PAGE
A/7X5
•not
TRIALLATE: Decision Document
«. Report Date
November 1980
7. Autfcorfm)
EPA, OPP, REGISTRATION DIVISION
•. Performing OnfenUetlon Rept. No.
540/09-90-101
•. P»ifen'»<«H Oc|»nli«fton Neme end Addmt
! . UWBOtWENIKL PROTECTION AGENCY
OFFICE OF PESTICIDE PROGRAMS
WASHINGTON, D.C. 20460
10. Protect/Teek/Wort Unit No.
11. Contract(C) or Grent(G) No.
(0
(G)
12. Sponsoring Or«*nlut(on Neme end Address
SAME AS
II. Typ« of Report & Period Covered
14.
IS. Supplementary Notct
16. Abetrect (Limit: ZOO words) . • • • . ••• '
This Position Document addresses the risks and benefits of pesticide products
containing the subject active ingredient. The Agency has determined that the use
of products containing the subject active ingredient may meet or exceed a risk.
criterion described in 40 CFR. Part 154. Potential hazards will be examined .
further to determine the nature and extent of the risk, and •considering the
benefits of the subject active ingredient, whether such risks cause unreasonable
adverse effects on the environment.
17. Document Anelytis e. Descriptor*
PESTICIDES, STANDARDS, REGULATIONS, MANUFACTURING, CHEMISTRY, TOXICOLOGY,
RESIDUES, ECOLOGY, PATH OF POLLUTANTS
b. Mentinen/Open-Ended Terms
c. COSATi n<>t<«/«?-
1C. Avc
PL
)AN!
EJBD
ARCHIVE
EPA
540-
09-
90-
101
ABLE
19. Security Clett (This Report)
UNCLASSIFIED -
ZO. Security Cleif (This Peed
UNCLASSIFIED
21. No. of
41
22. Price
See Imttrucflont on Reverse
OPTIONAL FORM 272 (4-77)
(Formerly NTIS-3S)
Department of Commerce
-------
540/09-90-101
TRIALLATE
DECISION DOCUMENT
NOVEMBER 1980
OFFICE OF PESTICIDES AND TOXIC SUBSTANCES
ENVIRONMENTAL PROTECTION AGENCY
401 M STREET S.W.
WASHINGTON, DC 20460
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Acknowledgments
PROJECT TEAM
Gary Baker, Project Manager, SPRD
Karl Bayer, Attorney, OGC
W. Thomas Edwards, Toxicologist, HED
Karen Flagstad, Writer-Editor, SPRD
Janice Jensen, Chemist, HED
Charles Lewis, Agronomist, BPSD
Irving Mauer, Toxicologist, HED
Abraham Mittelman, Chemist, HED
Esther Saito, Acting Section Head, SPRD
David Severn, Chemist, HED
Minnie Sochard, Project Manager, SPRD
Linda V. Zyadlo, Economist, BFSD
EPA PESTICIDE CHEMICAL REVIEW COMMITTEE (PCRC)
Charles Gregg, OWWPM
Richard N. Hill, OPTS
Allen L. Jennings, 0PM
Donna R. Kuroda, ORD
John J. Neylan, OE
Edward Tuark, OANR
Marcia Williams, Chairperson, SPRD, OPTS
Michael Winer, OGC
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Table of Contents
Section Page
I. Introduction 1
II. General Information 2
A. Chemical Identity 2
B. Chemistry 2
C. Pesticide Formulations 2
D. Production 2
E. Registered Uses 5
P. Pate in the Environment: Soil 5
G. Pate in the Environment: Plants 8
III. Exposure and Mammalian Metabolism 10
A. Tolerances 10
B. Avenues of Human Exposure 11
1. Dietary Exposure 11
2. Applicator (Dermal and Respiratory)
Exposure 12
C. Mammalian Metabolism 14
IV. Triallate as a Potential RPAR Candidate 16
A. Introduction 16
B. Evidence Pertaining to Oncogenicity 19
C. Evidence Pertaining to Mutagenicity 20
D. Evidence Pertaining to Teratogenic 24
and Petotoxic Effects
E. Evidence Pertaining to Neurotoxicity 27
V. Conclusions and Recommendations 29
A. Oncogenicity 29
B. Mutagenicity 30
C. Teratogenic and Petotoxic Effects 31
D. Neurotoxicity 32
E. Metabolic Effects 32
VI. Bibliography 33
APPENDIX: EPA Policy on IBT Generated Data A-1
-ii-
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List of Tables
Page
1. Comparison of Diallate and Triallate 3
2. Micrograms of Triallate Recovered Prom Soil-
Water Mixtures in a Closed System 7
3- Worst-Case Dietary Exposure to Triallate 12
4. Exposure and Total Body Doses—Applicators 13
5. Pivotal Triallate IBT Studies 18
6. Summary of Studies Pertaining to the Mutagenicity 21
of Triallate
-iii-
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I. INTRODUCTION
Triallate is a pre-emergent selective herbicide used to
control wild oats in small grains (barley and wheat) and in
field crops (lentils and peas). Triallate was referred to
the Special Pesticide Review Division as a possible candidate
for the Rebuttable Presumption Against Registration (RPAR)
process because of its structural similarity to diallate,
which had/been found to induce oncogenic effects in test
animals.- Structurally, triallate and diallate differ only
in that triallate possesses one additional chlorine atom, and
as a consequence of this basic structural difference,
triallate lacks the cis and trans isomers, which are part of
the structural formula of diallate. Given the similar use
patterns and chemical properties of the two herbicides, the
Agency felt that a review of triallate data to determine
adverse effects was warranted.
This document reports the results of the Agency's review
of currently available evidence concerning the potential
effects of triallate. It contains six parts. Part I is
this introduction. Part II presents general information
about triallate. Part III evaluates available exposure data
on triallate. Part IV discusses the hazard evidence for
considering triallate as an RPAR candidate. The conclusions
and recommendations given in Section V are based on considera-
tions of exposure as well as toxicological evidence. Part
VI is a bibliographical listing of studies cited.
—' The Agency issued a notice of Rebuttable Presumption
Against Registration (RPAR) for diallate on May 31, 1977.
(See Fed. Reg. 42 (104): 27669-27674 [May 31, 1977].)
The Agency presumed against diallate on the basis of onco-
genic effects in test animals and also requested additional
information on the following possible adverse effects:
mutagenicity, neurotoxicity, and reproductive effects.
In Diallate: Position Document 2/3 t'he Agency maintained
that the presumption of oncogenicity was unrebutted and that
a presumption based on mutagenicity was also warranted.
(See Fed. Reg. 45 (112): 38437-38440 [June 9, 1980].)
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II. GENERAL INFORMATION
A. Chemical Identity
Triallate was patented by the Monsanto Chemical
Company in July 1967 under United States Patents 3,330,643
andp3,330,821, and it is marketed under the trade names AVADEX
BW * and FAR-GOn. The Chemical Abstracts Service (CAS)
has assigned triallate the CAS registry number 2303-17-5 and
the following name:
S-(2,3,3-trichloroallyl) diisopropylthiocarbamate.
B. Chemistry
Triallate is manufactured by the reaction of a
diisopropylthiocarbamate salt with 1, 1, 1, 3-tetrachloro-
propene. Monsanto Company is the sole producer of technical
grade triallate in the United States. The technical grade
compound is 90# pure, with the remaining 10# consisting of
unreacted intermediates. Triallate is an amber liquid, is
soluble in most organic solvents, and is practically insoluble in
water (4 ppm at 25 C). Its boiling point.is 148 C, and it is
volatile with a vapor pressure of 1.2x10 mm Eg. (See Table 1,
which summarizes basic differences and similarities between
triallate and the RPAR chemical diallate.)
C. Pesticide Formulations
Triallate is marketed in the United States in two
formulations: as a granular, and as an emulsifiable concentrate
(4 pounds/gallon). The granular formulation consists of 10$
active ingredient triallate and 90$ inert ingredients. The
emulsifiable concentrate consists of 46.3# active ingredient
triallate and 53-7# inert ingredients.
D. Production
Under Section 7(c) of the Federal Insecticide,
Fungicide, and Rodenticide Act (FIFRA), producers and
formulators of triallate must submit data on the amount of
triallate which they produce or formulate each year.
However, these data are classified as Confidential Business
Information and are protected from disclosure to the public
under Section 10 of FIFRA-7.
2/
—' Data concerning production and formulation have been
made available to the EPA Administrator in a confidential
appendix to this report.
-2-
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Table 1. Comparison of Diallate and Triallate
Diallate
Triallate
•CH2-S-C-N
\
X
CH
CH
Cl
\
C=C'
Cl'
•CH2-S-C-N
CH^ -
/ XCH,
\
CH
\
CH,
Formula
C10H17C12NOS
Formula Weight
270.2
Solubility - Water
14 ppm, 25°C
Vapor Pressure
1.4 x 10~4 mm Hg, 25-30°C
State
Amber liquid
Formulations
10# granular*
Emulsifiable concentrate
(4 Ibs/gal)
Registered Use Profile
Pre-emergent herbicide against wild
oats in sugar beets, flax, barley,
lentils, peas, corn, forage legumes,
potatoes, and soybeans
Formula
Formula Weight
304.7
Solubility - Water
4 ppm, 25 °C
Vapor Pressure
1 .2 x 10~4 mm Hg, 25-30°C
State
Amber liquid
Formulations
10# granular
Emulsifiable concentrate
(4 Ibs/gal.)
Registered Use Profile
Pre-emergent herbicide
against wild oats in vheat,
barley, green peas, field
dried peas, and lentils
* Granular formulation of diallate registered for use only on sugar beets
-3-
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Table 1. Comparison of Diallate and:Triallate (Cont.)^
Diallate Triallate
40 CFR 162.11 Risk Criteria
Met or Exceeded
Oncogenicity
Mutagenicity
Other Areas of Concern
Neurotoxic Effects
Reproductive Effects
Fetotoxic Effects
Teratogenic Effects
Areas of Concern
Oncogenicity
Mutagenicity
Reproductive Effects
Fetotoxic Effects
Teratogenic Effects
Neurotoxicity
-4-
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E. Registered Uses
At the present time, two registrants hold six
registrations for the use of triallate.
