the
metabolism in animals apparently proceeds in a  similar manner as that in the
cotton plant, i.e., conversion to the mono-acid metabolite and further
degradation to the di-acid metabolite leading to  the elimination of respiratory
radioactive C09.

Since there are no registered uses which  result in feed items containing
residues of Terrazole and/or its mono-acid  metabolite, runinant feeding studies
are presently not required.  There is just  one  registered  use of Terrazole on
avocado trees.  Two petitions for tolerances for residues  resulting from the
use of Terrazole on strawberries (PP 8E2083) and on corn and wheat (PP OF2317
are pending.

Residue studies on avocados indicate no detectable residues for Terrazole and
its mono-acid metabolite resulting from the registered use.  Adequate methods
are available for identification, quantification and regulatory enforcement.
The established tolerance of 0.15 ppm is  adequate for the  combined residues of
Terraaole and its mono-acid metabolite in or on avocados which may result from
the registered use of Terrazole on avocado  trees.  There are no records of
incidents involving the enforcement of the tolerance.

REASSESSMENT OF ESTABLISHED TOLERANCES

Tolerances have been established for residues of Terrazole on avocados.  There
are, however, other tolerances which have been approved by the Agency's
Toxicology Branch (cottonseed, corn grain and strawberries) but which have not
been finalized by the Office of Pesticide Programs because of one or more
                                       88

-------
deficiencies in their respective petitions.  It should also be noted that the
use on cottonseed involves formulations which include more than one active
ingredient.  Accordingly, a tolerance reassessment, other than on avocados,
would be premature.  A complete tolerance reassessment will be performed when a
Standard is developed which covers mixtures of Terra zole with other pesticide
products.

Based on the established tolerance of 0.15 ppm for combined residues of
Terrazole and its mono-acid metabolite in avocados, the theoretical hunan
exposure to residues is calculated to be 0.00007 mg/day.  This figure is based
on the average adult eating patterns and on the assumption that avocados
contain residues which meet the established tolerance level of 0.15
                                                                         _2
The Agency has calculated a Terrazole acceptable daily intake of 2.5 x 10
mg/ kg/day for avocados.  This value is based on a no-observed-effect level
(NOEL) of 10 ppm established in a two year dog study (1 ppm = 0.025 mg/kg) ,  and
the incorporation of a 100 fold safety factor in translating the data fron
animal to man.
                                                     -2
Based on an acceptable daily intake value of 2.5 x 10   mg/kg/day and an
average mass of 60 kg for hunans, the Agency has calculated a maximun
permissable intake of 1.5 mg/day for avocados.

The theoretical maximun residue contribution of Terrazole to the, diet is less
than  the maximum permissable intake (i.e., 7.0 x 10   < 1.5 x 10 )   thus,
current tolerance levels appear to be more than adequate.

GENERIC DATA GAPS

None

-------
Bibliography

GS 009-0 03— Kucha r, E.J. , 1970  Hydrolybic stability of 3-carboxy-
    5-ethoxy-l, 2,4-thiadiazole and 3-carboxy-5-hydroxy-l, 2,4-thiadiazole under
    alkaline and acid conditions,  pg . 0997.
G3009-007 — Kuchar, E.J. 1975.  Residues of Terra zole and 3-carboxy-5-
    ethoxy-1, 2,4-thiadiazole in avocados, 1974-5 crop,  pg . 1747
                                                                     p
00001645 — Griffith, W.P. 1975.   Appendix:  Determination of Terrazole  (5-
    ethoxy~3-trichloromethyl-l, 2,4-thiadiazole)  in avocado:  CASR-19-76.
    Msthod CAM-23-75 dated June 12,  1975.  (Unpublished study received October
    20, 1976 under 1258-812; submitted by 01 in Corp.,  Agricultural Div., Little
    Rock, Ark0f- GEL:   228143-C)
                                                           ^
00001570— Griffith, W.P. 1973.   Determination of Terr^zale  (5-ethoxy-3-
    trichloronethyl-1, 2,4-thiadiazole)  and Terrachlor  (pentachloro-
    nitrobenzene)  and allied metabolite in plant tissues or harvest
    samples,  ffethod CM-24-73  dated July 3,  1975.   (Unpublished study received
    February 4, 1977 under 1258-812; submitted by 01 in Corp.  Agricultural
    Div., Little Ftock, Ark,; CDL:  95799-M)

00002255— Kuchar,  E.J.. 1971.  Residues of Terrazole (5-ethoxy-3-
    trichloromethyl-l,2~4~thiadiazole)  and 3-carboxy-5-ethoxy-lf 2,4-thiadiazole
    in irtmature cotton plants:   CASR-2-71.  (Unpublished study received July
    20, 1971 under CF0997;  submitted by 01 in  Corp.,  Chemicals Div., New fteven,
    Conn o ; CDL 097540-A)
         -Kuchar, E.J.   1970.   Analytical  studies concerning metabolism of
    Terrazole (5-ethoxy-3-trichloronethyl-l,2,4-thiadiazole) :  CASR-5-70.
    (Unpublished study received my 28,  1970  under OF0997;  submitted by 01 in
    Corpoi,  Stanford, Conn,;  CDL:  091717-G)

00001689—Me Kenn is, H., Jr.  and i^R.  Bowman.  1974.  Studies on the disposition
    and metabolism of lerrazole   C (3-trichloromethyl-5-ethoxy-l,2,4-
    thiadiaaDle)  in young cotton grown in  Terraaole   C treated soil.
    (Unpublished study received August 20,  1971 under QF0997; prepared by
    Medical College of Virginia Dept. of Pharmacology, submitted by 01 in
    Corporation,f Stanford,  Conn.;  CDL:  091717-EO

00002229—Thomas, R.j.  1970.  Determination of 3-carboxy-5-ethoxy-l,2,4-
    thiadiazole in cotton seeds:   analytical  method.  Method CAM-10-70
    (Tentative)  dated my 21,  1971  form  R.  F. Ehilpitt to W. H. MDrgan
    received my 2Sf 1970 under CF0997:  submitted by 01 in Corp., Stanford,
    Conn,,;  CDL:   091717-AI) „

GS0009-005—Thomas, R0J,, 1975.  The  liquid chromatographic determination of 3
    carboxy~5-ethoxy~l,2f4~Thiadiazole in  avocados.

GS009-006—Thomas, R.,  1975,  Trie liquid chromatographic determination
    of 3-carboxy~5-ethoxy-l,2,4-thiadiazole in soil. pg. 1747.
                                       90

-------
Chapter 7

ECOLOGICAL EFFECTS

Topical Discussions

The Topical Discussions listed below correspond to the sections in the
'Proposed Guidelines for Registering Pesticides'  of July 10, 1978  (Vol.
43, No. 132, 29696).  These sections explain the minimum data the  Agency
requires to assess Terrazole's effect on non-target organisms.

    Topical Discussions                     Guidelines

    Birds                                   163.71-1, -2
    Wild Mammals                            163.70-1, -3
    Aquatic Invertebrates                   163.72-2,
    Fish                                    163.72-1
    Ecosystem Effects                       163.71-5; 163.72-6
BIRDS

Birds may be exposed to pesticides by feeding directly on the pesticide
granules, indirectly feeding on contaminated plants or poisoned
invertebrates or animals, or by inhalation viien close to sprays and dusts
and by dermal contact.  Acute oral, dietary and possibly chronic tests on
the toxicity of Terrazole to birds are required to support the
Registration Standard.

Acute Oral Toxicity

A determination of the single-dose oral LD^ is usually required to
support the registration of every manufacturing-use product, and of each
formulated product intended for outdoor application.  This test should be
performed for one avian species:  a wild waterfowl (preferably the mallard
duck, Anas platyrhynchos) , or an upland game bird  (preferably the
bobvfoite~quail, Colinis virginianus) .  The species used in this test
should be the same as one of the two species used  in the avian dietary
tests.

Fletcher, (1972, 00003276) studied  the effect of Terrazole on bobwhite
quail using a 95-97% technical product.  The acute oral ED™ was 560
mg/kg.  This study characterizes Terrazole as slightly toxic to bobwhite
quail, and satisfies the  Agency requirements for single dose oral
toxicity testing for birds.

Another study by Fletcher, 1972  (00002238) with technical Terrazole
 (95-97 percent) yielded an acute oral LDb0 of  1640 mg/kg for mallard
ducks.  Although this study was not considered adequate due _ to  procedural
design, the data, as presented, reinforce  the  above conclusion  that
Terrazole is slightly toxic to birds.
                                  91

-------
Subacute Oral Toxicity

A detennination of the 8-day subacute dietary IC™ (5-day dietary
exposure followed by 3-day observation)  is required  to  support
registration of all manufacturing-use products and all  formulated products
intended for outdoor application.

Information regarding the subacute dietary exposure of  technical
Terrazole to birds is not available.

Chronic Toxicity

Chronic toxicity data (reproductive, and simulated or actual field tests) ,
may be required after information on persistence, degradation rates, and
bioaccunulation has been received by the Agency.

WILD
Data on acute toxicity to wild mammals are required to support the
registration of a formulated product when (1)  the proposed use pattern of
the pesticide indicates that wild mammals may be exposed to the pesticide
and  (2) , data in the Toxicology Chapter are not sufficient to assess the
potential hazard to wild manmals.  The need for mammalian acute toxicity
studies has not been demonstrated.

