DIALLATE FACT SHEET
Common Name; Oiallate
Chemical Name; (S (2,3-0ichIoroaI IyI 1 diisoproyIthiocarbonate)
Structure:
H CL 0 CH3
OC I
CL CH2 - S - C - N CH
I
CH3
CL
C=C
CL 0
CH2 - S - C - N
els Isomer
trans Isomer
Molecular Formula; C.gH.,CL
Chem i s try; Dial late, is the name applied to a thioarbamate
herbicide known by the trade name Avadex.
It is a 'iquid which is formulated as an emulsi-
ftable concentrate (4 pounds/gallon) and as a
granular product (10$). Its molecular weight
Is 270.2. Two Isomers, els and trans forms are
known.
Character i st i cs; Diallate is a volatile, amber colored liquid
with a melting point of 25-20C. > l-t is soluble
tn most organic solvents but only slightly
so IubIe in water.
-------
b). Teratoqenic Effects
A final report concerning reproductive effects
in 3 generations of rats is expected by the
Agency sometime in 1980. This study will be
evaluated by the Agency and results included in
Position Document 4.
Number of Products and Registrants
Three registrants and eight products.
Product ion
Confidential under section 7(c) and 10 of FIFRA.
Principal Manufacturer
Monsanto Co. is the sole importer of technical dial late in
the U.S.
Uses
Control of wild oats as a pre-emergence herbicide in
sugar beets (major.use), flax, lentils, dry peas,
alfalfa, barley, corn, potatoes, and soybeans.
Human Exposure
Principal human exposure is by dermal exposure. The
inhalational exposure is low and not of primary
concern. The principal population subject to these
exposures are applicators. The risk to the general
population from dietary exposure is low and the worst
case estimate is at 10 .
-------
Risk Criteria Met or Exceeded
I) RPAR Triggers
a) Oncogen i c i ty
Studies by- several laboratories indicate ingestion
of dial I ate by different rod-ent species results in a
significant increase in numbers of carcinomas and
other tumors in experimental animals when compared
w i th controIs.
b) Mutagen i c ? ty
Studies employing the Ames test for mutagenicity in
microbes indicated dial late induced gene mutations
in SaImoneI I a typh ? mur i urn but not in the lass
sensitive bacterium Escher i ch i a col i . Induction of
mitotic abberations were found in the yeast, Sac-
charomyces cerev i s ? ae« In a mammal ian ceI I culture
system, (mouse lymphoma) forward mutations were
found at the TK locus. Thus, evidence is presented
for in vitro mutagenic effects by dial late.
2) Non Triggers: Areas of Possible Adverse Effects
a ) Neurotox i c i ty
The Agency has determined that a neurotoxic
effect may occur upon exposure to dial late. It
has calculated the annual applicator exposure
and determined that the effect level is 600
times greater than the exposure level.
-------
DIALLATE
Position Doc went 2/3
April, 1980
Office of Pesticides and Toxic Substances
Environmental Protection Agency
401 'Mf Street, S.W.
Washington, D.C. 20460
-------
ACKNOWLEDGEMENTS
EPA Prop ect Support Team
James E. Wilson, Jr., Senior PM, SPUD
Minnie R. Sochard, Ph.D., PM, SPRD
Karl 0. Bayer, OGC
Tom Edwards, "*"
Roger Gardiner, BED
Janice Jensen, BED
Dave Johnson, BED
Charles Lewis, BFSO
Richard Stevens, BSD
Linda V. Zygadlo, BFSD
-------
TABLE OF CONTENTS
Page Number
I. Background 1-1
A. Introduction I-1
1. Organization of Position Document 1-1
2. Chemical and Physical Characteristics 1-1
3. Registered Uses 1-1
4. Tolerances 1-2
B. Applicable Sections of FTFRA 1-2
C. The "RPAR" Process 1-3
D. Regulatory History 1-3
E. Basis for the Rebuttable Presumption 1-4
II. Analysis and Assessment of Risk II-1
A. Analysis of Rebuttal Arguments
for Oncogenicity II-1
1. Rebuttal Pertaining to National
Cancer Institute (NCI) Rat
Study (Litton-Bionetics) II-1
2. Rebuttal Pertaining to Industrial
Bio-Test (IBT) Rat Study
(Sponsored by Monsanto Company) II-5
3. Rebuttal Pertaining to NCI
House Study (Innes Study) 11-11
B. Analysis of Data Submitted Since PD 1
for Other Possible Adverse Effects 11-14
1. Mutagenicity 11-14
2. Neurotoxicity 11-16
3. Reproductive Effects 11-17
C. Exposure Analysis 11-18
1. Spray Applicator Exposure 11-18
a. Spray Applicators 11-18
b. Granular Applicators 11-19
2. Dietary Exposure 11-19
D. Risk Assessment 11-19
1. Oncogenic Effects 11-19
2. Hutagenic Effects 11-24
E. Risks Associated with Alternative Chemicals 11-27
III. Benefit Analysis III-1
A. Sugar Beets III-2
B. Flax III-7
C. Lentils III-7
D. Peas III-8
E. Minor Uses III-9
IV. Development of Regulatory Options IV-1
A. Introduction IV-1
B. Salient Risk/Benefit Considerations IV-1
1. Salient Risk Considerations IV-1
2. Salient Benefit Considerations IV-2
-------
C. Risk/Benefit Analysis Options IV-3
1. Dietary Risk/Benefit Analysis 17-3
2. Applicator Risk/Benefit Analysis IV-4
D. Regulatory Options IV-6
1. Option 1 IV-6
2. Option 2 IV-7
3. Option 3 IV-7
V. Proposed Regulatory Decision V-1
VI. References
-------
DIALLATE: POSITION DOCDMENT 2/3
I. Background
A* Introduction
1 . Organization of Position Document:
This Position Document contains five parts* Part I is the
introductory section. Part II is an evaluation of the risk of diallate.