Triallate was first registered "by Monsanto on
February 15, 1962 (EPA Reg. No. 524-124). This registration
permitted the use of triallate on spring and durum wheat and
barley for pre-emergence control of wild oats. Triallate's
use was later extended to include dried field peas (on
February 20, 1963), and on winter wheat, green peas, and
lentils (May 8, 1972). Emulsifiable concentrate triallate
is now registered to control wild oats in winter wheat,
spring and durum wheat, barley, green peas, field dried
peas, and lentils. The granular formulation is registered
for use only to control wild oats in wheat and barley.
As a granular formulation or as an emulsifiable concentrate,
triallate is applied either in the spring or in the fall
(after harvest).
According to label directions, granular triallate must be
applied with 1) a ground broadcast applicator, such as a
grass seed attachment, 2) a specially designed ground
applicator, or 3) an airplane capable of applying small
quantities of granules evenly. In connection with ground
equipment, the label emphasizes the importance of proper
calibration so that even distribution is achieved and
neither too little nor too much of the product is applied.
In connection with aerial applications, attachments designed
for applying low volumes of granules are specifically
required. With respect to field preparation, the label
directs that all deep tillage by cultivation, or double disc
implements, must be completed prior to application. The
granular formulation should be incorporated within 48 hours
of application.
As an emulsifiable concentrate, triallate is
sprayed before seeding for selected crops and incorporated
with a disk-type implement to a depth of approximately two
inches, followed by two harrowings. The concentrate should
be incorporated into the soil on the day of application.
Boom sprayers are recommended for spraying the emulsifiable
concentrate, rather than other application procedures. If
applied to certain crops after planting, the herbicide is
sprayed onto the soil surface and then shallowly incorporated
into a layer above the level of seed placement. The herbicide
is incorporated by harrowing twice with a tandem disc or
other implement.
F. Fate in Environment: Soil
Triallate appears to be degraded in soil, primarily
through microbiological action. This degradation process
has been demonstrated in a study in which triallate degraded
-5-
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more rapidly in moist, non-sterile soils than- in moist,
sterile soils (Cullimore and Smith, 1972). After 16 .
weeks, less than 5$ of the triallate was lost from moist,
sterile clay and loam, whereas 65# and 75$ were lost from
moist, non-sterile clay and loam (Cullimore and Smith,
1972).
Available studies do not indicate that triallate
is likely to migrate through the soil. A study has shown
that triallate is well adsorbed to a variety of dry plains
soils, including clays and loams (Smith, 1970). However, in
situations where there is an excess of moisture, triallate
will desorb from clay soils, but not from organic soils
(Grover, 1974). The crops for which triallate is used
(wheat, barley, green peas, field dried peas, and lentils)
are grown in a wide variety of soils, though organic soils
are generally preferred over clay soils. Therefore, signifi-
cant triallate desorption as a result of excess moisture is
not expected.
Triallate's volatility has been demonstrated in
a closed system (Hance et al.f 1973) using composite soils
typical of those found in the areas where the chemical is
used. When different formulations and soil types were used,
the volatility of triallate was found to increase as the
water content for each soil type increased. A maximum of 4$
loss by volatility in sandy soils, and 2% in clay soils,
occurred with the liquid formulation. The granular formula-
tion was found to have the lowest volatility. Detailed
results from this study are shown in Table 2. The findings
of Hance et al. (1973) correspond with current label direc-
tions, which caution users against applying the herbicide
immediately before or after rain, since loss of efficacy due
to volatility occurs under these conditions.
Residues of triallate have been found to persist in
the soil from one growing season to the next. Data from the
Canadian prairie provinces indicate a carryover of about 15$
to 20$ in a 5-month growing season (Smith, 1970). However,
since triallate's persistence is to some extent related to
climatic temperature, the compound may be less persistent in
the warmer soil temperatures of the United States (Smith,
1969).
A report was submitted to the Agency in supoort
of triallate's registration (Monsanto, 1975 [Report #
524-124]) which contained results of laboratory and field
tests concerning the fate of the herbicide in soils.
Studies were included which pertained to dissipation,
degradation, and metabolism of triallate in soil, as were
leaching and runoff studies. The stated purpose of the
studies pertaining to the dissipation, degradation, and
metabolism of triallate in soils was to determine the rate
of dissipation and the mechanism of degradation. The
-6-
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Table 2. Micrograms of Triallate Recovered from Soil-Water Mixtures
in a Closed System
Micrograms of Triallate Recovered
Sandy Soil
Triallate Added
(micrograms)
Unfornmlated (a)
Liauid
formulation
Granular
formulation
Water
Content
2*
&
(b)
2%
&
(b)
2%
6*
(b)
10
0.10
0.20
0.30
0.05
0.30
0.40
<.02
0.20
0.24
50
0.34
0.80
1.35
0.38
1 .18
1.85
<.02
0.54
1 .00
100
0.52
2.00
2.35
0.88
2.62
3.60 (c)
<.02
0.92
1.70
Clay Soil
10
0.02
0.04
0.20
0.02
0.08
0.15
<.02
0.08
0.02
50
0.14
0.34
0.80
0.25
0.35
1 .10
<.02
0.30
0.32
100
0.20
0.50
1 .56
0.32
0.58
1.90 (
<.02
0.30
0.55
(a) Technical Grade
(b) Field capacity soil condition (moisture content) that
exists 24 hours after the water supply is shut off (i.e.,
stops raining, turn-off irrigation water, etc.).
(c) Highest volatility rounded to 4.0# in saturated sandy
soils.
(d) Highest volatility rounded to 2.0$in saturated clay
soils.
Source: Hance et al. (1973).
-7-
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Agency's review of these studies, however, pointed out,.a . •
number of deficiences which undermine the usefulness
of the experiments. Problems were noted, for example, in
the design of the experiments in that these laboratory
studies used 5 g of soil suspended in 100 ml of water.
Since the report states that the degradation rate of triallate
is moisture-dependent, these laboratory conditions represent
a poor model for actual field behavior. Mechanical problems
were also encountered in connection with the limited water
solubility of triallate. In addition, presentation was
inadequate to the extent that comparison of data from
various cultures was difficult, and the reports were
not internally consistent. In view of the deficiencies
outlined above, the Agency's judgment is that although
Monsanto's conclusion that triallate is "biologically
degraded by soil microflora as evidenced by the degradation
of carbon-14 labeled AVADEX BW to 14-CO?" may be correct,
it is not substantiated by the data submitted (Severn,
1977).
The leaching studies were done by a generally
acceptable procedure, the Helling soil TLC technique, which
yielded a comparison of the mobility of triallate in three
different types of agricultural soils. The types of soils
tested were Chillum soil, Hagerstown silty clay loam, and
Lakeland clay loam (Selim, 1978). In terms of Helling's
mobility classifications, triallate exhibited a mobility
typical of Class II pesticides (pesticides which move 10£ -
35# compared to water in the same type of soil). The
conclusion of Monsanto Co. (1975), that triallate "adsorbs
to soil and does not pose a threat to the environment due to
leaching" is in the Agency's judgment probably correct. The
Agency points out, however, that although triallate is in
general used in areas where the water table is relatively
low, triallate's entry into the water would be possible in
areas of heavy rainfall where the water table is near the
surface.
Runoff studies were done on a small, inclined
laboratory box filled with triallate-treated soils, using
sprinklers to simulate rainfall. Only 50 ml samples of
runoff were collected, and in the Agency's judgment, this
amount is much too small to evaluate runoff potential.
Runoff water and sediment contained 0.004-0.09^ of the
applied radioactivity. In view of the inadequate size of
the samples collected, Monsanto's conclusion, that "under
field conditions contamination of non-target land and
aquatic areas will be insignificant," cannot be regarded as
substantiated by this particular experiment (Severn, 1977).
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G. Fate in the Environment: Plants
A review of the available data indicates that
triallate does not bioaccumulate in plants, and the ability
of plants to degrade triallate lessens the potential for
bioaccumulation in soils. Some plants apparently absorb
triallate (a pre-emergent herbicide), or its metabolites and
degradation products, from the soil, as indicated in connec-
tion with wheat and peas in several studies submitted by
Monsanto in support of registration (PP OF0944). Specifi-
cally, these studies indicate that when soil is treated with
radiolabeled triallate, radioactivity is detected in plant
extracts. Radioactivity is found in the soluble protein,
lipids, soluble carbohydrates, insoluble cellulose and
lignin fractions, as well as in CO- captured above the
plant. In wheat and peas, the soluble fractions were found
to contain, respectively, 60# and 82$, and the insoluble
fractions, "*>}% and 11# of the radioactive labeling. Collec-
tively these studies also indicate that in view of the
detection of a small amount of the radioactivity (<5#) in
the released CO^ in both crops (wheat and peas), not only
absorption, but complete metabolism of triallate by the
plant may take place (Monsanto Chemical Co., PP OF0944).
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III. EXPOSURE AND MAMMALIAN METABOLISM
A. Tolerances
In order for a pesticide to be sold and used in the
production of a crop, the pesticide must not only be registered
for the particular use under FIFRA, but must have a tolerance
or an exemption from a tolerance under the Federal Food,
Drug and Cosmetic Act (FFDCA) for each individual crop on
which it will be used. Under Section 102 of the FFDCA, a
raw agricultural commodity or a processed food or feed which
contains a pesticide residue is considered "adulterated"
unless a tolerance (maximum allowable limit of pesticide
residue), and exemption from a tolerance, or a food additive
regulation has been established for the pesticide in question.
The authority for establishing tolerances and exemption from
tolerances for residues of pesticide chemicals on raw
agricultural commodities, and food additive regulations
allowing pesticide residues in processed food, is found in
Section 108 (raw agricultural commodities) and 109 (processed
food) of the Federal Food, Drug and Cosmetic Act, 21 U.S.C.
