-------
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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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.
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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
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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.
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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
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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.
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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.
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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.
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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
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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).
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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.
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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
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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.
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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.
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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
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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
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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
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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
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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
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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.
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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
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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
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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
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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
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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
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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.
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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
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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
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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
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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.
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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.
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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.
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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."
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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
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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
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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.
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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.
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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
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.
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
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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
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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
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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
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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
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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
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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
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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
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OFFICE OF PESTICIDE PROGRAMS
REGISTRATION STANDARD BIBLIOGRAPHY
Citations Judged to be Inappropriate for Use
in Developing this Standard
MRID CITATION
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log
-------
05001623 Fitzgerald, G.P. (1957) The control of the growth of algae with
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Landbouwwetenschappen, Rijksuniversiteit Gent.
[Communications of the Faculty of Agricultural Sciences,
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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-
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05001563 Harris, H.B.; Luttrell, E.S. (1955) Grain sorghun seed treatment
tests and diseases in Georgia for 1954. Plant Disease
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OFFICE PESTICIDE PROGRAMS
REGISTRATION STANDARD BIBLIOGRAPHY
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