It includes descriptions of the relevant data on toxicity, exposure, and
the Agency's present risk assessment. Part III is a summary of the
economic benefits of diallate. Part IV describes the range of the
regulatory options considered by the Agency. Part V puts forward the
Agency's reconmended option.
2. Ch«"1cal and Physical Characteristics
Diallate ( S- ( 2 , 3-Dichloroally 1 ) diisopropy 1 thiocarbamat e ) is
a thiocarbamate which is also known by the trade name AVADEX0. Diallate
acts as a pre-emergence selective herbicide. It is an amber-colored liquid
which is formulated as an emulsifiable concentrate (4 pounds/ gallon) and as
a granular (10%).— Its molecular weight is 270.2. Its structural
formula is as follows:
Diallate "trans looner ds isoaer
H a CH3 ci a CH3
^ f,
d ^CH,- 3-G-«-CH
XCH'CH- NCH— CH
\
3* Registered Pses
Monsanto Agricultural Products Company is the sole producer
of technical-grade diallate. As a registered pesticide, diallate is cur-
rently used to control wild oats in sugar beets, flax, barley, corn (grain
and silage), forage legumes (alfalfa, sweet, red and alsike clover),
As a granular, diallate is registered for use on sugar beets only.
1-1
-------
lentils, peas, potatoes, safflower, and soybeans. In combination with
pebnlate or cycloate, it is used also to control other grasses and broad-
leaf weeds in sugar beets. Diallate is incorporated into the soil in the
fall before the freeze or in the spring, either before or after seeding,
bat before emergence. Usually only one application is made by the user per
season.
Eight federal registrations of products containing diallate
are held by three registrants.
4. Tolerances
Tolerances for diallate in or on raw agricultural
commodities are listed in 40 CFR 180.277 as follows: negligible residues
on alfalfa (fresh and hay), barley (grain, forage, and straw), clover
(fresh and hay), field corn grain, fodder and forage, flaxseed, lentils,
peas, pea forage and hay, potatoes, safflower seed, soybeans, soybean
forage and hay, and sugar beet roots and tops at 0.05 part per million.
B. Applicable Sections of FIFRA
The Federal Insecticide, Fungicide and Rodenticide Act (7 U.S.C.
136 et seq.), as amended, confers authority on EPA to regulate pesticide
products. Section 3 (a) of the Act requires all pesticide products to be
registered by the Administrator before they may be sold or distributed.
Before the Administrator may register a pesticide, however, he must
determine that its use will not result in "unreasonable adverse effects on
the environment," defined in Section 2(bb) of FIFRA to mean "unreasonable
risk to man or the environment, taking into account the economic, social,
and environmental costs and benefits of the use of any pesticide." In
other words, any registration decision must take into account both risk and
benefits from the pesticide's uses.
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 to him 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
may cancel the registration of a pesticide whenever he determines that it
no longer satisfies the statutory standard for registration; this standard
requires, among other things, that the pesticide "perform its intended
function without unreasonable adverse effects on the environment" [FIFRA
3(c)(5)(C)]. Be may also cancel the registration of a pesticide if its
labeling does not comply with the misbranding provision of FIFRA, which
requires the labeling to contain certain language "adequate to protect
health and the environment* (FIFRA 2(q)).
1-2
-------
C« The "KPAR* Process
To implement its authorized functions, t*vt Agency has designed
the Rebuttable Presumption Against Registration (RPAR) process, which
involves gathering data on the risks y«* benefits associated with the uses
of suspect pesticides. By allowing all interested parties to participate by
submitting information, the process enables EPA to make balanced decisions
concerning problem pesticides.
If the presumptions of risk are not rebutted, the evidence
pertaining to benefits must be evaluated and considered together with the
evidence pertaining to risk. Various risk reduction methods and their
costs are analyzed. The Agency then determines whether the pesticide may
be regulated so that a balance is achieved between risks and benefits. If
the statutory balance cannot be reached for a use, the registrations for
that use must be cancelled.
D. Regulatory- History
The first registration for a product containing diallate was
granted to Monsanto on December 9, 1960 (EPA Registration Number 424-119).