Section 316(a), 3^8. In 1970, pursuant to the Reorganization
Plan No. 3 of 1970, 81 Stat. 3086, the authority for establishing
tolerances and exemptions from tolerances under Sections 108
and 109 of the FFDCA was transferred from the Food and Drug
Administration to the Administrator of EPA.
From the mid-fifties to the mid-sixties, tolerances
were established "at zero level" if data showed that no
detectable residues were present in the treated crop at the
time of harvest. Triallate was originally registered (in
1962) in conjunction with the establishment of a zero
tolerance under the "no residue-zero tolerance" concept.
In 1965, however, the National Research Council of
the National Academy of Sciences recommended that the "no
residue-zero tolerance" concept be abandoned because, as
applied in the registration and regulation of pesticides, the
concept had become scientifically and administratively
outmoded and untenable. Among the specific reasons cited
by the Council were that analytical methodology had improved,
and that small levels of pesticide residues had thereby
become detectable (Pesticide Residues Committee Report on
"No Residue" and "Zero Tolerance," NAS-NRC, June 1965). At
the same time, the Council also recommended that pesticides
previously registered under the "no residue" concept be , ,
registered on the basis of "negligible residue" tolerances.
In 10 CFR 180.1 (k)(1) the term "negligible residue"
is defined as "any amount of a pesticide chemical remaining
in or on a raw agricultural commodity or group of raw
agricultural commodities that would result in a daily intake
regarded as toxicologically insignificant on the basis of
(Cont'd on next page)
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The "no residue-zero tolerance" concept applied to
all pesticides, including triallate, until 1966. In 1966,
the USDA began to phase out this concept as a working policy
(Ifiil. M&*. 3 1(71): 5723-5725 [April 13, 1966]). -' Regis-
trants of pesticide products with a "no residue-zero tolerance"
classification were given — through a series of 1-year exten-
sions—until 1971 to convert the "no residue" tolerances
to finite tolerances.
In 1970, Monsanto Chemical Company petitioned for a
finite tolerance of 0.05 ppm in or on the following raw
agricultural commodities: grain and straw of barley and
wheat, lentils and lentil forage and hay, and peas and pea
forage'and hay (PP OF0944). The petition was granted, and
tolerances for triallate were set at 0.05 ppm in the above
commodities (40 CFR 180.314). The limit of detection of
triallate by chemical analytical methods was .02 ppm at that
time.
B. Avenues of Human Exposure
The Agency has identified human populations exposed
to triallate and examined the type and extent of their
exposure. Three avenues of exposure are at issue: dietary
(oral), dermal, and respiratory. Dietary exposure as a
result of triallate residues on food affects the general
population, including pesticide applicators. In addition,
applicators can be subject to dermal and respiratory exposure
to triallate during mixing and loading operations, during
application, and during re-entry into treated fields for
purposes of incorporating the herbicide into the soil.
1 . Dietary Exposure; Established tolerances
provide a basis for assessing theoretical maximum ("worst
case") residue levels in or on various agricultural products
at the time of harvest. Tolerances "for triallate have been
set at 0.05 ppm (negligible residue) in or on grain and
straw of barley and wheat, lentils and lentil forage and
hay, and peas and pea forage and hay (40 CFR 180.314 and
~L' (Cont'd) scientific judgment of adequate safety data.
Ordinarily this will add to the diet an amount which will be
less than 1/2,000 of the amount that has been demonstrated
to have no effect from feeding studies on the most sensitive
animal species tested. Such toxicity studies shall usually
include at least 90-day feeding studies in two species of
mammals."
— Pesticide registration and tolerance activities conducted
by the USDA were transferred to the Environmental Protection
Agency under Reorganization Act No. 3, December 3, 1970.
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Subsection III. A above). Assuming that triallate isv.always ,
present at tolerance levels in wheat, barley, and peas,,
dietary intake by the general population is nonetheless
expected to be low (0.16 ug/kg/day for a 60-kg person).
Table 3 below shows average daily consumption of-these items
and consequent daily intake based on tolerances.^
Table 3. Worst-Case Dietary Exposure to Triallate
Items
Wheat
Barley
Peas
Daily Consumption
In Grams
1.5
13.2
Tolerance
Level (ppm)
0.05
0.05
0.05
Total Daily
of Triallate
9.2 ug
0.1 ug
0.7 ug
Total Intake 0. 16*
(ug/kg/day)
* Assuming a 60-kg person
2 . Applicator (Dermal and Respiratory) Exposure
The Agency is aware of two studies, Voytenko et
al. (1972) and Arras et al . (1980) which have measured
exposure to triallate during application. Because the
information provided to the Agency in connection with the
Voytenko study is incomplete (the rate and duration of
application are not specified) the Agency has calculated
exposure and total body doses to applicators (excluding
dietary exposure) to triallate on the basis of the Arras et
al. (Monsanto) study.
In the study performed by Arras et al . , triallate
was applied as an eraulsifiable concentrate on six plots, and
as a granular formulation on three plots. The emulsifiable
concentrate was applied with a spray harrow on three plots,
and with a boom spray on three plots at an application rate
of 1 pound active ingredient per acre. The granular formula-
tion was applied at a rate of 1.5 pounds active ingredient
per acre on two fields, and at 1.35 pounds active ingredient
per acre on one field. Following standard application practice,
a second incorporation into the soil was made.
Source: Mittelman (1978).
-12-
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The calculations of applicator exposure made by
the Agency, as shown in Table 4, are based on the following
assumptions '.
a. For respiratory exposure, maximum values
were used in calculations, except for the
one anomalous inhalation value obtained
downwind during a tank fill and mix on an
excessively windy day.
b. For dermal exposure, average values obtained
for the forehead, back, and chest were used
in calculations (except for one anomalous
value detained for the chest).
c. An applicator weighs 60 kg.
d. Applicators follow label instructions
and wear gloves and goggles.
e. Applicators' arms are covered since
triallate is applied in cool weather.
Therefore only the face and neck are
exposed. The exposed skin area is 910
cm .
f. The average-size field is 100 acres,
and average application time is 8.3 hours.
g. Applicators' breathing rate is 1.8 nr
per hour.
h. One hundred percent of the inhaled material
is retained.
i. The rate of dermal absorption is 10?'for
emulsifiable concentrate formulations
and 1? for granular formulations.
As Table 1 shows, the Agency has calculated exposure
and absorbed body doses for applicators working with both
formulations of triallate (emulsifiable concentrate and
granular). An applicator working with the emulsifiable
concentrate formulation would be subject to 1) an estimated
body dose of 5.6 ug/kg of body weight per day during tank
fill and application procedures (day 1), and 2) an additional
estimated body dose of 2.5 ug/kg/day during the process of
incorporating the herbicide into the soil (day 2). An
applicator working with the granular formulation would be
Source: Jensen (1980)
-13-
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Table 4. Exposure and Total Body Doses—Applicators8'
Formulation Day
Emulslflahle 1
Concentrate 1
Concentrate
Granular 1
1
Granular 2
1
(Dermal
(Exposure . ,
Task (ugAg/day) D/
Tank fill 13.40
Application 4.40
Incorporation 3.40
Hopper fill 31.30
Application 4.98
Incorporation) 2.90
Total
Dermal
Exposure
(ugAg/day)
,,.*
3.4
36.3d/
2.9
Assumed
Dermal
Absorption
Rate
10%
10%
1%
1%
Dermal 1 Total Assumed Respiratory (Total
Body (Respiratory Respiratory Respiratory Body (Body Dose
Dose (Exposure Exposure Absorption Duso ((Dermal & Respiratory)
(ugAg/day) (ugAg/day) (uqAg/day) Rate (ugAg/day) (ug/kg/day)
1.8 0.073 .
3.785 S.BSSS' 100% 3.8 5.6 (Day 1- E.G.)
0.3 2.191 2.191 100% 2.2 2.5 (Day 2- E.G.)
0.912 ..
0.4 1.843 2.755^ 100% 2.7 3.1 (Day 1- Granular)
0.03 1.743 1.743 100% 1.7 1.8 (Day 2- Granular)
a/ Source: Jensen (1980)
I>/ Applicator body weight Is assumed to be 60 kg
c/ Tank fill and application
-------
subject to 1) an estimated body dose of .3.1 ug/kg/day
during hopper fill and application procedures (day 1), and
2) an additional estimated body dose of 1.8 ug/kg/day
during the process of incorporating triallate into the soil
(day 2). In sum, applicator exposure appears to be very low.
C. flamm,alian Metabolisp
When tolerances for negligible residues were
established for triallate, the USDA did not require animal
metabolism studies. This USDA policy was based on the
assumption that the amount of the residue was sufficiently
limited that it was considered to be of little or no toxico-
logical significance (USDA, 1968). Requirements for animal
metabolism studies have been established by the EPA, however,
as part of its requirements for registration of pesticides,
and the Proposed Guidelines for Registering Pesticides in
the U.S. 40 CFR 163.85-1 (lad,. JB££. 43 (163) :37394-37396
[August 22, 1978]) contain detailed protocols for testing
pesticide chemicals in specified mammalian species. As
stated in the Proposed Guidelines, general metabolism
studies are required for the following major purposes:
"(1) To identify and, to the extent possible, quantify
significant metabolites;
(2) To determine any possible accumulation and/or
bioretention of the test substance and/or
metabolites;
(3) To determine pesticide absorption as a
function of dose;
(4) To characterize route(s) and rate(s) of pesticide
excretion;
(5) To relate pesticide absorption to the duration
of exposure of the animal; and
(6) To obtain an estimate of binding of the test
substance and/or its metabolites by target
macromolecules in potential target organs."
Animal metabolism studies on triallate remain to be
submitted to the Agency. (This data gap is addressed in
Section V, "Conclusions and Recommendations," Subsection
V.E.)