AQUATIC INVERTEBRATES

A determination of the EC50 or E£50 for aquatic invertebrates is
usually required to support the registration of every manufacturing-use
product, and for each formulated product intended for outdoor
application.  Tnis test must be conducted using the technical material.
Since  no data are provided to satisfy this requirement, a data gap exists.

FISH

A determination of the 96-hour L£50 of the technical compound for one
cold-water species and one warm-water species is usually required to
support the registration of all manufacturing-use products and for each
formulated product for outdoor use.  A study by Sleight, (1971, 0001703)
reported 3.27 ppm as the 96-hour L£r0 for bluegill, and 1.21 ppm for
trout.  These data indicate that Terrazole is moderately toxic to both
warm and cold water fish.  This study fulfills the data requirements for
fish toxicity data.

Ecosystem Effects

Full scale field studies are requested only if problems are  identified
frcm the first tier tests.  As yet, sufficient data are not available to
determine the need for these studies.  After all the pertinent information
has been evaluated, the studies may be necessary.
                                   92

-------
 DISCIPLINARY REVIEW

Ecological Effects profile
Hazard Assessment
Generic Data Gaps
Suggested Labeling

ECOLOGICAL EFFECTS PROFILE

Manufacturing-Use Terrazole

A few scientifically sound studies are available that identify the
toxicity of Terrazole to non-target organisms.

Terrazole at field use doses markedly inhibited nitrification by soil
microbes for several weeks.  Effects on wastewater treatment
microorganisms have not yet been  investigated.  Acute oral tests on
bob white quail and mallard ducks  indicate that Terrazole is moderately
toxic to birds (560 mg/kg and 1640 mg/kg respectively);  but, only the
study on bobwhite quail satisfies guidelines requirements.  Avian dietary
studies on Terrazole as a single  active ingredient were not available to
further investigate the toxicity of Terrazole to birds.   A study was not
available to characterize technical Terrazole1 s toxicity to freshwater
aquatic invertebrates.  A study by Sleight  (1971, 00001703)  reported a 96
hour 1C   for bluegill and trout  as 3.27 and 1.21 ppm respectively.
These figures indicate a moderate toxicity  to fish.  Studies on the
phyto toxic effects of Terrazole on non target terrestrial plants were
available from the efficacy tests which examine the effects of the
fungicide on protected plants.  The studies reviewed did not indicate any
phytotoxicity at  the levels recommended for use.
 Formulated Terrazole

 Avian  field  tests with the  formulated  products are required wnen prior
 studies  and  a consideration of pertinent data indicate a need for more
 information.  Considering  the results  of the avian acute oral studies, it
 is  unlikely  that a  simulated or actual  field studies will be necessary.

 HAZARD ASSESSfrENT

 Considering  the use pattern, available toxicity data and available fate
 data,  the Agency does not  have serious concerns about the safety of non-
 target organisms.   It should be emphasized, however, that all required
 data are not available and as such,  this decision  is not final.

 GENERIC  DATA GAPS

 The following are  the minimum studies  needed  to meet data requirements to
 register Terrazole  according to the  Proposed Guidelines of  July  10, 1978
 (43 FR,  No.  132,  29696) .   It must be noted  that  these  Tier  I studies
 are the  mini-nun requirement.  Tier II  and  III  studies may be required  if
 an  analysis  of  the  Tier  I  studies indicates  problems.   These basic  studies
 test the technical  material  and are  used  to  assess the  hazard associated
 with the use of the formulated  products.


                                  93

-------
For Manufacturing-Use Terrazole:

                                                 Guidelines Section

    (1)  Subacute dietary LC™                     163.71-1
        (8-day dietary study;  on
        two avian species, an  upland
        game bird (preferably  bobwhite
        quail)  and a wild waterfoul
        (preferably mallard duck) .
    (2)  A EC   or I£   for a fresh-               163.72-2
        water aquatic invertebrate
        (preferably Daphnia magna)

For formulated products:   None at this time.

The need for chronic avian or  aquatic testing  can only be  assessed after
all preliminary toxicity studies  and environmental fate exposure data have
been received and reviewed.

Suggested Labeling

For all outdoor uses other than aquatic applications, the  minimum labeling
requirement is "Do not apply directly to lakes,  ponds or streams.   Eb not
contaminate water by cleaning  of  equipment or  disposal of  wastes."
                                    94

-------
                               BIBLIOGRAPHY

05001204—Davis, R.G., and Pinckard, J.A.  1971.  Comparative
    systemic  fungicidal activity and phytotoxicity of certain seed and
    soil fungicides potentially useful for control of cotton seedling
    diseases.  Plant Disease Reptr. 55 (12) : 1111-1115

00001800—DaNeve, R. T.  1973.  Soil Drench Phytotoxicity Test (73-1)
    of Banrot and Truban 25% E.G. on Selected South Florida Nursery
    Plants.   (Unpublished study including letter dated June 13,  1973 frcm
    R.T. DaNeve to Bill W.A. Snail, received June 19, 1973 under 372-46;
    prepared by La Casa Verde,  Inc., submitted by Mallinckrodt Chemical
    Works, St. Louis, MO.  CDL:0032-AA)

05006029—Dasai,  B.C.; Doriswamy, S.;  Geypens, M.; Van Assche,  C.  1972.
    Performance of Aatera.  (35%-ethoxy-3-trichloromethyl-l, 2,4-
    thiadiazole)  in controlling Phythiun  damping off of tana to,  pea and
    cauliflower.  Mededelingen van de Faculteit Landhouwwetenschappen
    Rijksuniversiteit Gent ./Communications of the Faculty of  Agricultural
    Sciences, State university of Ghent.  1 37 (2): 516-523

00001664—Erecegovich, C.D.   1976.  Effects of 5-ethoxy-3- (trichloronethyl) -
    1, 2,4-thiadiaaole  (Terrazole) on microorganisms and biochemical
    processes in soil: Report No. E-1/1-76 (0)  .   (Unpublished  study
    received October 20, 1976,  under 1258-812; prepared by Pennsylvania
    State University, University Park,  Pesticide Research Laboratory;
    submitted by Olin Corp., Agricultural Div., Little Rock,  AR.
    CDL: 228143^0.)

00002238—Fletcher, D.  1972.  Report to  Olin Corporation: Acute Oral Tbxicity
    Study with Olin Terrazole,  D8364 FCG in Bobwhite Quail:  IBT  No. J890.
    (Unpublished study including letter dated January 26, 1972 from J.C.
    Calandra to John H. Wedig,  received March 3, 1972 under  1258-826;
    prepared by Industrial Bio-Test Laboratories, Inc., submitted by Olin
    Corporation,  Stamford, CT:  CDL:005836-B

00001567—Kvien, C.  1975.  Nitrification  inhibition in soils by Terrazole
    Master's thesis, Southern Illinois University, Department of Plant and
    Soil Science.  (Unpublished study including report No. 3067, received
    February 4, 1977, under  1258-812;  submitted by Olin Corporation,
    Agricultural Division, Little Rock, AR  CDLH395799-J.)
 r
00002244—Mallinckrodt Chemical Works 1973.  Pothos—Root Rot.  (Unpublished
    study received June 12,  1973 under 372-47; CDL: 003217-H)

05006097—McCain, A.H.; Byrne,  T.G.  1966.  Chemical control  of  Pythiun root
    rot in ornamentals with Daxon and Terrazole.  California Agriculture
    20 (5): 14-15

00001633—Miller, H.N.  1970.  Soil Mix Phytotoxicity Studies on Foliage
    Plants  (Unpublished study received October  5, 1970 under 372-UG(43);
    submitted by Mallinckrodt Chemical Works, St. Louis, MO; CDL:003213-Q.
                                  95

-------
00001627—Miller, H.N.  1970.   Soil Mix Phytotoxicity Using M-4  Formulations,
     (Unpublished study received October 5,  1970 under 372-UG(43);  submitted
     by Mallinckrodt Chemical  Wbrks; CDL:003214-K

00001640—  Nichols, L. I.   1970.   Fhytotoxicity Test of Truban at Herman
    Lederer Sons, Parkerford,  PA.   (Unpublished study received October 5,
    1970 under 372-UG(43):  submitted by Mallinckrodt Chemical Wbrks, St.
    Louis, MO; CDL:003213-Y

00002231—Raabe, R.D.   1970.   African Violet:  Tbxicity Trial.
    (unpublished study received  October 5, 1970 under 372-43; Prepared by
    University of California—Berkeley, submitted by Mallinckrodt,  Inc.,
    St.  Louis, MO;  CDL:003213-S)

00001703—Sleight,  B.H. ,  III.   1971.   Bioassay Fteport:  Acute Tbxicity of
    Terrazole (D-8364)  to  BLuegill  (Lepomis machronirus)   and
    Rainbow Trout  (Salmo gairdneri) .   Unpublished  study that
    includes well water quality  analysis p. 13,  received  November 23,  1971
    under 1258-826;  prepared by  Bionomics, Inc.,  submitted by 01 in
    Corporation, Stamford,  CT; CDL:101583-A)
                                 96

-------
Chapter 8

REGULATORY RATIONALE
                                                                     p^
The Agency has determined  that  the technical and  formulated Terrazole
products covered  in this Standard can be registered for sale, distribution and
reformulation in  the (Jhited States.  Current registrations will be maintained
in effect if registrants fulfill the data gaps, as outlined, in accordance with
Agency determined deadlines.  New registrations will be granted if applicants
agree to submit or cite the data (in compliance with compensation guidelines)
listed in Chapter Two of this document.  Hie Agency considers the TerraaDle
products covered  in this Standard registerable because available data do not
indicate any unreasonable adverse effects as outlined in 40 CFR 162.11 (a) .