Use of diallate on corn", forage legumes, lentils, peas, potatoes,
safflower, and sugar beets was approved. Because no residues were detected
in or on these raw agricultural commodities the use of diallate was
accepted under the "no residue-zero tolerance" concept.
In 1954, the Food, Drug, and Cosmetic Act was amended to provide
for the establishment of tolerances or exemptions from tolerances for
pesticide chemicals in or on food crops. The amendments also provided for
the establishment of a tolerance "at zero level" if data showed that no
detectable residues were present in the treated crop at the time of
harvest. In 1965 the National Research Council of the National Academy of
Sciences recommended that the "no residue-zero tolerance" concept be
abandoned. This recommendation was based on the fact that this concept, as
applied in the registration and regulation of pesticides, had become
scientifically and administratively untenable. Among the reasons given by
the council were that analytical methodology had improved, and that small
levels of pesticide residues had become detectable (Pesticide Residues
Committee Report on "No Residue" and "Zero Tolerance", NAS-NRC, June 1965).
In 1966 the OSDA began to phase-out this concept (FR April 13-,
1966). Registrants of products under this concept were given (through a
series of 1 year extensions) until 1971 to convert the "no residue"
tolerances to finite tolerances.
The Council also recommended that pesticides previously regulated
under the "no residue* concept be regulated on the basis of "negligible
residue" tolerances. These tolerances could be established by supplying a
limited amount of data. It was concluded that a negligible residue is the
amount which will produce no effects in test animals, which (effects) are
1-3
-------
indistinguishable from control animals. The tolerance, in many cases, may
reflect the sensitivity of the method and require only two 90-day
(subacute) animal studies. Such was the case when the tolerance for
negligible residues was established for diallate.
During the phase-out period, Monsanto filed a petition (PP
7F0607) requesting a tolerance of 0.3 ppm on corn, forage legumes, lentils,
peas, potatoes, safflower, and sugar beets. That petition was subsequently
withdrawn and a second petition was filed (PP 9F832) requesting a tolerance
for negligible residues of 0.05 ppm on the above crops. Tolerances for
negligible residues of diallate were established in or on the above raw
agricultural commodities on July 28, 1971 (40 CFR 180.277).
On May 31, 1977, the Agency issued in the Federal Register (42
FR 27669) a notice of rebuttable presumption against registration and
continued registration of pesticide products containing diallate.
Diallate: Position Document 1, published together with the RPAR notice,
explained the background and supporting data for the presumption of risk
cited in the RPAR notice.
Following the publication of the RPAR notice, Monsanto Company
requested and was given a 60-day extension of the rebuttal period. The
extension was granted to all registrants and interested parties.
K. Basis for the Rebuttable Presumption
The rebuttable presumption against registration and continued
registration of pesticide products containing diallate was issued on the
basis of oncogenic effects in test animals as a risk criterion [40 CFR
162.11 (a)(3)]. Specifically, the presumption was based on the following
three long-term feeding studies which indicated that diallate is poten-
tially oncogenic: 1) a National Cancer Institute (NCI) Ulland et al.,
1973) rat study (Litton Bionetics), 2) an Industrial Bio-Test (IBT)
(Keplinger. 1976a) rat study (sponsored by Monsanto Company), and 3) an NCI
mouse study (Xnnes et al., 1969).—
Data from the rat study conducted by Ulland and coworkers at
Litton Bionetics were verified by the MCI and reviewed by the EPA
Carcinogen Assessment Group (CAG). The GAG concluded that the Litton
Bionetics study showed a statistically significant increase in malignant
tumors at the highest dose in male rats and in carcinomas at the higher
dose in female rats.
Industrial Bio-Test concluded from its rat study "that the
neoplastic lesions noted in the test and controls were considered normal
for rats of this age and strain." In its evaluation, the CAG concluded
that "the Industrial Bio-Test study in rats showed a statistically
significant excess of mammary carcinomas in females."
1-4
-------
The GAG also concluded that the mouse study conducted by Innes
and coworkers showed an increased incidence of liver-cell and pulmonary
tumors* This study was the basis for the Mrak Commission Report recommen-
dation that human exposure to diallate be minimized because there was
evidence of tumor induction in mice*
Respondents were given an opportunity to rebut the presumption
against diallate by showing (1) that the Agency's initial determination of
risk was in error, or (2) that given current use patterns, exposure to
diallate is not likely to result in any significant chronic adverse effects
[40 CFR 162.11(a)(4)]. Respondents were also invited to submit evidence on
behalf of the social, economic, and environmental benefits of the use of
the pesticide [40 CFR 162.11(a)(5)(iii)].
1-5
-------
II. Analysis and Assessment of Risk
A. Analysis of Rebuttal Arguments - for Oncogenicity
The Agency has analyzed the rebuttal-comments submitted to it in
response to to the presumption of oncogenicity— and responded to these
comments in *•*»*« section. From the analysis of rebuttal comments, the
Agency has concluded that the oncogenic presumption against diallate has
not been rebutted and that humans are subj ect to the risk of developing
cancer from the use of diallate.