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IV. TRIALLATE AS A POTENTIAL RPAR CANDIDATE
A. Introduction
Section 3(a) of FIFRA requires all pesticide products
to be registered by the Administrator of EPA before they may
be sold or distributed. Section 6(b) of FIFRA authorizes the
Administrator to issue a notice of intent to cancel the
registration of a pesticide or to change its classification if
it appears that the pesticide or its labeling "does not comply
with the provisions of [FIFRA] or, when used in accordance
with widespread and commonly recognized practice, generally
causes unreasonable adverse effects on the environment." Thus
the Administrator must cancel the registration of a pesticide
whenever he or she determines that it no longer satisfies the
statutory standard for registration, which requires, among
other things, that the pesticide not cause "unreasonable
adverse effects on the environment" [Section 3(c)(5) of
FIFRA]. These "unreasonable adverse effects" are defined in
Section 2(bb) of FIFRA to include "any unreasonable adverse
effects to man or the environment, taking into account the
economic, social and environmental costs and benefits of the
use of any pesticide."
The Agency created the RPAR process to facilitate
the identification of pesticide uses which may not satisfy
the statutory standard for registration and to provide a
public, informal procedure for the gathering and evaluation
of information about the risks and benefits of these uses.
The regulations governing the RPAR process are set forth at
llO CFR 162.11. In broad summary, these regulations set
forth certain criteria of risk and provide that an RPAR
shall arise against a pesticide if the Agency determines
that the ingredient(s), metabolite(s), or degradation
products(s) of the pesticide in question meet or exceed any
of these risk -criteria.
In administering the RPAR process, the Agency
adheres to the standard for initiating the RPAR process
established by Section 3(c)(8), one of the 1978 Amendments
to FIFRA, which provides that the Agency may not start an
RPAR unless it has "a validated test or other significant
evidence raising prudent concerns of unreasonable adverse
risk to man.or the environment". In determining whether
a particular pesticide raises "prudent concerns", the Agency
examines the degree of toxicity of the pesticide, as well as
the likelihood of human and environmental exposure. The
Agency applies this approach to all its risk triggers,
including oncogenicit.y and mutagenicity triggers which do
not on their face take exposure into account. This approach
allows the Agency to avoid the burdensome consequences of an
RPAR proceeding in those situations in which the uses of the
pesticide at current levels of exposure does not pose an
risk to man or the environment.
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Where the Agency publishes a notice indicating that
an RPAR has arisen the **0 CFR 162.11 regulations require that
an opportunity then be provided for registrants, applicants,
and interested persons to submit evidence to rebut the
presumption, or evidence relating to the economic, social,
and environmental benefits for any use of the pesticide. If
the presumptions of risk are not rebutted, the evidence on
the benefits of the pesticide is evaluated and considered
along with the information on the competing risks. The
Agency then analyzes various methods of reducing the amount
of risk from the pesticide together with their costs and
determines whether the pesticide can be regulated so that
the benefits of continued use outweigh the competing risks.
If measures short of cancellation cannot reduce the risks
associated with any given use of the pesticide to a level
which is outweighed by benefits, the use in question
must be cancelled.
To determine whether triallate might pose a hazard
warranting the continuation of a rebuttable presumption,
the Agency has reviewed all currently available data on the
potential effects of the herbicide and, where appropriate,
has taken considerations of exposure into account. The
potential effects which warrant concern, and which are at
issue in this review, are oncogenicity, mutagenicity,
teratogenicity and fetotoxicity, and neurotoxicity.
By way of introduction to a discussion of triallate
as an RPAR candidate, it is necessary to address the following
considerations regarding the toxicological data base on
which existing triallate registrations and tolerances
were established. In 1977, the EPA Office of Pesticide
Programs established a Toxicology Data Audit Program (TDAP),
the function of which was to assure the reliability and
integrity of data supplied to the Agency by pesticide
manufacturers for purposes of -support-ing pesticide registra-
tions and tolerances. Industrial Bio-Test Laboratories
(IBT), which performed a large volume of testing used by the
Agency in its regulatory decision-making concerning numerous
chemicals (including triallate), was one of the initial
laboratories audited jointly by the EPA and the Food and
Drug Administration. During the audit at IBT, a number of
questionable scientific practices were documented, and this
led the Agency to require supporting evidence (raw data) for
purposes of reevaluating all IBT studies -used in support of
pesticide registrations and tolerances. (See Appendix for
an updated policy statement, issued by the Agency on July
29, 1980, on IBT-generated data.)
The workload of this reevaluation/validation program
was shared with the Canadian government, in cases wherein
chemicals were registered in the U.S. and in Canada on identical
data bases. Triallate was one of these chemicals, and the
Canadian Government conducted the evaluation of the triallate
data base. A number of the studies reviewed lacked complete
protocols and/or supportive data.
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Table 5 lists those five IBT studies which are * :.•
pivotal in this review of triallate as a potential RPAR ;
candidate, together with the results of the Canadian govern- '
ment/TDAP audit. The following subsections proceed with a
summary review and evaluation of currently available toxico-
logical evidence, including IBT studies, concerning triallate.
Considerations of exposure are taken into account as appropriate
in the Agency's evaluation of the potential hazards of
triallate under current use patterns. Conclusions and
recommendations arising from this review of the herbicide as
a potential RPAR candidate are summarized in Section V.
B. Evidence Pertaining to Oncogenicity
HO CFR l62.11(a)(3)(ii)(A) provides that a
rebuttable presumption shall arise if a pesticide's ingre-
dients(s), metabolite(s), or degradation product(s) "induces
oncogenic effects in experimental mammalian species or in man
as a result of oral, inhalational, or dermal exposure." As
described in the Proposed Guidelines for Registering Pesticides
in the U.S., 40 CFR 163.83-1,-2 (Efid. Reg. 43 (163):37346-37347
[August 22, 1978]), oncogenicity testing "focuses on the
detection of malignant and benign tumors and preneoplastic
lesions" in at least one mammalian species. The species
shall normally be a generally recognized species of laboratory
rat. Dosing should begin as soon as possible after weaning
and acclimation and in any case before the animals are 6
weeks old. Dosing should continue for a lifetime or,
alternatively, for a pre-determined time span from early
adulthood to past maturity, depending on the animal's life
span.
The single available study for determining the
oncogenic potential of triallate is a 2-year feeding study
in Charles River albino rats performed by IBT for Monsanto
Company (IBT "No. 622-05251 [Calandra, T976, 1977 (-with
addendum)]). Male and female rats (50 in each group) were
fed 0, 50, 100, or 200 ppm of AVADEX BW (triallate) technical
in dry, pulverized Purina Chow for 24 1/2 months. Control
rats were the same as those used in a parallel diallate
study. Food consumption and body weights were recorded, as
were hematology, selected blood chemistries, and urinalyses
at periodic intervals. On all rats killed and on all rats
found dead except for advanced 'autolysis, complete gross
necropsies were reportedly conducted, and terminal weights
were taken of brain, gonads, heart, kidney, and spleen.
Detailed histopathological examinations were done on "selected
animals sacrificed." All neoplasms and tissues with suspected
"neoplastic lesions" were studied. According to food
consumption measurements, the amount of food eaten by test
animals was similar to that of controls', and there was no
statistically significant difference in mortality between
treated and control groups.
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Table 5- Pivotal Triallate IBT Studies
Type of Study
Chronic Oral—Rat
(with Addendum)
Mutagenicity—Mouse
Neurotoxicity—Chicken
(with Addendum)
Neurotoxicity—Chicken
IBT No.
622-05251
622-O5253
8580-09120
8580-10814
Status Remarks
Invalid Valid as an oncogenic
screen test
Valid
Valid
Provisionally Reports not signed by
Invalid responsible IBT staff
Teratogenic ity—Rabbit
651-05255
Invalid
No raw data submitted
-19-
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Upon reviewing this study, the EPA Carcinogen
Assessment Group pointed out a number of deficiencies,
including failure to section all tissues routinely and
failure to conduct histopathological examinations on all
animals sacrificed "in extremis" (Albert, 1977; 1979).
Taking these deficiences into account, however, the CAG was
able to conclude that "the tumor data did not indicate a
statistically significant increase of total tumors or of
tumors by anatomical site in either the treated males or
females relative to their respective controls." The CAG
recommended that an additional oncogenicity study in mice be
conducted (Anderson, 1977).
Dr. I. N. Dubin of the Medical College of
Pennsylvania reviewed for the CAG all of the available
slides from all animals in the control group and the 100 ppm
dose group (which showed the highest tumor incidence).
According to Dr. Dubin's report, the only tumor incidence
which might be considered statistically significant (p<.01)
involved pituitary chromophobe adenomas in female rats (9/22
control versus 13/15 treated). Dr. Dubin pointed out,
however, that because this type of tumor has a high sponta-
neous occurrence, the increased incidence noted may not be
biologically significant, and his overall conclusion was
that triallate did not produce a carcinogenic effect in this
study (Dubin, 1977).
Subsequent to the CAG review, this 2-year feeding
study was subject to audit by the Canadian government
in conjunction with the EPA Toxicology Data Audit Program.
As result of this audit, the study was pronounced valid only
as an oncogenic screening test but otherwise invalid for
risk assessment purposes. This determination was made on
the basis of deficiencies in experimental design (Auerbach,
1979). Taking into account the limited usefulness of this
study-as an oncogenic screening test only, the -Agency
regards the current data base as inadequate to satisfy
registration requirements but concludes that no rebuttable
presumption against triallate is warranted on the basis of
oncogenicity at this time. (See Section V, "Conclusions and
Recommendations," Subsection V.A.)
C. Evidence Pertaining to Mutagenicity
40 CFR 162.11(a)(3)(ii)(A) states that "a rebuttable
presumption shall arise if a pesticide's ingredient(s)
metabolite(s), or degradation product(s)... induces mutagenic
effects, as determined by multitest evidence." Section
162.3(y) defines mutagenicity as "the property of a substance
or mixture of substances to induce changes in the genetic
complement of either somatic or germinal tissue in subsequent
generations." Mutagenic chemicals are recognized as posing
a potential risk to human health because of their ability to
cause heritable changes in genes and chromosomes. Such
-20-
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germline changes can, for example, lead to birth defects or
to the accumulation of deleterious mutations in the human
gene pool. In addition, somatic mutations may be involved in
the etiology of cancer.