PRODUCT COJVPOSITION STANDARDS

The Agency will consider for registration manufacturing-use and formulated
products which contain any percentage of Terrazole as an active ingredient.
I^fenufacturing-use products covered under this Standard may contain at least
95% active ingredient since data submitted are for technical  products
containing no less than 95% active ingredient.  Ebrmulations covered  under this
Standard may contain the following maximun percentages of Terra zole active
ingredient:

    Wettable Powders                   35%
    Bnulsifiable  Concentrates          25% and 4 Ibs./gallon
    Wettable Fowders/Dust              30%
    Granular                            5%

The above limits  are set according to submitted data on each of the
formulations.

ACUTE TOXICITY LIMITS

The Agency will register manufacturing-use grade Terrazole products v^hich have
Toxicity Categories I through IV because the use pattern does not indicate
possible adverse  exposure to the general public and because the pesticide
industry can be required by the Occupational Health and Safety Administration
to provide safe working conditions.

Ebr formulated products, the Agency will consider any Ibxicity Category;
however, the available data will limit present registrations to Toxicity
Categories no higher than those outlined in Chapter Two.  These categories are
assigned according to product composition and use patterns.  Current  use
patterns indicate that applicators are at risk from both dermal and inhalation
exposure.   Appropriate labeling which reflects a formulation's potential harm
is developed from Ibxicity Categories and provides for proper advisement in the
use of Terrazole  products.   For formulations which are currently lacking
toxicity data, the Agency assumes a Category I potential until sufficient data
prove otherwise.
                                    97

-------
USE PATTERNS

Under this Standard, manufacturing-use Terrazole may only be used in the
formulation of specific end-use products which contain currently accepted
ranges of active ingredient.  Formulated products may be used v\hen indicated by
product efficacy and in accordance with all  label reconmendations and
restrictions.  Fbr food uses, at present Terrazole is only registered for use
on avocados and only in California although  the Agency has no reason to object
to registration in other areas if pest conditions warrant.  These formulations
are the 5% granular and the 4 Ib a.i/gal emulsifiable concentrate.

E&TA REQUIREfrENTS

All data requirements are specified in Chapter Two of this Standard.  The
Agency's need for such data is thoroughly discussed  in the Proposed  Guidelines
(43 FR Nos. 132, 163) .  These Guidelines present both data specifications and a
rationale for each data requirement.

REQUIRED LABELING

All required labeling is specified in  Chapter  Two of this Standard.
                                 98

-------
                       Guide to Use of This Bibliography

1.  Concent of Bibliography.  Tins bibliography contains citations of all
    the studies reviewed by EPA in arriving at the positions and conclusions
    stated elsewhere in this standard.  The bibliography is divided into
    3 sections: (1)  citations that contributed information useful to the review
    of the chemical and cons id era] to be part of the data base supporting
    registrations under the standard, (2)  citations examined and judged to be
    inappropriate for use in developing the standard, and (3) standard
    reference material.  Primary sources for studies in this bibliography have
    been the body of data submitted to EPA and its predecessor agencies in
    support of past regulatory decisions,  and the published technical
    literature.

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 Ajency has sou;.jht to identify docunents at a level parallel to
    a published article from within the typically larger volu.ies 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 re^ie*;, and
    can be described with a conventional bibliographic citation.  'Hie Ajency
    has attanpted also  to unite basic docments and commentaries upon them,
    treating then as a single study.

3.  Identification of Entries.  The entries in this bibliography are sorted
    by author, date of docunent, and title.  Each entry bears, to the left of
    the citation proper, an eight-digit numeric identifier.  This nunber is
    unique to the citations, and should be called the "Mastur Record
    Identifier", or "MRID" .  It is not related to the six-digit "Accession
    Number" which has been used to identify volunes of submitted data; see
    paragraph 4 (d) (4) below for a further explanation.  In a few cases, entries
    added to the bibliography late in the review may 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 for the Anerican National Standards
    Institute (ANSI), expanded to provide for certain special needs.  Sane
    explanatory notes of specific elanents follow:

      a. Author.   Whene/er the Ajency could confidently identify one,
         the Agency lias chosen to show a personal author.  When no individual
         was identified, the Agency has sliovji an identifiable laboratory or
         testing facility as author.  As a last resort, the Agency has shown
         the first knovvn submitter as author.

      b. Document Date.   When the date appears as four digits with no
         question marks, the Agency took it directly from the docunent.  When a
         four-digit date is followed by a question mark, tne bibliographer
         deduced the date frcm evidence in the docunent.  When the date
         appears as (19??) , the Agency was unable to determine or estimate the
         date of the document.
                                   99

-------
.
   Title.  Tills is the third element in the citation.  In some cases it
   lias been necessary for the Agency bibliographers to create or enhance
   a document title.  Any such editorial insertions are contained
   between square brackets.

d. Trailing Parenthesis.  For studies submitted to us in the past, the
   trailing parenthesis include (in addition to any self-explanatory
   text) the following elements describing the earliest known submission.

         (1)  Submission Date.  Immediately following the word
             'received'  appears the date of the earliest known
             submission.

         (2)  Administrative Number.  The next element, immediately
             following the word 'under', is the registration nunber,
             experimental permit number, petition nunber, or other
             administrative nunber associated with the earliest known
             submission.

         (3)  Submitter.  The third element is the submitter, following
             the phrase 'submitted by'.  When authorship is defaulted to
             the submitter, this element is omitted.

         (4)  Volume Identification.  The final element in the trailing
             parenthesis identifies the EPA accession number of the
             volume in which the original submission ofo the study
             appears.  The six-digit accession number follows the symbol
             '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.
             Ebr exanple , within accession number 123456, the first
             study 'would be 123455-A;  the second, 123455-B;  the 26th,
             123456-Z; and the 27th 123455-AA.
                             TOO

-------
                         OFFICE OF PESTICIDE PROGRAMS
                    REGISTRATION STAN CARD BIBLIOGRAPHY

             Citations Considered to be Fart  of the Data Base
               Supporting Registration Under This Standard

GS0009-037—Martin, H., ad C.R. Worthing, eds.  1977.  Pesticide Index:
    Basic information on the chemicals used as active components of
    pesticides, 5th ed. British Corp. Protection Council, Worcestershire,
    England.

GS0009-038— Pesticide Chemical Use Pattern Profile for Terrazole
    (0847011)"  U.S. Environmental Protection Agency, Office of Pesticide
    Programs, Benefits and Field Studies Division, May 1979.

GS0009-048—Pesticide Process Encyclopedia, 1977, Noyes Data Corp.  Park
    Ridge, New Jersey.

00001553—01 in Corporation. 1977? Terrazole  Technical Grade—Data Sheet
    (Unpublished study that includes data sheets A. 1-A. 2, A.3-A.4,
    received Feb. 4, 1977 under 1258-812; CDL: 095799-A)
                                                             p^
0001556—01 in Corporation. 1966.  Technical Data:  Terrachlor  Super X:
    (Terraclor  + Terrazole) .   (Unpublished study received Jan 1, 1966?
    under 1258-Q; CDL: 110045-A)

00001760—01 in Mathieson Chemical Corporation. 1964?  Chemical and
    Physical Properties for Terrazole.  (Unpublished study received Dec
    15, 1964 under 1258-740;  CDL: 119218-A)
                                                                  j^
00002232—Schingh, J.E.  1976.   Vapor Pressure Studies of Terrazole  (5-
    Ethoxy-3-trichloromethyl-l,2,4-thiadiazole) :  CASR-21-76.
    (Unpublished study received Oct 10,  1976 under 1258-312; submitted by
    Olin Corp., Agricultural  Div.,  Little Rock,  Ark.; CDL: 228143-0)

GS0009-020—Geomet Technologies, Inc., Compilation of Data Related to Exposure
    to Terrazole,  Geomet Technologies, Inc., Rockville,  MD,  May 14, 1980a.

GS0009-021—Geomet Technologies, Inc., Use Data for Exposure Analysis of
    Terrazole, Geomet Technologies,  Inc.,  Rockville, MD, July 17, 1980b.

GS0009-070—Sparks, D. ,  Sales Manager, Crop Protection Chemicals, Olin Corp.,
    Little Rock,  Ark, personal corrmunication to E.N. Pelletier, BFSD,  EPA,
    Washing to, D.C.  March 31,  1980 a.

GS0009-071—Sparks, D. ,  Sales Manager, Crop Protection Chemicals, Olin Corp.,
    Little Rock,   Ark, personal communication to E.N.  Pelletier,  BFSD,  EPA,
    Washington, D.C.,  Aug.  11, 1980b.

00001664—Ercegovich, C.D.  1976.  Effects of 5-ethoxy-3-(tric hi oromethyl)-
    1,2,4-thiadiazole (Terrazole) on microorganisms and  biochemical
    processes in  soil:  Report No.  E-l/1/76 (0).  (Unpublished study
    received Oct.  20,  1976,  under 1258-812; prepared by  PA.  State Univ.,
    University park,  Pesticide Research Laboratory; sumbitted by Olin
    Corp., Agricultural  Div.,  Little Rock,  Ark.  CDL:  228143-AD.
                                 101

-------
05001190—Helling, C.S., D.G. Dennison, ard D.D. Kaufinan, 1974.  Fungicide
    movement in soil.  Phytopath  64(8):  1091-1100.