1. Rebuttal Pertaining to national Cancer Institute (NCI) Rat
Study (Litton Bionetics)
a. Errors in Tabulated Data
Monsanto Company ncted errors in the data cited in the
EPA1s Carcinogen Assessment Group (CAG) (Albert, 1979) report and in
rebuttal presented a retabulation of the raw data (Monsanto Co.,
#1A[30000/15]).
The Agency acknowledges Monsanto's rebuttal on this
point. The CAG has re-evaluated the raw data and has"" corrected its report
accordingly. However, these corrections do not change the Agency's
interpretations of the study.
The CAG's revised tabulation of the data (shown in
Tables II-1 and IX-2) differs somewhat from the data presented by Monsanto.
Most of these differences are due to the classification of gliomas and
leukemias as sarcomas by the CAG and as carcinomas by Monsanto. These
differences in classification are unimportant since the Agency bases its
regulatory decisions on oncogenic risks which include all tumors (Albert,
1979a).
b. Statistical Difference in the Malignant Tumors in Males
Monsanto Company contended that according to their
analysis of the data, there is no statistical difference in the number of
malignant tumors in the diallate-treated male rats (both dose groups
combined) compared to pooled controls (13/52 treated vs. 11/64 controls,p *
.21). Monsanto asserted further that there is no statistical difference in
the number of malignant tumors or of sarcomas in either treated group of
male rats (high or low dose) as compared to control groups (Monsanto Co.,
t1A[30000/1S]).
The respondent acknowledged an increased incidence of
carcinomas in the high-dose male group as compared to the controls, but
submitted that the incidence in the low-dose male group was not different
from either control group (Monsanto Co., #1A[330000/15]).
2/ In addition to the above-mentioned rebuttals, the Agency received
16 responses pertaining to the benefits of diallate. Comments
submitted on benefits are addressed in Section III, "Benefit Analysis."
II-l
-------
Table II-1. Nd Rat Study, Incidence of Malignant Tumors in
Hale Bats Ingesting Avadex (Diallate)—
Comparison of Low- and High-Dose Groups to Pooled Controls
NO. of Bats with No. of
Pooled Control
Low Dose
High Dose
4/64
3/26
4/26
(6%) .
(12%)^
(15%)
7/64
1/26
4/26
(11%)
(4%)
(15%)
11/6,4
4/26
10/26
(17%)
(15%)f/ /
(38%)-
* Revised GAG tabulation. (Albert, 1979a)
—. Gliomas and leukemias were counted as sarcomas.
G/
—' Rats with carcinomas did not have sarcomas.
^. Corrected for survival.
—' Two of these rats with carcinomas had metastases (carcinomas of the
prostate metastatic to lung and lymph nodes; islet cell carcinomas of
. . the pancreas with metastases to the heart).
— The tumor incidence in the high dose group compared to the pooled
control group is statistically significant (p - .032) (Fisher Exact
. Test).
** The total incidence of 10/26 includes 2 unclassified malignant
tumors in the subcutaneous tissue.
II-2
-------
Table II-2. NCI Bat Study, Incidence of Malignant Tumors In
Female Bats Ingesting Avadex (Diallate)—
Comparison of Low- and High-Dose Groups to Pooled Controls
No. of Bats withNo. of Rats,withTotal No. of Rats
Carcinomas Sarcomas— with Malignant TumorsS/
.
Pooled Control
Low Dose
High Dose
3/64 (5%}.y
2/26 (8% J-2'
5/26 (19%)-'
4/64 (6%)
2/26 (8%)
0/26 (0%)
7/64 (11%)
4/26 (15%)
5/26 (19%)
* Revised GAG tabulation. (Albert, 1979a).
—, Gliomas and leukemias were counted as sarcomas.
— Rats with carcinomas did not have sarcomas.
d/ .
— The two rats with carcinomas of the mammary gland had aetastases to
. the lungs.
-f The tumor incidence in the high dose group compared to the pooled
control group is statistically significant (p - .042) (Fisher Exact Test)
n-3
-------
The Agency rejects Monsanto's rebuttal on this point.
The GAG analyzed twv incidence from each treatment group individually,
whereas Monsanto Company combined the data from the high- and low-dose
groups and in combining the data the significance found in the high dose
group was masked* The GAG re-evaluation of the data demonstrated a statis-
tically significant increase in total malignant tumors in male rats of the
high-dose group as compared to pooled controls (10/26 treated vs.11/64
controls; p - .032) (Refer to Table 11-1} (Albert, 1979a).
c. Statistical Significance of Carcinomas, Sarcomas,
and Total Malignant Tumors in Females
From their analysis of the data on female rats,
Monsanto Company concluded that there is no statistically significant
increase in carcinomas, sarcomas, or total malignant tumors in either
treated group (Monsanto Co., *1A[30000/15]).