To determine whether or not triallate might pose a
mutagenic hazard warranting a rebuttable presumption, the
Agency has reviewed available data to assess the rautagenic
potential of the compound. (See Table 6, which summarizes
studies pertaining to the rautagenioity of triallate.)
In a dominant lethal test performed by IBT (IBT No.
622-05253 [Calandra, 197Ma]), Charles River strain albino
mice were administered single intraperitoneal injections of
either 200 or HOO mg/kg triallate. Negative results were
reported. Battelle Laboratories reviewed this study and
despite minor objections to the methodology employed,
concurred that triallate did not appear to be mutagenic in
the dominant lethal test (Freudenthal et al., 1977). A
second review by an Agency scientist (Pertel, 1977) likewise
confirmed the negative findings of IBT regarding the dominant
lethal assay but pointed out that the dominant lethal is a
relatively insensitive test capable of detecting only the
most potent mutagens. Subsequently, the negative results of
the IBT dominant lethal test in mice were declared valid
following a review of the raw data by the Canadian government
in conjunction with EPA's Toxicology Data Audit Program.
Triallate has subsequently been tested in the in
vitro mouse lymphoma assay, and conflicting results have
been reported. Brusick (1977b) reported that triallate did
not cause forward mutations at the TK locus of strain L5178Y
cells. More recently, however, Mitchell (1980) conducted a
similar test and reported that triallate was positive for
forward mutations at the TK locus of strain L5178Y cells.
The Agency has reviewed these studies and points out that
the conflict in evidence can be resolved only if additional
studies are conducted.
Triallate has also been tested in the standard
battery of bacterial Salmonella typhimurium strains, both
with and without metabolic activation (Ames assay) by a
number of researchers including Andersen et al. (1972),
Sikka and Florczyk (1978 [ pre-pub'lication copy reviewed by
the Agency in 1977]), Brusick (1977a), De Lorenzo et al.
(1978), and Simmon et al. (1978). Triallate has also been
tested in the WP2 strain of £. coli (Simmon et al., 1978).
Triallate has likewise been tested for mutagenicity using
the yeast Saccharomyces. cerevisiae. Using Saccharomvces
cerevisiae strain D3, Simmon et al. (1978) reported positive
results for mitotic recombinations in that strain. However,
Brusick (1977a) reported negative results in Saccharomvces
cerevisiae strain D*J.
-21-
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Table 6. Summary of Studies Pertaining to the Mutagenicity_9f Triallate
i
r\>
Test
Species
Albino
Mice
Bacteria
S. typhimurium
with metabolic
activation
Bacteria
S. typhimurium
with no
metabolic
activation
Bacteria
S. typhimurium
with metabolic
activation
Bacteria
S. typpimurium
iNo activation)
Bacteria
S. jtyphimurium
with activation
Bacteria
S . typh iraur ium
with activation
Bacteria
E.coli
strain WP2
Author,
Date
Calandra,
1974a
(IBT Study)
Sikka &
Florczyk,
1978
Sikka ft
Florczyk,
1978
DeLorenzo
et al. ,
1978
Anderson
et al. ,
1972
Bruslck,
1977
Simmon
et al. ,
1978
Simmon
et al. ,
1978
Results Agency
Reported Comments
Dominant lethal test - Pronounced valid following
triallate does not cause audit by the Canadian govern-
heri table lethal mutagenic raent in conjunction with
effects EPA1 s TDAP
Positive for base pair
conversions in strains
TA 100, TA 1535
Negative for base pair
conversions in strains
TA 100, TA 1535, TA 98,
TA 1538
Positive for base pair conver-
sions
Negative for base pair
conversions
Positive for base pair :
conversions
Positive for base pair
conversions
Negative for base pair
conversions
-------
Table 6. Summary of Studies Pertaining to the Mutagenicity of Triallate (Cont.)
I
ro
Test
Species
Author,
Date
Results
Reported
Agency
Review
Yeast
Saccharorayqes
Cerevisiae
Yeast
Saccharomyces
Cerevisiae
Mouse lymphoma
cells LY5178Y
Simmon
et al . ,
1978
Positive for mitotic
recombinations in strain D3
Mouse lymphoma
cells LY5178Y
Brusick,
1977
Brusick,
J.977
Mitchell,
1980
Negative for gene conversion
in strain D4
Negative for forward mutations
at the TK J~ locus
Positive for forward mutations
at the TK /~ locus
Bacteria
S. tyj)himurium
Care re
et al. ,
1978b
Bacteria
Streptomyces
coelicolor
Care re
et al. ,
1978b
Positive for base pair
conversions in strain TA 1535
Positive for base pair
conversions
Under Agency
Review
Under Agency
Review
Yeast
Aspergillus
sp.
Care re
et al. ,
1978a
Positive mutagenic effect
Under Agency
Review
Yeast
Aspergillus
sp.
Bignami
et al. ,
1977
Positive mutagenic effect
Under Agency
Review
Plant
Pelargonium
Zonale
Polheim
et al. ,
1977"
Positive mutagenic effect
Under Agency
Review
-------
The Agency has reviewed, these bacterial iand yeast
tests and concludes 1} that triallate induced base-pair: •
substitution (positive) with metabolic activation (MA) in
strains TA-100 and TA-1535, 2) that strain 98 showed a
"weak" positive (only in the presence of MA), 3) that the
WP2 strain of E. coli showed a negative response, and 4)
that evidence of triallate's ability to enhance mitotic
recombination in yeast is suggestive but not conclusive
(Mauer, 1980).
In addition to the studies discussed above, the
work of Carere et al. (1978) and Polheim et al. (1977) is
currently under review by the Agency. Carere et al. tested
triallate in Salmonella typhimurium and Streptomyces coelicolor
and reported the chemical to be a "powerful mutagen" in
strain TA1535 and positive for base pair conversions in S.
coelicolor. Carere et al. also tested triallate for mutageni-
city using the yeast Aspergillus sp. and reported a positive
mutagenic effect. Polheim et al. (1977) reported that
triallate showed a strong mutagenic influence in the monoha-
ploid Pelargonium zonale, a plant.
Although the studies performed by Carere et al.
(1978) and Polheim et al. (1977) remain to be evaluated by
the Agency, and although reported results in similar test
systems are at variance, the 40 CFR 162.11(a)(3)(ii)(B) risk
criterion of "mutagenic effects, as determined by multitest
evidence" has been met. Additional information is necessary,
however, to determine the potential of triallate to reach
the mammalian gonad, and thereby to more fully assess the
potential of triallate to cause heritable effects. In view
of the low level of exposure (Subsection III. B.) and the
lack of data indicating a strong mutagenic potential
the Agency has concluded that the potential for triallate to
produce mutagenic events in humans is very low. Hence, the
Agency, has determined that the issuance of .a rebuttable
presumption against registration for triallate on the basis
of mutagenicity is not warranted at this time. In essence,
the Agency has made a determination in accordance with 40
CFR 162.11 (a)(4)(ii) that the RPAR concerning mutagenicity
which has technically been raised has been rebutted by the
exposure information available to the Agency, and that the
"pesticide will not concentrate, persist or accrue to levels
in man or the environment likely to result in any significant
chronic adverse effects." The Agency has in effect rebutted
its own presumption based on exposure. The Agency will,
however, require additional tests in the area of mutagenicity
to enable a better characterization of the mutagenic potential
of the compound. (See Section V, "Conclusions and Recommenda-
tions" Subsections V.B. and V.E.)
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E. Evidenc^/Pertaining to Teratogenic and Fetotoxic
Effects^'
40 CFR 162.11(a)(3)(ii)(B) provides that "a rebutt-
able presumption shall arise if a pesticide's ingredient(s),
metabolite(s), or degradation products(s)...produces any
other chronic or delayed toxic effect [i.e., other than
oncogenic or mutagenic effects] in test animals at any dosage
up to a level, as determined by the Administrator, which is
substantially higher than that to which humans can reasonably
be anticipated to be exposed, taking into account an ample
margin of safety." Currently available information pertain-
ing to the teratogenic and fetotoxic potential of triallate
is limited to a single study performed by Industrial Bio-Test
Laboratories (IBT Report No. 651-05255 [Calandra, 1974b])
and submitted to the Agency by Monsanto Company. Two groups
of New Zealand albino rabbits were administered triallate
(AVADEX BW technical) at doses of 3 mg/kg/day and 10 mg/kg/
day for 12 days during gestation. IBT reported that "no
dose or test material related" fetotoxic or teratogenic
effects were observed which could be attributed to treatment
with triallate. A "no observable effect level" (NOEL) was
not established.
This study was reviewed for the Agency by Battelle
Laboratories, which noted that 1 out of 70 triallate treated
fetuses displayed talipomanus (club foot), while none of the
189 control fetuses were affected and concluded 1) that
depending upon the background incidence of this abnormality
in albino rabbits, this observation may represent a low
level of teratogenic activity, and 2) that additional
testing in at least one more species would be necessary for
purposes of assessing the teratogenic potential of triallate
in animals. A second review of this study by an Agency
scientist (Chernoff, 1977) pointed out further 1) that the
number of resorption sites/100 implantation sites were
greater in both experimental groups as compared to the
control group, 2) that historical rather than concurrent
control groups were used and no explanation for this depar-
ture from accepted practice was provided, and 3) that
calculation of fetal weights on a litter basis indicates
that a significant (p<0.05) dose-related reduction in fetal
weight occurred in treated litters in both dose groups. In.
view of the above, Chernoff (1977) recommended that this
study be repeated in the rabbit and that an additional study
be conducted in another species such as the rat.
7 /
-L' A 3-generation reproduction study of triallate in rats
(Industrial Bio-Test No. 623-06842) has been contracted by
Monsanto Company. The Agency has as yet received data
pertaining only to the F (parental) generation. Because
the final report has not been submitted or evaluated, the
Agency cannot comment on this study at this time.