GS0009-039—lacoviello, S.A. 1979.  Activated sludge test for Terrazole 3-
      C (3-trichloromethyl-5-ethoxy-l,2,4-thiadia2Dle) .  (01 in Cbrp.
    report CASR-14-79, prepared Apr. 12, 1979 by 01 in Research Center,
    Analytical Department, New Haven, CM).  (MRID unknowi; CDL:  238774)

00001663—Iwan, G.R. 1976.  01 in—14C Terrazole channel catfish
    (jctalurus punctatus Rafinesque) , static bioaccLmulation study.
    (Unpublished study received Oct. 20, 1976, under 1258-812; prepared by
    Union Carbide Corp, Aquatic Environmental Sciences; submitted by 01 in
    Corp., Agricultural Div., Little Rock,  Ark.  CDL:   228143-AB.)

00001763—Kuchar, E.J. 1972.  Residues of Terrachlor, Terrazole and
    metabolites in soil:  CASR-5-72.  (Unpublished study including  letter
    dated Oct. 12, 1972, from R.F. Fhilpitt to P.C. Williams, received
    Oct. 17, 1972, under 1258-Q; submitted  by 01 in Corp.,  New Haven ,  CN
    CDL:  120359-A) .

00001661—Kuchar, E.J. 1973.  Residues of Terrachlor and Terrazole in soil
    —1972 studies:   CASR-19-73.  (Unpublished study received Oct.  20,
    1976,  under 1258-812;  submitted  by 01 in Corp., Agricultural Div.,
    Little Rock, Ark CDL:   228143-X.)

00001659—Kuchar, E.J. 1976.  Field  soil dissipation studies concerned
    with Terrazole (5-ethoxy-3-tr ichloronethyl-1,2,4-thiadiazole :   CASR-6-
    76.  (Unpublished study received Oct. 20,  1978, under  1258-312;
    submitted by 01 in Corp., Agricultural Div.,  Little  Rock,  Ark.   CDL:
    228142-S.)

00001660—Kuchar, E.J. 1976.  Terrazole (5-ethoxy-3-trichloromethyl-
    1,2,4-thiadiazole)  greenhouse studies in soil:  CASR-24-76.
    (Unpublished study received Oct. 20, 1976, under 1258-812; submitted
    by 01 in Corp., Agricultural Div.,  Little Rock, Ark.  CDL:   228143-Y) .

00001567—Kvien, C.  1975.  Nitrification inhibition in soils by Terrazole.
    Master's thesis, Southern Illinois University, Department of  Plant and
    Soil Science.  (Unpublished study including  report no. 3067,  received
    Feb. 4, 1977, under 1258-812; submitted by 01 in Corp.,  Agricultural
    Div.,  Little Rock, Ark. CDL-095799-J.)

00001650—Thomas, R.J. 1975. Analytical investigations concerned  with the
    rate of hydrolysis of Terrazole-C-14: CASR-7-75.   (Unpublished  study
    received Oct. 20, 1976, under 1258-812; submitted by Olin Corp.,
    Agricultural Div., Little Rock,  Ark. CDL: 228143-fl.)

00001652—Thcmas, R.J. 1975. Analytical investigations concerned  with the
    rate of hydrolysis of Terrazole-C-14: CAER-7-75.   Supplement #1.
    (Unpublished study received Oct. 20, 1976 under 1258-812; submitted by
    Olin Corp., Agricultural Div., Little Rock,  Ark. CDL: 228143-J.)
                                  102

-------
00001657—Thomas,  R.J. 1976.  Laboratory  soil metabolism  studies concerned
    with  Terrazole (5-ethoxy-3-trichloromethyl-l, 2,4-thiadiazole) : CASR-7-
    76.   (Unpublished study received  Oct. 20, 1976  under 1258-812;
    submitted  by din Cbrp.,  Agricultural Div.,  Little Rock, Ark.
    CDL:228143-Q.)

00001655—Thomas,  R.J. 1976.  Laboratory  soil leaching studies concerned
    with  Terrazole (5-ethoxy-3-trichloronethyl-l,2,4-thiadiazole) : CASR-4-
    76.   (Unpublished study received  Oct. 20, 1976  under 1258-812;
    submitted by 01 in Cbrp.,  Agricultural Div.,  Little Rock, Ark.
     GEL: 228143-M.)

GS009-030—Anon, 1978.  Skin  sensitization Test  with Terrazole Technical in
    Guinea Pigs; 1ST #8530-10903.

GS009-031—Anon, 1979, Eye Irritation Test in Rabbits.   Scientific Associates,
    Inc.;  6200  S.  Lindebergh  St,  St. Louis, MO  63123.

00001591—Carson,  S. 1964.  Test for  Acute Inhalation Toxicity in Rats.  Report
    (unpublished study received 12/16/64 under 1258-740, prepared by Food and
    Drug  Research  Labs, Inc.  for Squibb  Institute;  submitted by 01 in Mathieson
    Chanical Corp., Stamford, Conn.

05004729—Dalvi, R.R. and HDwell,  C.D. 1977.  Toxic Effects of a Fungicide,
    (Terrazole) on the Hepatic  Drug Metabolizing  Enzyme  Systati in Mice.
    Bulletin Environ. Contain. Tbxicol. 17-225-232  (MRID  05004729).

0000182—Dreir,  H.  Borath, L.L., and  Lindberg, D.C. 1978.  Aerosol Inhalation
    Study with Terrazole Fungicide 4  lb., Emulsifiable in Albino Rats.  IBT
    #8562-10907.   Unpublished study received 11/1/78; under 6E1747 prepared by
    IBT Labs,  Inc.  submitted  by Olin  Corp., Stamford, CN.

00001831—Duhanel,  C.G. and Poa, H. 1978.  Report to Olin Corp.  Acute Dermal
    Toxicity Study with Terrazole  Fungicide (4 lb.  Bnulsifiable)  in Albino
    Rabbits, P.O.  # RC-38830.   IBT #  8530-10906.   (Unpublished study received
    11/15/78, under 6E1747, prepared  by  IBT labs,  Inc.

GS0009-032—Ercegovich, C.D., and  K.A. Rashid 1977.  The Mutaganic'Evaluation
    of Terrazole for Matagenic  Effects in Bacterial Test Systems.  Unpublished
    data  from Pesticide Research Laboratory, PA,  State University, University
    Park, PA.  CDL:  240890.

GS0009-033—Knickerbocker, M. and  Re, T.A. 1979.  Teratologic Evaluation of
    Terrazole Tech. in Dutch-belted Rabbits (Unpublished).  No F/MID#.  Lab
    #5845 received 7/6/78.

00001597	Kuchar, E.J. 1970a.  Determination of Terrazole Residues in Beagle
    Dog Tissues, CASR-2-70.   Includes method date 2/13/70.  (Unpublished study
    received 3/28/70)

00001601	Kuchar, E.J. 1970b.  Analytical Studies—Terrazole ( ) in Simulated
    Gastric Juice CASR-2-70.  (Unpublished study received 5/28/70 under OF0997,
    submitted by Olin Corp.,  Stamford, Conn.
                                 103

-------
00001600—Larson, P.S 1963(a) Toxicology Studies on the Effect of Adding OM-2424
    to the Diet of Albino Rats.  (Unpublished study including letter dated
    9/3/63 form P.S. Larson to Sylvan I. Cbhen, received 12/16/64 under 1258-
    740, prepared by radical College of Va., Bept of Pharmacology, submitted by
    01 in Mathieson Chemical Corp.,  Stanford, CN.

00001605—Larson, P.S. 1963 (b) Toxicological Studies on the Effect of Adding
    CM-2424 to the Diet of Beagle Dogs:   Three Month Study.   (unpublished study
    received Eec. 16, 1964, under 1258-741); prepared by Medical College of
    VA.; Dept. of Pharm, 01 in Mathieson  Chem. Corp.  Stamford, CN.; CDL:
    050922.

00001588—Larson, P.S. 1963 (c) Toxicologic Studies on the Effect of Adding Olin
    2424 to  the Diet of Mongrel Dogs:  Range Finding Studies  (4 weeks) .
    (Unpublished study including addendum and letter dated June 17, 1963, from
    1258-740; prepared by Medical College of VA.; Dept. of Pharm., submitted
    by Olin  Mathieson Ohem. Corp.  Stamford, CN.

00002227—Larson, P.S. and Borzelleca,  J.F.  1964 (a) Acute Percutaneous Toxicity
    of Olin  2424 in Albino Rabbits (Olin 2424-9-0, Technical)  .  (Unpublished
    study including letter to Sylvan I.  Cohen, received ec. 16,  1964, under
    1258-740; prepared by Medical College of VA, Dapt. of Pharm.,  submitted by
    Olin Mathieson Chemical Co., Stamford, CN.

00001590—Larson, P.S. and Borzelleca,  J.F.  1964 (b) Eye Irritation Properties
    of Olin  2424 in Rabbits (Olin 2424-9-0,  Technical) .  (unpublished study
    including letter dated Nov. 17,  1964, under 1258-740;  prepared by Medical
    College  of VA, Dept. of Pharm,  submitted by Olin Mathieson Chem.  Corp.,
    Stamford, CN.

00001571—Larson, P.S. and Borzelleca,  1965   The Percutaneous  Toxicity to
    Rabbits  (Abraded skin)  of Olin  Compound  2424 (Olin 2424-9-0,  Technical) .
    (Unpublished study including letter  dated Jan. 11,  1961,  under 1258-Q;
    Prepared by Medical College of  VA.,  Dept. of Pharm., submitted by Olin
    Mathieson Chemical Corp., Stamford,  CN.