The Agency rejects this rebuttal attempt. From the
CAG's revised tabulation of the data, it is apparent that there is a
statistically significant increase of carcinomas in the female rats of the
high-dose group as compared to pooled controls (5/26 treated vs. 3/64
controls; p * .042). (Albert, 1979a.) (Refer to Table II-2.)
d. Low number of Tumors in High-Dose Male Rats
Monsanto Company asserted that the number of tumor-
bearing rats in each diallate-treated group is lower than in either control
group, and emphasized that the high-dose group has the lowest number of
animals with tumors (Monsanto Co., #1A[30000/1S]).
The Agency rej ects this point of rebuttal. The number
tabulated by the GAG for the controls was 11/64 (17%) as compared with 10/
26 (38%) and 4/26 (15%) in the high-and low-dose male groups, respectively.
The individual numbers of animals possessing tumors is not relevant. The
appropriate comparison is the percentage of animals which have tumors. The
percentage of animals with tumors in the high-dose group is statistically
greater tfa*n the percentage of animals with tumors in the control group.
(Albert, 1979a.)
e. No Apparent Effect of Diallate on the Formation of
Individual Tumor Types
Monsanto contended that an evaluation of individual
tumor types/sites is necessary to conclude that a compound is carcinogenic,
and that there was no apparent effect of diallate on the formation of
individual tumor types (Monsanto Co., #1A[30000/15]).
The Agency rejects this rebuttal attempt. Although
there was no statistically significant incidence of individual tumor types,
there was a statistically significant increase of total malignant tumors in
rr-4
-------
male rats of the high-dose group relative to pooled controls. Moreover,
there was a statistically significant increase of carcinomas in female rats
of the high-dose group compared to pooled controls. The use of total tumor
data in evaluating carcinogenicity is discussed in a recent Interagency
Regulatory Liaison Group (IKLG) document as follows:
"At the present timn there is considerable
uncertainty about the interpretation of carcinogenic
responses in terms of the total tumor yield in contrast
to the response in terms of a statistically significant
increase of tumors in specific target organs or
tissues. Traditionally, carcinogens have been
recognized in human and aT•*m*"* studies by a decisive
increase in tumors of target organs. However, it is
conceivable that a generalized increase in total tumor
yield, in the absence of an excess incidence in one or
more target tissues', could occur, for example by a
promoting effect that generally increases the
spontaneous incidence of tumors in test animals or by
the action of a multipotent carcinogen whose response
did not reach statistical significance in any one organ
even at the maximum tolerated dose.— "
2. Rebuttal Pertaining to Industrial Bio-Test (1ST) Rat
Study (Sponsored by Monsanto Co.)
The existing registrations and tolerances for diallate were
established and supported by data contained in studies conducted by
Industrial Bio-Test Laboratories (IBT) for Monsanto.
In 1977, subsequent to the publication of Position Document
1, the Agency, in the Office of Pesticide Programs, established a
Toxicology Data Audit Program (TDAP) to assure the reliability and
integrity of data supplied to the Agency by pesticide manufacturers. These
data are the integral component of the information upon which pesticides
are registered and tolerances are established in the United States.
Industrial Bio-Test Laboratories (IBT) was one of the
initial laboratories audited jointly with the Food and Drug Administration.
The IBT laboratory performed a large volume of testing utilized by the
Agency in its regulatory decision-making. During an audit at the facility,
numerous significant departures from acceptable laboratory practice were
noted. As a result, the Agency decided to reevaluate all pivotal IBT
studies used in support of tolerances. The workload of this evaluation
program was shared with the r*-n»M an Government in cases where chemicals
were registered on identical data bases. The IBT studies for diallate were
evaluated by Canada and the results are shown in Table II-2a.
3/ IRLG (February 6, 1979), Scientific Bases for Identifying Potential
Carcinogens and Estimating Their Risks.
IX-5
-------
Table II-2a. Diallata 1ST Studies
Type of Study
1ST Ho.
Status
Remarks
Fish & Wildlife
8-Day LC Mallard Duck
8-Day Dietary LC-Q Bob-
white Quail
8-Day Dietary LC_0 Bob-
white Quail
8-Day Dietary I»C-Q Bob-
white Quail
4-Day Fish Tox
Fish & Wildlife
Fish & Wildlife
Fish & Wildlife
Acute Studies
4-week Pilot oral study
Pilot feeding study/mice
Acute Inhalation
Acute cholinesterase
651-3026
J-6672
J-6673
651-3025
Valid
Valid
Valid
Valid
665-3027
A-6675
A-6674
A-6849
8531-9714
8532-9820
59-13-3
8530-9030
Valid
Invalid No raw data
Invalid No raw data
Invalid No raw data
Valid
Invalid Incomplete raw data
Invalid No raw data
Valid
II-6
-------
Table II-2a. (continued).. Diallate IBT Studies
Type of Study .
Subacute Studies
Subchronic oral
Subchronic oral
Subchronic oral
Subchronic oral
IBT Ho.