-25-
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This IBT sludy was .subsequently audited by the
Canadian government in .conjunction with EPA's Toxicology
Data Audit Program and was pronounced not valid: "In the
absence of raw data on fetal skeletal development and on
internal development, the study cannot be validated" (Auerbach,
1979). A second Agency scientist (Edwards, 1979) has
pointed out that although this study has been declared not valid
and is inadequate for registration, it contains indications
of adverse effects which must be acknowleged. More specifi-
cally, 1) a possible effect on fecundity is indicated by
the reduced percent of pregnancies reported in the treated
groups; 2) reduced weights of progeny at birth were noted
in treated groups, and though these differences were seemingly
small, they were significant at the 99% confidence level for
both triallate-treated groups; and 3) a greater incidence of
fetal abnormalities was found in the progeny of treated than
of untreated groups. Except for reduced birth weights, all
the fetal effects noted above were more extensive in the low
dose group (3 mg/kg) than in the high dose group (10 mg/kg),
and this irregular relationship is unexplained. Noting that
both dose groups nonetheless showed indications of adverse
effects, Edwards (1979) recommended that an additional
teratology study be conducted according to the latest
guidelines and that a NOEL be determined.
Given the deficiencies which have been pointed out
in connection with this IBT test as the single available
study of teratogenic and fetotoxic potential of triallate,
the Agency regards the current data base as clearly inadequate
to satisfy registration requirements. However, the available
study by IBT (Calandra, 1974b) provides a basis on which to
conduct a rough assessment of the teratogenic and fetotoxic
potential of triallate.
Ordinarily, when a pesticide has been shown to
produce teratogenic and/or -f.etot.ox.ic -effects in -laboratory
animals, the Agency assesses human risk by comparing the no
observable effect level (NOEL), as established in animal
studies, with the highest estimated daily acute exposure to
humans. The ratio of the NOEL to the estimated human expo-
sure is used to determine margins of safety. As discussed
above, a NOEL was not established by Calandra (1974b), and
additional testing is necessary to determine a NOEL for
triallate-related teratogenic and fetotoxic effects.
In the absence of an established NOEL, the Agency
has calculated a rough, preliminary estimate of human risk
by comparing the lowest dose level tested (3 mg/kg body
weight per day in rabbits) with the estimated daily acute
exposure 1) to applicators, who represent the human population
subject to the highest estimated levels of exposure (dermal,
-26-
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respiratory, and dietary) to triallate, and 2) to the
general public, which is subject to dietary exposure as a
result of triallate residues on wheat, barley, and peas.
(Refer to Subsection III.B.)
Applicators who work with the emulsifiable concen-
trate formulation of triallate are subject to somewhat
higher levels of exposure than are applicators who work with
the granular formulation. With either formulation, only one
application is made per year, per field. During tank fill
and application procedures involving emulsifiable concentrate
triallate, an applicator is exposed to an estimated 5.6
ug/kg body weight per day in addition to an estimated 0.2
ug/kg/day as a result of dietary exposure to triallate.
This represents a level of exposure (6.6 ug/kg/day) which is
approximately l/500th the level at which fetotoxic effects
were observed in rabbits (3 ug/kg/day). During the process
of incorporating emulsifiable concentrate triallate into the
soil, an applicator is exposed to an estimated 2.7 ug/kg/day,
including an estimated 0.2 ug/kg/day as a result of dietary
exposure. This level of exposure is approximately l/1100th
the level of exposure at which fetotoxic effects were
observed in rabbits. During hopper fill and application
procedures involving granular triallate, and during the
process of incorporating the granular formulation into the
soil, an applicator is exposed to an estimated 3«3 and 1.9
ug/kg/day, respectively, again taking dietary exposure into
account. These levels of exposure represent approximately
l/900th and l/1500th, respectively, the level at which
fetotoxic effects were observed in rabbits.
At an estimated 0.2 ug/kg/day, dietary exposure
(worst-case) to the general public represents a level of
exposure which is roughly 1/19,000th the level at which
fetotoxic effects were observed in rabbits.
Taking into account the decidedly limited toxico-
logical evidence presently available in the IBT test conducted
by Calandra (I974b), considered together with the low levels
of exposure (dermal, respiratory, and dietary) associated
with triallate under current use patterns, the Agency
regards the current data base as inadequate to satisfy
registration requirements but concludes that no rebuttable
presumption against triallate'on the basis of teratogenic
and fetotoxic effects is warranted at this time. (See
Section V, "Conclusions and Recommendations", Subsection
V.C.).
E. Evidence Pertaining to Neurotoxicity
As stated above in connection with teratogenic
and fetotoxic effects, 40 CFR 162.11(a)(3)(ii)(B) provides
that "a rebuttable presumption shall arise if a pesticide's
ingredient(s), metabolite(s), or degradation products(s)...
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produces any other chronic or delayed toxic effect 'in test
animals at any dosage up to a level, as determined by the:
Administrator, which is substantially higher than that to*'
which humans can reasonably be anticipated to be exposed,'
taking into account an ample margin of safety." A neurotoxic'.
pesticide is defined as one which causes damage to the
nervous system. Neurotoxicity is discussed in the following
paragraphs 1) in terms of acute delayed neurotoxicity and
2) in terms of another type of neurotoxicity which might be
associated with exposure to triallate.
As defined in the Proposed Guidelines for
Registering Pesticides in the U.S., acute delayed neurotoxi-
city is a syndrome in which signs of nerve damage first
appear several days to a few weeks after exposure to a
neurotoxic pesticide. Hence the effect is termed "delayed."
Delayed neurotoxicity may result in permanent paralysis. As
stated in the Proposed Guidelines, "EPA's experience indicates
that every compound which produces delayed neurotoxicity in
any test system will also cause delayed neurotoxicity when
given in a very large dose to hens under an acute regimen.
[Hens are therefore the test animals of choice for delayed
neurotoxicity studies.] Thus, the acute delayed neurotoxicity
study would be used to identify these compounds, and if
positive results are observed in the study further testing
would be required" (Fed. Reg. 43 (163):37345 [August 22,
1978]).
Regarding acute delayed neurotoxicity as a
possible adverse effect of exposure to triallate, two
studies are available, both of which were performed by
Industrial Bio-Test Laboratories (IBT Nos. 8580-09120 and
8580-10814) for Monsanto Company. In IBT study No. 8580-09120,
conducted by Keplinger (1976), 10 chickens were given doses
of 312 mg/kg twice daily by gavage on days 1 through 3 and
on days 21 through 23- -Following a revrew of-the-raw data,
this study was pronounced valid by the Canadian government
in conjunction with EPA's Toxicology Data Audit Program
(Auerbach, 1979). The raw data were found to agree with
the final report. All birds showed moderate ataxia and
lethargy and general weakness of legs and wings, from which 7
of the 10 birds recovered by the end of the experiment.
Only one bird reportedly showed lesions of the nervous
system—the most severe effect noted in this experiment—
upon histopathologic examination. Subsequent review by an
Agency scientist (Edwards, 1979), however, questioned the
credibility of a severe effect (neurotoxic lesions) in one
hen when there were no comparable effects in nine. Marek's
disease was also found in these animals.
In IBT study No. 8580-10814 • (Keplinger, 1978),
multiple doses (0.01, 0.02, 0.04, 0.08, 0.16, and 0.32
gram/kg) were administered to hens twice daily for two 3-day
periods (days 0, 1, 2, 21, 22, and 23). (The cumulative
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dose per hen was thus 0.12, 0.24, O.H8, 1.92, or 3.8^4
gram/kg body weight). Following an audit of the raw data by
the Canadian government in conjunction with the EPA Toxicology
Data Audit Program, this study was pronounced "provisionally
invalid" because signatures of responsible IBT staff members
were not available (Auerbach, 1979). This study was
subsequently reviewed by an Agency scientist (Edwards,
1979), who pointed out 1) that no behavioral signs were
found in treated animals, and 2) that focal lesions of
axonal degeneration were found in one of ten birds which
received 0.16 gram/kg but in none of the ten which received
0.32 gram/kg. Edwards (1979) concluded that the degeneration
could not be treatment-related.
The possibility that triallate might be associated
with another type of neurotoxicity has been raised.by a
study reported to the Agency by Monsanto Company.^-
Rats were treated with a mixture of chemicals, one of which
was triallate. Treatment resulted in symptoms including
circling behavior, head tremors, and head tilt to one side.
Symptoms were exacerbated by external stimulation. In
addition, these symptoms were said to have been observed in
quail which had been treated with triallate alone, and this
suggests that the effects observed in rats were due to
triallate. Because observation of the rats ceased after the
end of dosing, no distinction could be made between transient
effects and permanent damage, and the issue of whether or
not the effects in question are persistent remains to be
resolved .
With respect to acute delayed neurotoxicity as a
possible adverse effect of exposure to triallate, the Agency
has determined that no rebuttable presumption is warranted
and that no further testing is necessary. With respect to
the adverse effects seen in the rat study described above,
however, appropriate neurotoxicity testing in rats is
required to clarify the nature of this potential hazard and
to determine a no observable effect level (NOEL). Monsanto
Company has agreed to submit data to clarify this area of
concern and to collaborate with the appropriate Agency
scientist regarding study protocols and time frame projec-
tions. Taking all currently available evidence into account,
the Agency concludes that no rebuttable presumption against
triallate on the basis of neurotoxicity is warranted at this
time. (See Section V, "Conclusions and Recommendations,"
Subsection V.D.)
8/
The results of this study were reported verbally at
the EPA/Monsanto meeting of September 9, 1980, the purpose
of which was to informally discuss data requirements and
testing protocols. A final report of the study is not
available.
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V. Conclusions and
The conclusions and recommendations arising from thrs .
review of triallate as a potential RPAR candidate are based
1) on considerations of toxicity as determined by the
Agency's review and evaluation of available toxicological
data, and 2) on considerations of exposure. In summary, the
Agency has determined that triallate should be returned to
the registration process with the stipulation that a FIFRA
Section 3(c)(2)(B) action ("additional data to support
existing registrations") be initiated to obtain the toxicity
data necessary to fully evaluate the potential hazards of
triallate. Though certain risk criteria have been met, and
even though the Agency remains concerned regarding oncogeni-
city, mutagenicity, fetoxicity and teratogenicity , and
neurotoxicity, this action is recommended because exposure
to triallate is expected to be insignificant.