00001555—Larson,  P.S. and Borzelleca,  J.F.  1967.  Acute Oral  Toxicities and
    Potentiation Studies of Terrachlor  and Terrazole in Male Albino Rats.
    (Unpublished study prepared by  Medical  College of VA.,  Dept. of Pharm.,
    submitted by Olin Mathieson Chemical Corp., Stamford, CN.

00001697—Larson,  P.S. and Borzelleca, J.F.  1968 (a) Toxicological  Study on  the
    Effect of Adding Terrazole to the Diet of Beagle Dogs for  a Period of Iwo
    Years.  (Unpublished study received  Nov. 18, 1968,  under 0F0997;prepared by
    Medical  College of VA.,  Dept. of Pharm., submitted by Olin Mathieson
    Chemical Corp.,  Stamford,  CN.

00001698—Larson, P.S. and Borzelleca,  J.F.  1968 (b) . Three Generation
    Reproduction Study on Rats Receiving Terrazole in Their Diet.   (Unpublished
    study received June 9, 1970, under  0F0997;  prepared by .Medical College of
    VA., Dept. of Pharm., submitted  by  Olin  Mathieson Chemical Corp., Stamford,
    CN.
                                104

-------
00001792—Larson, P.S. and Borzelleca, J.F. 1970.  Acute Oral Toxicity of
    Terrazole  in Male Albino Rabbits.  (Unpublished study received June 9, 1970,
    under 0F0907; prepared by Medical College of VA., Dapt. of Pharm.,
    submitted  by 01 in Mathieson Chemical Corp., Stamford,  CN.

00001599—McKennis, H., Jr., Bownan, E.R. a^ Dar, M.S. 1970.  Studies on the
    Physiological Disposition of Terrazole-  C.  (Unpublished study received
    May 28, 1970, under 0F0997; prepared by Medical College of VA., Dept. of
    Pharm., submitted by CO. in Corp., Stamford, CN.

00001589—Medical College of Virginia, Department of Pharmacology. 1963.
    Toxicologic Studies on the Effect of Adding Olin-2424 to the Diet to Albino
    Rats:   Range-Finding Studies (3 weeks) . from P.S. Larson to Sylvan I.
    Cohen, received Dae. 16, 1964,  under 1258-740; submitted by Olin Mathieson
    Chsnical Corp., Stamford, CN.

00001586—Miller, M. 1961. Acute Oral Tbxicity in Mice:  Ph. 425/B.
    (Unpublished study received Dec. 16, 1964, under 1258-740; submitted by
    Olin Mathieson Chemical Corp.,  Stamford, CN.

00001593—Mill stein, L. 1961 Experimental Pesticides 1306 and 2424 (SQ542424) :
    Acute Dermal Tbxicity in Rabbits:  TH.  08/B.  (Unpublished study including
    letter dated Oct. 26, 1961, from L. Mill stein to J.W. Poutsiaka,  received
    Dec. 16, 1964, under 1248-70, submitted by Olin Mathieson Chemical Corp.,
    Stamford, CN.

00001592—Moulton, R.H. 1970 (a) Acute Oral  Tbxicity (LD50)  Study in Rats.
    Truban 30% W.P.:  S.A. No. R-5719a .  (unpublished study received  Oct.  ,
    1970 under 372-43; prepared by Scientific Associates, Inc.  Submitted by
    Mallinckrodt Chemical Vforks, St. Louis, MO.

00001593—Mo ul ton, R.H. 1970 (b) .  Acute Dermal Tbxicity (MLD) in Rabbits;
    Truban 30% W.P.:  S.A. No. R-5719b.  (Unpublished study received  Oct. 1970
    under 372-43; prepared by Scientific Associates, Inc.,  submitted  by
    Mallinckrodt Chemical Wbrks, St. Louis, MO.

GS0009-034---Wham, Dan, et al. 10/27/77.  Acute Oral Tbxicity of 53 in Rats.
    Acute  Dermal, Eye Irritation and Primary Skin Irritation Tests of Terrazole
    5G in  Rabbits.

00001557—Olin Corporation. 1965.  Metabolism of Olin 2424  in Mongrel Dogs:
    CASR-10-65.  Includes method dated Nov. 17, 1965.  (Unpublished study
    received Nov. 17, 1965 (?)  , under 1258-Q.

00001828—Palanker, A. L., and Goldhamer, R. E. 1973.   Acute  Oral LDc-0  in Rats
    Primary Dermal Irritation in Rabbits:  Terrazole:  A-851.  (Unpublished
    study received Nov. 15, 1978, under 6E1747; prepared by Biometric Testing,
    Inc.,  submitted by Olin Corp.,  Stamford, CN.

00001830—Scibor, G.  1978.   Report  to Olin  Corporation:  Eye Irritation Studies
    Irritation Studies with Terrazole Fungicide in Albino Rabbits:  P.O. No.
    38830:   1ST No. 8530-10906.  (Unpublished study received Nov. 15, 1978,
    under  6E1747; prepared by Industrial Bio-Test Laboratories, Inc., submitted
    by Olin Corp., Stamford, CN.
                                    105

-------
GS0009-035—Weaver, J. and John W.  Grade and D.J.  Sullivan 11/2/77.   Acute Dust
    Inhalation Tbxicity Study of Terrazole 5G in Rats.

GS0009-035—Webig, J.H., Kennedy,  G.L.,  Jr., Knickerbocker,  M., and  Smith, S.
    1980 Teratologic Evaluation of Etridiazol in Pats and Rabbits.
    (Unpublished)
                                                                     n
00001645—Griffith, W.P. 1975.  Appendix:  Determination of Terrazole  (5-
    ethoxy-3-trichloromethyl-l,2,4-thiadiazole)  in avocado:   CASR-19-76.
    Pfethod CAM-23-75 dated June 12,  1975.  (Unpublished study received October
    20, 1976 under 1258-812; submitted by Olin Corp.,  Agricultural Div.,  Little
    Rock, Ark.; CDL:  228143-C)
                                                          p^
00001570—Griffith, W.P. 1973.  Determination of Terrazole  (5-ethoxy-3-
    trichloromethyl-1,2,4-thiadiazole) and Terrachlor  (pentachloro-
    nitrobenzene)  and allied metabolite  in plant tissues or  harvest
    samples,  Pfethod CAM-24-73 dated July 3, 1975.  (Unpublished study received
    February 4, 1977 under 1258-812; submitted by  Olin Corp.   Agricultural
    Div., Little Rock, Ark.; CDL:  95799-M)

GS0009-003—Kuchar, E.J., 1970.  Hydrolytic stability of 3-carboxy-5-
    ethoxy-1,2,4-thiadiazole and 3-carboxy-5-hydroxy-l, 2,4-thiadiazole under
    alkaline and acid conditions,   pg. 0997.

00001600—Kuchar, E.J.  1970.  Analytical studies  concerning  metabolism of
    Terrazole  (5-ethoxy-3-trichloromethyl-l,2,4-thiadiazole) :  CASR-5-70.
    (Unpublished study received my 28,  1970 under OF0997;  submitted by Olin
    Corp., Stamford, Cbnn.; CDL: 091717-G)

GS009-007—Kuchar, E.J., 1975.  Residues of Terrazole and 3-carboxy-5-
    ethoxy-1,2,4-thiadiazole in avocados, 1974-5 crop.  pg.  1747

00002255—Kuchar, E.J..  1971.  Residues  of Terrazole (5-ethoxy-3-
    trichloromethyl-l,2-4-thiadiazole) and 3-carboxy-5-ethoxy-l,2,4-thiadiazole
    in immature cotton plants:  CASR-2-71.   (Unpublished study received July
    20, 1971 under OF0997; submitted by  Olin Corp.,  Chemicals Div.,  New Haven,
    Conn.; CDL 097540-A)

00001689—McKennis, H.,  Jr. and E R. Bownan. 1974.  Studies on the dispositon
    and metabolism of Terrazole   C (3-trichloromethyl-5-ethoxy-l, 2,4-
    thiadiazole)  in young cotton grovvn  in Terrazole   C treated soil.
    (Unpublished study received August 20,  1971 under CF0997; prepared by
    Msdical College of Virginia Dept. of Pharmacology, submitted by Olin
    Corporation.,  Stanford, Conn.;  CDL:  091717-F)

00002229—Thomas, R.J. 1970.  Determination of 3-carboxy-5-ethoxy-l, 2,4-
    thiadiazole in cotton seeds:  analytical method.  Method  CM-10-70
    (Tentative) dated my 21, 1971  form  R.  F. Philpitt to W.  H. Nbrgan
    received my 28, 1970 under CF0997:  submitted  by Olin Corp., Stamford,
    Conn.; CDL:  091717-AI) .

GS0009-005—Thomas, R.J., 1975.  The liquid chromatographic determination
    of 3-carboxy-5-ethoxy-l,2,4-thiadiazole in avocados.

GS009-006—Thomas, R.J., 1975.  The liquid chromatographic determinant
    of 3-carboxy-5-ethoxy-l,2,4-thiadiazole in soil.  pg. 1747.