59-13A
59-13-2
59-13
59-13-1
Status
Invalid
Invalid
Invalid
Invalid
Remarks
No raw data
Ho raw data
Ho raw data
Ho raw data
Chronic Studies
Teratogenicity/rabbits 651-5254 Invalid
Mutagenicity/mice 622-5252 Invalid
Heurotoxicity/chicken 85 80-9119 Valid
Heurotoxicity/chicken 8580-10813 Invalid
Chronic feeding/rats 622-5250 Invalid
Deficiencies in
experimental
design
Ho raw data
Ho raw data
Incomplete raw
data
II-7
-------
TDAP Evaluation of 1ST Rat Study
The IBT study sunitted by Monsanto was evaluated by the
Office of Pesticide Program's Toxicology Data Audit Program (TDAP). The
analysis of the study indicates that the 2-year feeding study is invalid
because of the lack of histopathology data, food consumption data, organ
weight data on surviving animals, and dietary preparation data to show
unequivocally that doses were correctly prepared. Therefore, no scientific
conclusions can be drawn from +h±* study.
•« Errors in Tabulated Data
Monsanto observed errors in the data cited in the GAG
report and in their rebuttal submitted a retabulation of the raw data.
Monsanto contended there are no statistically significant differences in
the number of animals with tumors in the diallate-treated groups as
compared to the controls (Monsanto Co., #1A[30000/1S] ) .
The GAG has re-evaluated the raw data and has corrected
its report accordingly. The revised GAG tabulation (shown in Tables II-3
and 11-4} now agrees with the retabulation submitted by Monsanto Company.
The data indicate that there is no statistically significant increase
either of total tumors (benign and malignant) or of tumors of any
anatomical site in any diallate-treated group of male rats as compared to
controls.
As Table II-5 indicates, however, female rats treated
with 100 ppm diallate (middle dose) showed a statistically significant
increase of benign mammary tumors (p » .021) and hence of total mammary
gland tumors (Albert, 1979). Therefore, the last portion of this rebuttal
is rej acted.
b. Ho Statistical Increase in Mammary Tumors
The incidence of mammary tumors in diallate-treated
female rats is shown in Table II-5. Monsanto Company pointed out that
there was no statistically significant increase in the number of mammary
tumors in the treated female rats of the high- or low-dose groups as
compared to the controls. The respondent argued that the admittedly
statistically significant increase in mammary tumor among the middle-dose
groups represents a random event, since there was no dose response.
Monsanto pointed out further that there is no statistically significant
increase of mammary carcinomas. (Monsanto Co., f 1A[30000/15] )
As Monsanto noted, the female rats of the middle dose
group exhibited a statistically significant increase of total mammary
tumors (p - .021), which was attributable to the statistically significant
increase in benign mammary tumors (p - .021). This increase of benign
mammary tumors in the middle-dose group may indicate an adverse effect,
although the possibility that this response may be a random event cannot be
11-8
-------
Table II-3. 1ST Bat Study, Incidence of Benign and Malignant
Tumors in Male Rats Ingesting Diallate--
Dose Group
No. of Bats with
Benign Tumors
Mo. of Bats with
Malignant Tumor:
a/c/
Total No. of Bats
with Tumors
Control
50
100
200
1/50 (2%)
0/50 (0%)
2/49 (4%)
1/50 (2%)
4/50 (8%)
7/50 (14%)
4/49 (8%)
6/50 (12%)
5/50 (10%)
7/50 (14%)
6/49 (12%)
7/50 (14%)
*/ Revised GAG tabulation (Albert, 1979a).
— . Rats with endocrine tumors are not included.
— Rats with both benign and malignant tumors were tabulated as having
malignant tumors. •
n-9
-------
Table II-4.
ZBT Rat Study, Incidence of Carcinomas Ȥd. / /
Sarcomas in Male Rats Ingesting Diallate-'-'-'
MO. of Rats with
Dose Group
No. of
Sarcoma
with Total No. of Rats
with Malignant Tumors^/
Control
50
100
200
0/50 (0%)
3/50 (6%)
1/49 (2%)
2/50 (4%)
4/50 (8%)
4/50 (8%) .
3/49 (6%)-/
4/50 (8%)
4/50 (8%)
7/50 (14%)
4/49 (8%)
6/50 (12%)
-' Revised GAG tabulation (Albert, 1979a).
— Table II-4 is an elaboration of Total Malignant Tumors column in
. Table II-3.
—' Rats with endocrine tumors are not included.
— Rats with both benign and malignant tumors were tabulated as having
e/
malignant tumors.
One rat had metastatic fibrosarcoma to the lung and liver, another
to the lung. Mo primary sarcomas were found in the two rats.
H-10
-------
unequivocally refuted (Albert, 1979a). However, the high percentage of
test ««^"«i« with tumors in the high dose group strongly suggests that
there is an adverse effect.
c. Spontaneous Pituitary Adenomas
Monsanto Company pointed out that there is a high
spontaneous incidence of pituitary adenomas in the 1ST rat study. The
respondent pointed out further that there is no apparent significant
increase in the incidence of this tumor in any treated group, nor any
linear increase by dose observed (Monsanto Co., f 1A[30000/15] ) .