Upon receipt and evaluation of the necessary data, the
Agency will reassess the potential hazards of triallate,
taking the complete data base into account. Conclusions and
recommendations regarding the specific areas o'f concern
addressed in this review are given below.
A. Qncogenicitv
The Agency has concluded that the current data base
is inadequate to satisfy registration requirements. However,
the available study by Industrial Bio-Test Laboratories (IBT
No. 622-05251 [Calandra, 1976, 1977 (with addendum)] which
is valid as an oncogenic screening test only, is considered
evidence that no rebuttable presumption on the basis of
oncogenicity is warranted at this time. Studies are required
as specified in the Proposed Guidelines for Registering
Pesticides in the U.S., 40 CFR 163.83-1 and -2 (Fed. Reg.
43(l63):37346-373^7 [August 22, 1978]).
B. Mutagenicity
The Office of Pesticide Programs (OPP) Working Paper
on Mutagenic Risk Assessment Policy, issued in October,
1980, states that "Qualitative assessments of risk will be
made based upon scientific evaluation of a chemical's
behavior in various mutational test systems, knowledge of
the chemical's entry into the mammalian gonad , and the
expected pattern and level of exposure." In the case of
triallate, conflicting test results impede a conclusive
determination of the chemical's behavior in various mutational
test systems. In the absence of data concerning the metabo-
lism of triallate in mammals, moreover, it is not possible
to estimate the likelihood of the chemical's entry into the
mammalian gonad. This difficulty, coupled with an expected
low level of exposure, results in a determination that there
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is insufficient information available at this time to
determine whether current uses of triallate pose a mutagenic
risk to human populations. As discussed previously, the
currently available toxicological data base, when considered
in conjunction with the low exposure potential for triallate,
indicate that the potential risks of mutagenicity are very
low for triallate. Consequently, the Agency has determined
that the issuance of an RPAR is not warranted at this time,
because several key pieces of data are lacking. The
Agency will require additional tests to provide further
indication as to whether the chemical presents an unreasonable
mutagenic risk to humans.
q/
The following mutagenicity tests are required.
(See also Subsection V.E. below.)
1. For point (gene) mutation; Mammalian cell
culture, using the same cell type (mouse
lymphoma L5178Y); or CHO, or V79 (i.e.,
another locus).
2. For chromosome effects: Several tests from
the following types:
a. In vitro cytogenetics, using mammalian
cells; or sister chromatid exchange in
mammalian cells
3. For DNA damage effects:
a. In vitro repair assays, either bacterial
(e.g., E. cojli Pol A; B. sijbtilis Rec),
or mammalian (e.g., unscheduled DNA
synthesis)
b. in vivo cytogenetics, -in rats (e.g.
micronucleus; or bone marrow.)
c. pominant lethalt either in rats, or
repeat in mice. This could be combined
with sperm morphology, or inhibition
of testicular DNA synthesis, or (mouse)
spermatocyte test.
* Protocols for two tests have been•received and approved
by the Agency: mammalian cell culture for point mutation;
and in vivo cytogenetics in rats.
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C. Teratogenic and Fetotoxic Effects
The Agency has determined that the current data' base .
is inadequate to satisfy registration requirements. However/,-
the available study in rabbits by Industrial Bio-Test
Laboratories (1ST No. 651-05255 [Calandra, 1974b]) provides ..
a basis on which to conduct a rough, preliminary assessment
of the potential teratogenic and fetotoxic effects of
exposure to triallate.
The current regulations covering fetotoxic and
teratogenic effects require consideration of potential
exposure in connection with the issuance of an RPAR.
Based on applicator exposure data submitted by Monsanto
Company (Arras, 1980) and evaluated by the Agency, total
absorbed body doses for applicators working with emulsifiable
concentrate triallate during tank fill and application
procedures, and during the process of incorporating the
herbicide in the soil, have been estimated at roughly
l/500th and l/1100th, respectively, of the level of exposure
at which fetotoxic effects were observed in rabbits (3
nig/kg/day). Total body doses to applicators working with
the granular formulation during hopper fill and application
procedures, and during the process of incorporating granular
triallate into the soil, have been estimated at l/900th and
1,500th, respectively, of the level at which fetotoxic
effects were observed in rabbits. Based on tolerances for
triallate, worst-case dietary exposure to the general public
has been estimated as roughly 1/19,000th of the level at
which fetotoxic effects were observed in rabbits.
Taking into account the decidedly limited toxicological
evidence presently available in the IBT test conducted by
Calandra (1974b), considered together with the low levels of
exposure associated with triallate under current use patterns,
the Agency-has determined that no rebuttable presumption
against triallate on the basis of teratogenic and fetotoxic
effects is warranted at this time. Studies on the reproductive,
fetotoxic, and teratogenic effects of triallate are required
as specified in the Proposed Guidelines for Registering
Pesticides in the U.S., 40 CFR 163.83-3 and -4 (Fed. Reg.
43(163):37382-37385 [August 22, 1978]).
D. Neurotoxicity
Regarding acute delayed neurotoxicity as a possible
adverse effect of exposure to triallate, the Agency has
determined that in view of currently available evidence (IBT
Studies, Nos. 8580-09120 and 8580-10814 [Keplinger 1976;
1978]), no trigger has been met and no further testing is
necessary.
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Regarding the adverse effects reportedly observed in
a recent study in which rats were treated with a mixture of
chemicals, one of which was triallate, further testing
in rats is required to clarify the nature of this potential
hazard and to determine a no observable effect level (NOEL).
The symptoms observed in rats—including circling behavior,
head tremors, and head tilt to one side (symptoms were
exacerbated by external stimulation)—were said to have been
likewise observed in quail which had been treated with
triallate alone, and this suggests that the effects observed
in rats might have been due to triallate.
Taking all currently available evidence into account,
the Agency has determined that a rebuttable presumption
against triallate is not warranted on the basis of neurotoxicity
at this time, though the current data base is not sufficient
to support registration.
E. Metabolic Effects
A general metabolism study is required to determine
absorption, distribution, metabolism, and excretion of
triallate in mammals. The study protocol published in the
Proposed Guidelines for Registering Pesticides in the U.S.,
HO CFR 163.85-1 (fed. Reg. *n( 163): 373QH-373Q6 [August 22,
1978]), should be utilized in designing this study. For
triallate, the blood kinetics and tissue binding tests will
not be required. Since the guidelines are applied on a case
by case basis, the registrant should present the protocol to
the Agency before starting the study in order to insure that
it meets Agency requirements.
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VI. BIBLIOGRAPHY
Albert, Roy E. , M.D. 1977. The Carcinogen Assessment
Group's Preliminary Review of Oncogenicity of Avadex
(Diallate and Triallate). With Addendum. (Unpublished.)
Albert, Roy E., M.D. 1979. The Carcinogen Assessment
Group's Risk Assessment of Avadex (Diallate and Triallate).
Includes Dubin, 1977, as appendix. (Unpublished.)
Andersen, K.J., E.G. Leighty, and M.T. Takahashi. 1972.
Evaluation of herbicides for possible mutagenic properties.
J. Agr. Pood Chem. 20: 649-656.
Anderson, Elizabeth L. 1977. Memorandum: Carcinogenic
Potential of Triallate (Avadex BW), dated September 21,
1977. Prom Elizabeth L. Anderson, Executive Director,
Carcinogen Assessment Group, to Richard Troast, Project
Manager, Office of Special Pesticide Review.
Arras, D.D., R. Lauer, and S. Dubelman. 1980. Applicator
Exposure Study for Avadex BW Herbicide under Actual Field
Conditions. Monsanto Report MSL-1155- (Confidential.)
Auerbach, Jan. 1979- Memorandum and attachments: Review of
IBT Studies on Triallate, dated August 17, 1979- Prom Jan
Auerbach, Chief, Regulatory Analysis and Lab Audits Branch,
Special Pesticide Review Division to Bob Brown, Chief,
Chemical Review Branch 3, Special Pesticide Review Division.
Bignami, M., P. Aulicino, A. Velich, A. Carere, and G.
Morpurgo. 1977. Mutagenic and recombinogenic action of
pesticides in Aspergillus nidulans. Mut. Res. 46: 395-402.
Brusick, D.J. 1977a. Mutagenic Evaluation of CP 23426
('Pinal'Report, July 1977). Submitted to'Monsanto Co., -Inc.
by Litton Bionetics, Inc., Project No. 2683. Submitted to
EPA March 22, 1978. EPA Accession No. 233353-
Brusick, D.J. 1977b. Mutagenic Evaluation of CP 23426 in
the Mouse Lymphoma assay (Pinal Report, August, 1977).
Submitted to Monsanto Co., Inc. by Litton Bionetics, Inc.,
Project No. 2684. Submitted to EPA March 22, 1978. EPA-
Accession No. 233353.
Calandra, J.C. (industrial Bio-Test Laboratories, Inc.).
1974a. Mutagenic Study with Avadex BW in Albino Mice
(BTL-74-16). Submitted by Monsanto Company October 1974.
(Confidential; unpublished.)
Calandra, J.C. (Industrial Bio-Test Laboratories, Inc.).
1974b. Teratogenic Study with Avadex BW Technical (CP23436)
in Albino Rabbits (BTL-74-17). Submitted by Monsanto
Chemical Co. January 1975- (Confidential; unpublished.)
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Calandra, J.C. (Industrial Bio-Test Laboratories, Inc.).
1976, 1977. Two-Year Chronic Oral Toxicity Study with
AVADEX BW Technical in Albino Rats (BTL No. 74-15). With
addendum. Individual Animal Data. Submitted by Monsanto
Company February 4., 1977. (Confidential; unpublished.)
Carere, A., V.A. Ortali, G. Cardamone, M. Torracea, and R.