                                    106

-------
05001204— Davis,  R.G.,  and  Pinckard, J.A.  1971.   Comparative
    systemic  fungicidal  activity and phytotoxicity of certain  seed  and
    soil  fungicides  potentially useful  for control of cotton seedling
    diseases,   plant Disease Reptr . 55  (12) : 1111-1115

00001800—DaNeve, R.T.   1973.  Soil Drench Phytotoxicity lest  (73-1)
    of  Banrot and Truban 25% E.G. on Selected South Florida Nursery
    Plants.   (Unpublished study including letter dated June 13, 1973 from
    R.T.  DeNeve to Bill  W.A. Small, received June  19, 1973 under 372-45;
    prepared by La Casa  Verde, Inc., submitted by  Mallinckrodt Chemical
    Vtorks, St.  Louis, MO.   CDL:0032-AA)

05006029—Dasai, B.C.; Doriswamy, S.; Geypens, M.; Van Assche,  C,  1972.
    Performance of Aatera.  (35%-ethoxy-3-trichloromethyl-l, 2,4-
    thiadiazole) in controlling Phythiun damping off of tomato, pea and
    cauliflower.  Msdedelingen van de Faculteit Landhouwwetenschappen
    Rijksuniversiteit Gent ./Conrnunications of the  Faculty of Agricultural
    Sciences, State  University of Ghent. 1 37 (2): 516-523

00001664—Erecegovich, C.D.  1976.  Effects of 5-ethoxy-3-(tr ichloromethyl) -
    1, 2,4-thiadiazole (Terrazole)  on microorganisms and biochemical
    processes in soil: Report No. E-l/1-76 (0) .  (Unpublished study
    received October 20, 1976, under 1258-812; prepared by Pennsylvania
    State University, University Park,  Pesticide Research Laboratory;
    submitted by Olin Corp., Agricultural Div., Little Rock, AR.
    CDL: 228143^0.)

00002238—Fletcher, D.   1972.   Report to Olin Corporation:  Acute  Oral Tbxicity
    Study with  Olin Terrazole, D8364 FCG in Bobwhite Quail:  IBT No.  J890.
    (Unpublished study including letter dated January 26, 1972  from J.C.
    Calandra to John H. Wedig, received March 3, 1972 under  1258-826;
    prepared by Industrial  Bio-Test Laboratories,  Inc.,  submitted by Olin
    Corporation, Stamford, CT: CDL:005836-B

00002246—Mallinckrodt Chemical torks (19??)  Pothos—Root Rot.  (Unpublished
    study received June 12,  1973 under 372-47; CDL:003217-fl)

05006097—McCain, A.H.; Byrne, T.G.  1966.   Chemical control of Pythian root
    rot in ornamentals with Dexon and Terrazole.  California Agriculture
    20 (5): 14-15

00001633—Miller, H.N.   1970.   Soil Mix Phytotoxicity Studies on  Foliage
    Plants (Unpublished study received  October 5,  1970 under 372-UG(43);
    submitted by Mallinckrodt Chemical  torks, St. Louis, MO; CDL:003213-Q.


00001627—Miller,  H.N.   1970?   Soil Mix Phytotoxicity Using  M-4  Formulations.
     (Unpublished study received October 5,  1970 under 372-UG(43);  submitted
    by Mallinckrodt  Chemical  Wbrks; CDL:003214-K
                               107

-------
00001640—  Nichols,  L.  I.   1970.   Fhytotoxicity Test of Truban at Herman
    Lederer Sons, E&rkerford, PA.   (Unpublished study received October 5,
    1970 under 372-U3(43):  submitted  by Mallinckrodt Chemical  Works,  St.
    Louis, MO; CDL:003213-Y

00002231—Raabe, R.D.   1970.   African Violet:  Toxicity Trial.
    (Unpublished study received  October 5,  1970 under 372-43;  Prepared by
    University of California—Berkeley, submitted  by Mai 1 inckrodt, Inc.,
    St.  Louis, MO;  CDL:003213-S)

00001703—Sleight,  B.H.,  III.   1971.   Bioassay Report:  Acute Toxicity of
    Terrazole (D-8364)  to  Bluegill  (  lepomis machronirus )  and
    Rainbow Trout ( Salmo  gairdneri )~.   Unpublished  study  that
    includes well vrater quality  analysis p.  13,  received November 23,  1971
    under 1258-826; prepared  by Bionomics,  Inc., submitted  by  01 in
    Corporation, Stamford,  CT; CDL:101583-A)
                                   108

-------
                         OFFICE  OF  PESTICIDE  PROGRAMS
                      REGISTRATION  STANDARD BIBLIOGRAPHY
                Citations Judged  to be  Inappropriate  for Use
                         in Developing  this  Standard


MRID          CITATION


05001692      Attiah, H.H.; Wahba, M.L.  (1973) Phosphorus compounds as a cause
                   of an increase  in numbers of the flat mite.  Pages 193-196,
                   _In Proceedings of the 3rd International Congress of
                   Acarology; Aug 31-Sep 6, 1971, Prague.
05001604      Babu, B.H.; Rao, N.V.S. (1968) Search for physiologically active
                   compounds: Part XII.  Synthesis and fungistatic activity of
                   5:6-and 5:8-quinoline quinones.  Pages 31-36, In Proceedings-
                   Indian Academy of Science, Section A.   Vol. 67~ Bangalore,
                   India: Indian Academy of Sciences.
05010147      Bald, J.G.; Paulus, A.O.; Lenz, J.V. (1973)  Fungicidal dips for
                   Easter lily bulbs	treatment before shipment.  California
                   Agriculture 27(12):8-10.
05001662      Beckman, H.; Garber , D. (1969) Recovery of 65 organo phosphor us
                   pesticides from Florisil with a new solvent elution system.
                   Journal of the Association of Official Analytical Chemists
                   52(2):236-293.
05001663      Benson, W.R.  (1969) The chemistry of pesticides.  Annals of the
                   New York Academy of  Sciences 160(l):7-29.
05002823      Buchenauer, H. (1975) Differences in light  stability of some
                   carboxylic acid anilide fungicides in  relation to their
                   applicability for seed and foliar treatment.  Pesticide
                   Science 6 (5) :525-535.
05001649      Burchfield, H.P. ;  Storrs, E. E. (1977)  Residue analysis.  Pages
                   463-505,  _In Antifungal Compounds: Vol. 1.   Edited by M.R.
                   Siegel andd  H.D. Sisler.   New York: Marcel  Dskker.
05001701      Caswall, R. L.  (1969)  Report on pesticide formulations.  Journal
                   of the Association of Official Analytical  Chemists 52(2):
                   220-221.
05001564      Daines, R.H.  (1955) Sweet potato scurf control  studies in New
                   Jersey,  1942-1952.  Plant Disease Reporter 39 (10):739-745.
05001601      Darby, J.F. (1953) Recent developments in the control of the
                   major diseases of unstaked tomatoes grown  on the sandy soils
                   of south Florida.  Pages 103-107,  In Proceedings—Florida
                   State Horticultural Society.  (Florida Agricultural
                   Experiment Station Journal series, no. 220)
05003276      Dittmer, D.S., ed. (1959)  Handbook of  Toxicology.  Volune V:
                   Fungicides.   Philadelphia, Pa.: W.B. Saunders.  (Available
                   from:  University Microfilms International,  Ann Arbor,  MI)
05006656      Dye, G.A.  (1975)  The application and uses of terrazole soil
                   fungicide.  Pages 302-306, _In Combined Proceedings of the
                   International Plant Propagators'  Society.   Vol.  25.
                   Cleveland, Ohio: International Plant Propagators'  Society.
05001651      Dye, H.W.,  inventor;  Food Machinery and Chemical Corp., assignee
                   (1956) Composition for controlling growth of fungi
                   comprising dichloronapthaquinone  and bentonite sulfur.
                   U.S.  patent 2,771,389.  Nov 20.  2 p.