The Agency agrees with 'this conclusion (Albert, 1979).
3. Rebuttal Pertaining to the NCI Mouse Study (Innes Study)
a. Study Invalid
Monsanto Company claimed that the Innes study is
invalid for the following two reasons:
1) Only one dose level, the "QiHtnvm tolerated dose
(MID), was used in the study. The rebuttal contended that the MTD has been
redefined, thereby making the doses used in the study higher than what is
now considered the MTD and invalidating the experiment.
2) The experimental design necessitated the dosing
of litter-mates. The rebuttal contended that biological and statistical
significance cannot be drawn from this inferior experimental design.
Monsanto suggested that a bias of inherited tendencies (e.g., predisposi-
tion to hepatoma formation) cannot be eliminated because the litter mates
were not randomly distributed among the test groups (Monsanto Co.,
*1A[30000/15).
The Agency rejects this rebuttal argument.
Concerning Monsanto 'S point 1) above, the Agency points out that the MTD is
defined in the NCI Guidelines as "...the highest dose of the test agent
given during the chronic study that can be predicted not to alter tlje.
animal's normal longevity from effects other than carcinogenicity."-
Innes et al. reported that the MTD was
selected on the basis of a series of studies in which the maximal level
given in a-single dose, in 6 daily and in 19 daily doses, resulted in zero
mortality .-
—' NCI Guidelines for Carcinogen Bioassay in Small Rodents, NCI Tech.
Report Ser. No. 1, Feb., 1976, p. 14. U.S. Dept. of Health, Education
and Welfare, PHS, NIH, NCI-CG-TR-1.
£/ Innes, J.R.M. et al (1969) Bioassay of Pesticides and Industrial
Chemicals for Tumorigenicity in Mice: A Preliminary Note. J. Nat.
Cancer Inst. Vol. 42, p. 1102.
n-ii
-------
Table II-5. IBT Bat: Study, Incidence of Benign and Malignant Tumors of
the Mammary Gland in Female Rats Ingesting Diallate^
Dose Group (ppm)
Ho. of Rats with
Benign Tumors-
No, of Rats with
Malignant Tumors
Total No. of Rats
with Tumors
Control
50
100
200
14/50 (28%)
19/49 (39%)
24/48 (50%)
15/46 (33%)
5/50 (10%)
4/49 (8%)
5/48 (10%)
10/46 (22%)
19/50 (38%)
23/49 (47%) ,
29/48 (60%)-
25/46 (54%)
~. Revised GAG tabulation (Albert, 1979a).
— Rats with both benign and malignant tumors were counted as
. malignant.
— The tumor incidence in the 100 ppm dose group compared to the
control group is statistically significant (p » .021) (Fisher Exact Test).
11-12
-------
A comparison of the survival data in the carcino-
genicity study indicates that the number of 18-month survivors in the
diallate-treated groups was similar to that of the vehicle (0.5% gelatin)
and untreated control groups for each respective species/sex. Hence the
doses given in the study were tolerated by the treated animals and
therefore did not exceed the MTD.
In reference to Monsanto's point 2) above, Innes
administered diallate to mice (in 0.5% gelatin) by stomach tube from 7 days
to 4 weeks of age. Thereafter, the mice were weaned and were given
diallate (without a vehicle) in the diet. Since the study began prior to
weaning, each test group (e.g., diallate-treated, positive or negative
control group) was comprised of litter-mates instead of a random assortment
of litter-mates, which was precluded by the study design.
Darin? the MRAK Commission review of this study,
which recommended that human exposure to diallate be minimized,— Mr.
Carrol Weil presented a dissenting opinion which included criticism of the
non-random allocation of animals. Monsanto cited Mr. Weil's criticism in
its rebuttal.
In response to Mr. Weil's criticism on non-
randomization, the MRAK Commission reported that "...the data were
reexamined on a litter basis, in keeping with the Epstein-Mantel approach,
rather than on the single-animals basis employed in the Journal of the
National Cancer Institute report. All compounds which had been judged
positive for tumor ^nduction (significant at the 0.01 level, or stronger),
remained positive.*— Thus, although non-randomization of litter-mates
is not the optimal experiment design, there is no evidence in this study
that a bias existed for a gene-tic predisposition to tumor occurrence
(Albert, 1979a).
b. Sex Specificity—Increased Hepatomas in Male Mice
Monsanto Company acknowledged the statistically
significant increase in hepatomas in male mice in the Innes study, but
contended that the apparent sex-specificity is unusual (Monsanto Co.,
f 1A[30000/15]).
The Agency rejects this rebuttal point. The data from
the Innes study indicate a statistically significant increase in hepatomas
in both strains of male mice when compared with either their respective
matched (vehicle) control, negative control, or pooled negative control
6/
— Report of the Secretary's Commission of Pesticides and Their
Relationship to Environmental Health, Parts I and II. U.S. Dept. of
Health, Education and Welfare, Washington, D.C. (1969), p. 470.