Reschatti, 1978a. Microbial mutagenicity studies of
pesticides in vitro. Mut. Res. 57: 277-286.
Carere, A., V.A. Ortali, G. Cardamone and G. Morpurgo.
1978b. Mutagenicity of dichlorvos and other structurally
related pesticides in Salmonella and Streptomyces. Chem. -
Biol. Interactions 22: 297-308.
Chernoff. 1977. Memorandum: Review of Teratology Study on
Triallate, dated September 23, 1977. Prom Neil Chernoff,
Ph.D., Experimental Biology Division, HERL-RTP (MD-74) to
Mr. Richard Troast, WH-566, Project Leader, OSPR [Office of
Special Pesticide Reviews].
Cullimore, D. R. and A. E. Smith. 1972. Initial studies on
the microbial breakdown of triallate. Bull. Environ.
Contam. Toxicol. 7: 36-42.
DeLorenzo, P. N. Staiano, L. Silengo, and R. Cortese. 1978.
Mutagenicity of diallate, sulfallate and triallate and
relationship between structure and mutagenic effects of
carbamates widely used in agriculture. Cancer Res. 38:
13-15.
Dubin, I. N., M.D. 1977. Report on Histopathologic Studies of
Monsanto Triallate (Avadex-BW) Experiment on Charles
River Albino CD Rats. Included as appendix in Albert,
1979- (Unpublished.)
Edwards, W. Thomas. 1979. Memorandum: Triallate RPAR,
dated July 16, 1979- Prom W. Thomas Edwards, Triallate
RPAR Team Member, Pharmacologist, Toxicology Branch, RED
(TS-769) to Richard Troast, Project Manager, SPRD (TS-791).
Preudenthal, R. I. and R. P. Leber. 1977. Report on the
Evaluation of Diallate/Triallate Toxicity Data to Determine
its Potential Health Hazards in Man and Domestic Animals.
Battelle Memorial Laboratories, Columbus, Ohio. (Unpublished.)
Grover, R. 1974. Adsorption and desorption of trifluralin,
diallate and triallate by various adsorbents. Weed Sci.
22(4): 405-408. .
Hance R. J., J. Holroyd, and C. E. McKone. 1973. Some
aspects of triallate volatility. Pest. Sci. 4: 13-17.
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Innes, J. R. M., B. M. Ulland, M. G. Valeri.o, L. Pet.rucelli,
L. Pishben, E. R. Hart, A. J. Pollotta, R. R. Bates, .B. L.
Falk, J. J. Gart, M. Klein, I. Mitchell and J. Peters. 1979-
Bioassay of pesticides and industrial chemicals for tumorige*.
city in mice: a preliminary note. J. Nat. Cancer Inst.
42: 1101.
Jennings, Allen. 1977. Memorandum: Triallate, dated
October 4, 1977. From Allen Jennings, Standards and
Regulations Evaluation Division, to Richard Troast
Project Manager, Office of Special Pesticide Review.
Jensen, Janice. 1980. Data Evaluation—Triallate (Monsanto
Report MSL-1155). Completed by Janice Jensen, Environmental
Fate Branch.
Keplinger, M.L. (Industrial Bio-Test Laboratories, Inc.).
1976. Neurotoxicity Study with Avadex BW in Chickens.
Submitted by Monsanto Company February 16, 1977. (Confi-
dential; unpublished.)
Keplinger, M.L. (Industrial Bio-Test Laboratories,- Inc.).
1978. Neurotoxicity Study with Avadex BW in Chickens.
Submitted by Monsanto Company July 19, 1978. (Confidential;
unpublished.)
Lehman, A. J. 1962. The annual per capital consumption of
selected items of food in the United States. Quarterly
Bulletin of the Association of Food and Drug Officials
26: 149-
Mauer, Irving. 1980. Memorandum: Mutagenicity of Triallate,
dated May 8, 1980. From Irving Mauer, Toxicology Branch,
HED, to Minnie Sochard, SPRD, Review Branch 3-
Mitchell, A.D. 1980. An Evaluation of the Mutagenic Potential
of Triallate Employing the L5178Y TK /" Mouse Lymphoma
Assay. SRI International, 333 Ravenswood Ave., Menlo Park,
CA. 94025-
Mittelman, A. 1978. Memorandum: Triallate Exposure Analysis
Review, dated March 16, 1978. From A. Mittelman, Criteria
and Evaluation Division, to Richard Troast, Project
Manager, Special Pesticid'e Review Division.
Melnikov, N. W. 1971. In Chemistry of Pesticides, F. A.
Canther and J. D. Gunther eds. New York: Springer-Verlag.
Monsanto Co., 1979- Acute Toxicity Studies Submitted in
Support of Avadex BW Herbicide. Monsanto Co. Agricul-
tural Products Co., St. Louis, Mo: EPA Accession No.
241271-6.
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Monsanto Co., 1980. Report on triallate. Monsanto Co.
Agricultural Products Co., St. Louis, Mo. EPA Accession No.
243009.
Monsanto Co. 1975. Report #524-124 on Triallate. Monsanto
Co. Agricultural Products Co., St. Louis, Mo.
Pertel, Ruth. 1977. Memorandum: Triallate mutagenicity,
dated August 17, 1977. Prom Partel, Ph.D., Project
Manager, OSPR, to Richard Troast, Project Manager, OSPR.
Pesticide Petition OP0944. Submitted by Monsanto Chemical
Company January 10, 1970. (Confidential.)
Pohlheim, E., F. Pohlheim, and G. Gunther. 1977. Mutagenicity
testing of herbicides with a haploid pelargonium. Mut. Res.
1 46: 232.
Selim, Sami. 1978. Environmental Fate Profile: Triallate.
Prepared by Sami Selim, Environmental Fate Branch, Hazard
Evaluation Division, Office of Pesticide Programs.
Severn, David J. 1977. Memorandum: Validation of Monsanto
Report #524-124 on Triallate, dated February 17, 1977.
From David J. Severn, Ph.D., Chemist, Chemistry Branch, C
& ED, to Project Manager, OSPR.
Sikka, H. C. and P. Florczyk. 1978. Mutagenic activity of
thiocarbamate pesticides in a microbial test system.
J. Agr. Food. Chem. 26:146-148.
Simmon, V. F., E. S. Riccio and A. Griffin. 1978. In Vitro
Microbiological Mutagenicity Assays of Diallate and
Triallate (Final Report, April 1978). Stanford Research
Institute International, Project LSU-3493. Prepared for
"EPA (HERL/RTP) under"Contract No. 68-01-2458.
Smith, A. E. 1971. Disappearance of triallate from field
soils. Weed Res. 19(5): 536-537.
Smith, A. E. 1970. Degradation, adsorption and volatility
of diallate and triallate in prairie soils. Weed Res.
10: 331-339.
Smith, A. E. 1969. Factors affecting" the loss of triallate
from soils. Weed Res. 9: 306-313-
U.S. Congress, Senate, Committee on Agriculture, Nutrition,
and Forestry. . 1979- Conference Report on S. 1678. 95th
Congress, 2d Session.
Voytenko, G. A., Ye N. Burkatskaya, V. I. Matyuskima, T. V.
Dyadicheva, L. A. Matokhnyuk, T. L. Medved, A. G. Pestova,
L. G. Aleksandrova, Z. V. Ivanova, and N. G. Stepanchenko.
1972. Inst. Gig. Tr. Profzabol. 16: 4-8.
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Appendix: EPA Policy on IBT-Generated Data*
1. The moratorium which has been in effect for all chemicals .
supported by IBT data is now lifted.
2. In cases where the invalidation of IBT data results in
major data gap(s) (see below), the registrant will be
required to fill the data gap(s) as soon as possible in
accordance with Section 3(c)(2)(B) of PIPRA. Failure to
meet the requirements of Section 3(c)(2)(B) will result
in suspension of the registration.
3- In cases where the invalidation of IBT data results in
minor data gaps, the gaps will be filled through the
Registration Standard data call-in process. This will
occur over the next one to five years.
4. In cases where virtually the entire data base is invalid
and there is a strong possibility of substantial health
risk, EPA will consider that the Section 3(c) requirement
to provide an adequate basis for the registration of the
chemical is unfulfilled by the registrant. In these
cases, EPA will consider canceling the current registration
of the chemical under Section 6(b) for failure to comply
with the requirements of the Act. This cancellation
would remain in effect until the studies required under
Section 3(c)(2)(B) are completed, reviewed and a determina-
tion made on the safety of the chemical. The Agency's
determination of strong possibility of substantial
health risk will be based on whatever data are available
to assess chemical toxicity and consideration of exposure
levels of the chemical.
5. In cases where close review of the raw data indicates
that some adverse health effects 'data were not reported
to EPA, the registrant will be required to reconduct the
studies as soon as possible in accordance with Section
3(c)(2)(B) of the Act. Also, EPA will consider further
regulatory action, such as RPAR, expedited RPAR, or
conduct of a Section 6(b)(2) hearing. The nature of the
regulatory action will depend on the expected level of
adverse health risk.
Issued July 29, 1980
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6. Data will he considered invalid for any one of the
following reasons:
a. failure to submit raw data required to be submitted
by February 29, 1980,
b. failure to submit validation of a pivotal study
required to be submitted by February 29, 1980, or
c. determination of invalidation by EPA based on
comparison of raw data with the final report
originally submitted to the Agency.
7. Determination of whether a data gap is minor or major
will be made on a case-by-case basis. In general,
however, chronic/oncogenicity studies, three generation
reproduction studies, teratology studies and neurotoxicity
studies are considered pivotal to the Agency's decision-
making process. Therefore, the presence of one or more
studies which are invalid due to significant scientific
problems in any of these categories would constitute a
major data gap. An invalid suhchronic study could be
considered a major data gap if no longer term study
exists in the data base, which addresses the same
toxicity endpoint. A minor data gap is, for example,
one involving an acute study, or the invalidity of a
chronic study due to administrative deficiencies which
have little or no influence on the scientific soundness
of the study.
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