                                     log

-------
05001623      Fitzgerald,  G.P.  (1957)  The control of the  growth of algae  with
                   CMU.   Transactions of the Wisconsin Academy of Sciences,
                   Arts  and Letters  46:281-294.
05001650      Fletcher,  H.H.,  inventor;  United States Rubber Cb., assignee
                   (1947)  Manufacture of chlorinated quinones.   U.S.  patent
                   2,422,229.   Jun 17.  2 p.
05003964      Geypens, M.; Desai,  B.C.;  Van  Assche,  C. (1974)  Pectolytic  and
                   cellulolytic enzymes  produced  by 3 Pythium ultimum isolates
                   in association  with 3 fungicides  in stem-bases of  pea
                   seedlings.   Mededelingen  van de  Faculteit
                   Landbouwwetenschappen, Rijksuniversiteit  Gent.
                   [Communications of the Faculty of Agricultural Sciences,
                   State University  of Ghent].  39 (2): 979-990.
05001658      Cuba, E.F. (1954)  Control  of Fusicoccun peach  canker.  Pages
                   69-70,  Jin Massachusetts Fruit  Growers' Association.  Report
                   of the  Annual Meeting, No.  60.  North  Amherst, Mass.:
                   Massachusetts Fruit Growers' Association.
05001628      Hamdi,  Y.A.; Moharram,  A.A.; Lofti, M. (1974)  Effect of certain
                   fungicides on some rhizobia-legune-symbiotic systems.
                   Zentralblatt fuer  Bakteriologie,  parasitenkunde,
                   Infektionskrankheiten und Hygiene, Abteilung II 129 (3/4): 363-
                   368.
05001563      Harris, H.B.; Luttrell, E.S.  (1955) Grain sorghun seed  treatment
                   tests and diseases in Georgia  for 1954.   Plant Disease
                   Reporter 39 (4): 329-331.
05001699      Horn, N.L. (1961)  Control  of Botrytis  rot of stravvberries.   Plant
                    Disease Reporter 45 (10):818-822.
05013485      Hopkins, D. L.; Elmstrom, G.W.  (1975) Chemical  control of  fusariun
                   wilt  of watermelon.  Pages 196-200,  _In Proceedings of  the
                   Florida State Horticultural Society.   Vol. 88.   Lake Alfred,
                   Fla.: Florida State Horticultural Society.   (Florida
                   Agricultural  Experiment Stations  journal  series no. 8011)
05009248      Ivy, H.W.  0-973)  Response  of cotton to herbicide  and fungicide-
                   insecticide  combinations  applied  at  planting.   Pages 132-
                   132,  _In Proceedings of the  Southern Vfeed  Science Society.
                   Vol.  26. Athens,  Ga.: Southern Weed Science Society.
05001643      Jacks,  H.; Brook,  P.J.  (1954)  Control  of black spot of  apples.
                   Jstew Zealand  Journal of Science and  Technology 36A:78-89.
05001626      Jansen, L.L.; Centner,  W.A.; Hilton, J. L. (1958)  A new  method for
                   evaluating potential  algicides and determination of the
                   algicidal properties  of several substituted-urea and s-
                   triazine con pounds.  Weeds  6:390-398.                ~~
05001782      Johnson, H.R.; Me In tire, M.S.  (1975) Pesticide poisoning  in
                   children: a  review from Children's  Memorial  Hospital,  Omaha,
                   Nebraska from 1960-1973.   Part I.  Nebraska Medical Journal
                   60 (2):40-43.
05006642      Kappelman, A.J. ;  Jr.;  Buchanan,  G.A.  (1968) Influence of
                   fungicides,  herbicides and  combinations on emergence and
                   seedling growth of cotton.  Agronomy Journal 60 (6): 660-662.
05001696      Kinoshita, F.K.;  Frawley,  J.P.;  Keplinger,  M.L.;  Calandra,  J.C.
                   (1976)  Relative cholinesterase and  aliesterase inhibition in
                   rat and hunan blood from  exposure to an organic phosphate
                   pesticide.   Toxicology and  Applied  Pharmacology 37(1): 168.
                                    110

-------
05011937      Fftauss, J.F.  (1972) Field evaluation of  several soil fungicides
                   for control of Scindapsus aureus cutting decay incited by
                   Pythium splendens.  Plant Disease Reporter 56 (12): 1074-
                   1077:
05011938      Knauss, J.F. (1977) Soil fungicides for tropical foliage
                   plants—efficacy and other considerations.  Pages 340-342,
                    In Proceedings of the Florida State Horticultural Society.
                   Vol. 90. Lake Alfred, Fla.; Florida State Horticultural
                   Society.  (Florida Agricultural Experiment Stations journal
                   series no. 762)
00002257      Kuchar, E.J. (1971) Residues of 3-Carboxy-5-ethoxy-l, 2,4-thiadia-
                   zole in Cotton Seed: CASR-3-71.  Includes method  CAM-11-71
                   dated Jul 19, 1971.  (Unpublished study received  Jul 22,
                   1971 under 0F0997; submitted by Olin Corp.,  New Haven,
                   Conn.; COL: 097541-A)
05011881      Laski,  R.R.; Watts, R.R. (1973) Gas chromatography of
                   organonitrogen pesticides, using a nitrogen-specific
                   detection system.  Journal of the Association of  Official
                   Analytical Chemists 56 (2): 328-332.
05001573      Leukel, R.W.; Webster, O.J.;  Earhart, R.W. (1956) Seed-treatment
                   tests on sorghum in 1956.  Plant Disease Reporter
                   40 (12):1071-1072.
05001558      Leukel, R.W.; Webster, 0.J. ;  Porter, R.H.  (1954)  Sorghum seed-
                   treatment tests in 1954.   Plant Disease  Reporter  38 (11):769-
                   770.
05001602      Magie, R.0. (1953) Gladiolus  corm treatments  in the control of
                   fusariun rot.  Pages 318-321,  _In Proceedings—Florida State
                   Horticultural Society.   Vol. 66. Lake Alfred,  Fla.:  Florida
                   State Horticulutral Society.  (Florida Agricultural
                   Experiment Station Journal series,  No. 192)
00001575      Mallinckrodt Chemical Works (1968)  Supporting Data: Koban: [Its
                   Use and Efficacy] .  (Unpublished study received Mar 31,  1971
                   under 372-34; CDL: 026860-A)
00001765      Mallinckrodt, Incorporated (1970?)  Ingredient Statement:
                   [Truban] .  (Unpublished  study received Oct 5,  1970 under 372-
                   43;  CDL:105640-A)
00002243      Mallinckrodt Chemical Works (19??)  Composition of Truban.
                   (Unpublished study received Jun 12,  1973 under 372-47;
                   CDL:003217-A)
05001625      Maloney,  T.E.; Palmer, C.M.  (1956)  Toxicity of six chemical
                   compounds to thirty cultures of algae.  Water and Sewage
                   Works 103(11) : 509-513.
05009871      Malzer, G.L.; Randall, G.W. (1976)  Nitrification  inhibitor
                   (Terrazole)  application for corn production at Waseca.
                   Pages 103-104, In University of Minnesota Agricultural
                   Extension Service,  Soil  Series No.  97.  Minneapolis,  Minn.:
                   University of Minnesota, Agricultural Extension Service.
05010154      Malzer, G. L.; Randall, G.W. (1977)  Nitrification  inhibitor
                   (Terrazole)  application for corn production in southern
                   Minnesota.  Pages 108-116, In University of Minnesota
                   Agricultural Extension Service, Soil Series  No. 99.
                   Minneapolis, Minn.:  University of Minnesota, Agricultural
                   Extension Service.
                                     Ill

-------
05010153      Malzer, G.L.; Randall, G.W. (1978)  Use of Terrazole as a
                   nitrification inhibitor in fall vs. spring nitrogen
                   application programs for corn  production in southern
                   Minnesota.  Pages 115-118, _In  University of Minnesota
                   Agricultural Extension Service, Soil Series No. 103.
                   Minneapolis, Minn.:  University of Minnesota, Agricultural
                   Extension Service.
05001593      Me In tosh, D. L. (1971)  Dilution plates used to evaluate initial
                   and residual toxicity of fungicides in soils to zoospores of
                   Phytophthora cactorum, the cause of crowi rot of apple
                   trees.   Plant Disease Reporter 55 (3) :213-216.
05012996      Mills, J.T.;  Wallace,  H.A.H.  (1968)  Determination of selective
                   action of fungicides on  the microflora of barley seed.
                   Canadian Journal  of Plant Science 48 (6): 587-594.
05001572      Miller, P.M.;  Stoddard,  E.M.  (1956)  Field  control  of grey mold of
                   stravtoerries.  Plant Disease Reporter 40 (9): 788-789.
05002910      Mitchell, L.C. (1963)   Sensitivity  tests for 22 different
                   chlorinated organic pesticides by paper chromatography.
                   Journal  of the  Association of  Official Agricultural  Chemists
                   46 (6):988-992.
05011939      Muller, G.J.;  Linn,  M.B.; Sinclair., J.B.  (1972)  Translocation,
                   disease  remission and persistence of thiabendazole  and 5-
                   ethoxy-3 (tr ichioromethyl) -1, 2,4-thiadiazole in tomato
                   seedlings.   Plant Disease Reporter 56 (12) :1054-1057.
05001624      Nebeker, A.V. ; Gaufin, A.R.  (1964)  Bioassays to determine
                   pesticide toxicity to the amphipod crustacean, Gammarus
                   Lacustris.   Pages 64-67,  _In Utah Academy of Sciences
                   Proceedings.  Vol.  41,  Part I.   Salt  Lake  City,  Utah:  Utah
                   Academy  of Sciences, Arts and  Letters.
05001594      Neely,  D. (1971)  Depostion and  tenacity of foliage  protectant
                   fungicides.  Plant Disease Reporter 55 (10):898-902.
05001654      Neely,  W.C.;  Smith,  R.C.;  Cody,  R.M. ;  McDuffie,  J.R.;  Lansden,
                   J.A.; Ellis, S.P.  (1973)  Biological and  Photobiological
                   Action of Pollutants on Aquatic Microorganisms.   Auburn,
                   Ala.: Water Resources Research Institute,  Auburn
                   University.  (WRRI  Bulletin 9;  also available  from:  NTIS,
                   Springfield,  VA;  PB-220  167).
05009250      Nelson, D.W.;  Sommers,  L.E.;  Huber,  D.M.;  Warren,  H.L.  (1977)
                   Conserving  Energy with Nitrification  Inhibitors (Energy in
                   Agriculture).  Washington,  D.C.:   National  Science
                   Foundation.  (National Science Foundation report no.  NSF/RA-
                   770243;  Purdue  University  Agricultural  Experiment Station
                   journal  paper no.  6289; available from:  NTIS,  Springfield,
                   VA;  PB 277  199) .
                                      112

-------
05001639      Newhook, F.. Davison, R.M.  (1956) Incorporation of fungicides in
                   fruit-setting sprays for control of Botrytis fruit rot in
                   glasshouse tomatoes. I.  Introduction and screening trials.
                   New Zealand Journal of Science and Technology 38A: 166-176.
05006545      Narayanan, V. L.; Bernstein, J. ; Willians, J.  (1966)  Antifungal-
                   Substituted-3-(trichloromethyl)-l,2,4-thiadiazoles.  Journal
                   of Pharmaceutical Sciences 55 (2) :217-218.
00001688      01 in Chemicals (1971?) Cotton Seed—Residues of 3-Carboxy-5-
                   Ethoxy-l,2,4-Thiadiazole .   (Uhpublished study received Aug
                   20, 1971 under CF0997; CDL: 091720-A)
05001702      Csweiler,  G.D. (1969) Incidence and  diagnostic considerations of
                   major small animal toxicoses.  Journal of the American
                   Veterinary Medical Association  155 (12) :2011-2015.
05001575      Palm, E.T.; Young, R.A. (1957) The compatibility of certain
                   organic fungicides and antibiotics in treatment mixtures as
                   indicated by stability and phytotoxicity.  Plant Disease
                   Reporter 41 (3) :151-155.
05001795      Patten, B.M. (1969) Neuropathy induced  by hemorrhage.  Archives
                   of Neurology 21 (4) :381-386.
05001711      Pedersen, P.V. ; Crooks, M. J. ; Browi, K.F. (1977)  Method of
                   obtaining drug-macromolecule binding parameters directly
                   from dynamic dialysis data.  Journal of Pharmaceutical
                   Sciences 66 (10) :1458-1461.
05001797      Pond, S.M.; Graham, G.G. ; Birkett, D.J. ; Wade, D.N.  (1975)  Effect
                   of tricyclic antidepressants on drug metabolism.  Clinical
                   Pharmacology and Therapeutics 18 (2): 191-199.
05004243      Powell, D. (1957)  An evaluation of some of the common fungicides
                   for control of apple scab.  Transactions of the Illinois
                   State Horticultural Society and the Illinois  Fruit Council
                   91:28-29.
05001585      Powell, D. (1960)  The inhibitory effects of certain fungicide
                   formulations to apple scab conidia.   Plant Disease Reporter
                   44(3):176-178.
05005882      Reilly, J. J. ; Klarman, W.L. (1971) Induction of the soybean
                   phytoalexin hydroxyphaseollin wiith fungicides [abstract].
                   Phytopathology 61 (8): 907.
05012577      Rowe, R.C. ; Beute, M.K. ; Wells, J.C. ; Wynne, J.C.  (1974)
                   Incidence and control of Cylindrocladium black rot of
                   peanuts in North Carolina during 1973.  Plant Disease
                   Reporter 58 (4): 348-352.
05001559      Schenider, I.R.; Campana, R.J.  (1955)  Fungicide tests in 1954 for
                   the control of sycamore anthracnose.  Plant Disease Reporter
                   39 (l):64-65.
05006543      Sen, A.B.; Gupta, S.K. (1962) Possible antiamoebic agents.  Part
                   XIX.   Synthesis of 1, 3,4-thiadiazol ines and di-1, 3,4-thiadia-
                   zolines.  Journal of the Indian Chemical Society 39 (9): 628-
                   634.
05001606      Shakra, S.A.; Porter, R. H.  (1960) Control of stinking smut (bunt)
                   of v^heat in the Middle East.  Pages 1-17, In American
                   diversity of Beirut Faculty of Agricultural Sciences.
                   Publication No. 11.  Beirut, Lebanon: American University of
                   Beirut.
05001653      Sjoestrand, B.T.L., inventor;  (1960) Manufacture of halogenated
                   organic compounds.  U.S. patent 2,955,117.  Get  4.  3 p.
                                     113

-------
05001718
05001603
00001646
00001644
05001700



05006544


05006652

05002824



05001787
05001554

05001566


05009249
05012625
 Snith,  S.E.; Rawlins, M.D.  (1974) predication of drug oxidation
      rates in man: lack of correlation with serum gamma-glutamyl
      transpeptidase and urinary excretion of D-glucaric acid and
      6-beta-hydroxycortisol.  European Journal of Clinical
      Pharmacology 7 (1): 71-75.
 Stall,  R.E.  (1964) Fungicidal control of Botrytis cinerea Pers.
      ex Fr. on tomato.  Pages 242-244, _In Proceedings—Florida
      State Horticultural Society.  Vol. 77.  Lake Alfred, Fla.:
      Florida State Horticultural Society.  (Florida Agricultural
      Experiment Station Journal series No. 1986)         ,R,
 Thomas, R.J. (1976) Chemodynamic Parameter of Terrazole _   (5-
      Ethoxy-3-Trichloranethyl-l,2,4-Thiadiazole)  Partition
      Coefficient-n-Octanol vs Water: CASR-18-76.   (Unpublished
      study received Oct 20, 1976 under 1258-812;  submitted by
      Olin Corp., Agricultural Div., Little Rock,  Ark.; CDL:228143-

      D)                                                 (R)
 Thomas, R.J. (1976) Chemodynamic Parameter of Terrazole    (5-
      Ethoxy-3-Trichloronethyl-l,2,4-Thiadiazole)  Water
      Solubility: CASR-19-76.  (Unpublished study received Oct 20,
      1976 under 1258-812; submitted by Olin Corp., Agricultural
      Div., Little Rock, Ark.; CDL: 228143-B)
 Tonizawa, C.; Sato, T.; Yoshii, H. (1960)  Uptake  of fungicides by
      fungus spores.  Nbgyo Gijutsu Kenkyusho Hokoku C.  [Bulletin
      of the National Institute of Agricultural Sciences, Series
      C.]  12:171-180.
 Tripathy, P. B.; Rout, M.K. (1962) Un symmetrical cyanines derived
      from thiazoles and thiadiazoles.   Journal of the Indian
      Chemical Society 39 (2): 103-108.
 Turner, F.T. (1977) Terrazole as a nitrification  inhibitor.   In-
      ternational Rice Research Newsletter 2(1): 11.
 Ulrich, J.T.; Mathre, D.E. (1972)  Mode of action  of oxathiin
      systemic fungicides.  V.  Effect on electron transport
      system of Ustilago maydis and Saccharomyces  cerevisiae .
      Journal of Bacteriology 110 (2):628-632.
 Vesell, E.S. (1975) Pharmacogenetic factors as determinants of
      drug activity.  Pages 982-988,  _In Neuropsychopharmacology;
      Proceedings of the IX Congress of the "Collegium
      Internationale Neuropsychopharmacologicun";  Jul 7-12, 1974,
      Paris.  Amsterdam, Netherlands:  Excerpta  Medica.   (Excerpta
      Medica International Congress series no.  359)
 Wall en, V. R. (1953) Treatment of vegetable seed  for improved
      emergence.  Plant Disease Reporter 37 (12): 620-622.
 Wall en, V.R.; Bell, W. (1956) Treatment of vegetable seed for
      improved emergence—1955.  Plant Disease  Reporter 40(2): 129-
      132.
 Westerman, R. L. ; Tucker, B.B. (1977)  An evaluation of the
      effectiveness of Terrazole as a nitrification inhibitor  when
      urea is applied to grain sorghum.  Pages  14-16, In Oklahoma
      Agricultural Experiment Station Research  Report No. 758.
      Stillwater, Ckla.: Oklahoma State University, Agricultural
      Experiment  Station.
Wbjtowicz, J.A.; Bhutani, S.K. ; inventors; Olin Corp., assignee
      (1975)  Ethanolysis of 3-trichloronethyl-5-chloro-l,2,4-
      thiadiazole employing aqueous base.  U.S.  patent 3,890,338.
     June 17.   5 p. Int.  Cl.  C 07d 91/60;  U.S.  Cl. 260/302 D.
                                   114

-------
05002234      Zimmerman, A. (1974)  Fhylloquinone Epoxide Reductase:  Doctoral
                   Dissertation.  St. Louis, MD .;  St. Louis University.
                   (Available  from:  University Microfilms,  Ann Arbor,  MI,  order
                   no. 75-26,348)
                                      115

-------
                           OFFICE PESTICIDE  PROGRAMS
                       REGISTRATION STANDARD BIBLIOGRAPHY

                          Standard Reference Material

Farm Chemical Handbook. (1979) Meister publishing.   Willoughby.   Ohio.

The Federal Insecticide, Fungicide, and Rodenticide  Act,  as amended in 1978,
    7th U.S. Code, Chapter 135, 61 Statute 163.78 Statute 190.

Pesticide Process Encyclopedia , 1977, Noyes Data Corp.,  Park Ridge, New
    Jersey.

Pesticide Index:  Basic information on_ the chemicals used as_ active
    components of pesticides.  ; Martin, H., and Worthington,  C.R.,  eds.,  1977.
    5th ed., British Corp. Protection Council, Worcestershire,  England

U.S. Environmental Protection Agency (1978a);  Proposed  Guidelines for
    Registering Pesticides in the United States.   Federal Register,  43  (132)
    29696.

U.S. Environmental Protection Agency (1978b);  Proposed  Guidelines for
    Registering Pesticides in the United States; Hazard Evaluation:   Humans and
    Domestic Animals.  Federal Register, 43  (163) 37336.

U.S. Environmental Protection Agency (1980); Regulations  for  the  Enforcement
    of the Federal Insecticide, Fungicide, and Rodenticide Act, Title 40,
    Chapter 1, Part 162.

U.S. Environmental Protection Agency (in press) Proposed  Guidelines for
    Registering Pesticides in the United States.  Subparts G  (Product
    Performance) and H (Label Development).
                                                     *U S GOVERNMENT PRINTING OFFICE: 1980 341-085/3948
                                         116

-------