-' Ibid p. 483.
n-13
-------
groups; and a statistically significant incidence in female mice of strain
X when compared with the pooled negative control group only. Contrary to
Monsanto'a assertion, hepatic tumors are known to occur more frequently in
male mice th*n in females.- (Albert, 1979a).
c. Mo Statistically Significant Increase in Pulmonary
Adenomas
Monsanto Company argued that there was no statistically
significant increase in pulmonary adenomas in either sex of either strain
of mouse, whereas the GAG report indicated a small statistically
significant increase of lung adenomas in both sexes of strain X and in
males of strain Y (Monsanto Co., #1A[30000/15]).
The Agency rejects this point of rebuttal. Having re-
analyzed the data, the CAG finds a borderline statistically significant
increase of pulmonary adenomas in the diallate-treated males of strain X as
compared with the matched (vehicle) control group (p - .051) and with
the pooled control groups (p • .041). (See Table II-6) (Albert, 1979a).
B. Analysis of Data Submitted Since PD 1 for Other Possible
Adverse Effects
1. Mutaqenicity
In PD 1 the Agency, based on the two available studies,
stated that it had insufficient data to indicate diallate is mutagenic.
The two studies were one, an Ames test in bacteria, and the second, a
dominant lethal study in mice (Keplinger 1974). On the basis of this
conclusion, the Agency requested comments and information on diallate's
mutagenic potential. Additional studies were submitted and evaluated, and
the Agency now concludes that diallate meets the criteria stated in 40 CFR
162.11 for mutagenicity by multi-test evidence. The additional studies
which led to the Agency's finding are discussed below.
In response to the Agency's request for additional
information with regard to the possible mutagenic properties of diallate,
Rinkus and Legator (1977) submitted a study entitled "Mutagenicity of
Diallate." This study, an Ames test, investigated the mutagenic effects of
diallate in five strains of Salmonella. Diallate exhibited mutagenic
activity in strains TA 1535 and TA 100 which exceeded the mutation
frequency of controls by factors of approximately 20 and 12 respectively.
This activity was only observed in the presence of a microsomal activation
system. No activity was observed in strains TA 1537, TA 1538, and TA 98 in
identical tests.
Stewart, H. L. (1976). Comparative aspects of certain cancers.
Chpt. 10 in Cancer, A Comprehensive Treatise, Vol. 4, P. F. Becker
(ed.), Plenum Press, Mew York.
n-14
-------
Table II-6. NCI Mouse Study (Innes Study)> Lung Tumors in Mice
Ingesting Avadex (Diallate)
Dose
Group
Strain X
Strain Y
Male
Female
Male
Female
Pulmonary Adenoma Matched Control
Pulmonary Carcinoma
0/16*(0%) 0/16 (0%)2/18 (11%) 1/17(5%)
0/16 (0%) 0/16 (0%)0/18 (0%) 0/17(0%)
Pulmonary Adenoma Negative Control
Pulmonary Carcinoma
2/17 (12%) 1/18 (5%)2/18 (11%) 0/17(0%)
0/17 (0%) 0/18 (0%)0/18 (0%) 0/17(0%)
Pulmonary Adenoma Pooled Control
Pulmonary Carcinoma
5/79**(6%) 3/87 (3%)10/90(11%) 3/82(4%)
0/79 (0%) 0/87 (0%) 0/90 (0%) 0/82(0%)
Pulmonary Adenoma 560 ppm
Pulmonary Carcinoma
4/16 (25%) 2/16 -"
Ul
* p » .051 (Fisher Exact Test) for the Incidence of pulmonary adenomas in
the treated group compared with the matched control.
** p m .041 (Fisher Exact Test) for the incidence of pulmonary adenomas in
the treated group compared with the pooled control.
-------
In PD 1 an unevaluated study by Sikka and Florczyk (1978)
was mentioned. The study investigated the ability of diallate to induce
nutations in four strains of Salmonella typhimurium (TA 100, TA 1535, TA
98, and TA 1538) with and without a rat-liver microsomal activation system.
The study has now been evaluated and found to show activity at the 1 ug per
plate level in the TA 100 and TA 1535 strains indicating base-pair substi-
tutions with metabolic activation. Diallate did not cause nutation in
strains TA 98 and TA 1538 (frameshift mutants). These results confirm the
findings of Rinkus and Legator.
Litton Bionetics, Inc. (LSI) (Brusick, 1977b) investigated
the effects of diallate in the L5178Y mouse lymphoma cell. The study
concluded that "The test compound, CP 15336, induced forward mutation at
the TK locus in L5178Y mouse lymphoma cells in the presence of an uninduced
mouse liver S-9 metabolic .activation system.* No dose-related effects were
observed in the absence of metabolic activation.
Studies by SRI International (Simon, 1978) for EPA show that
diallate does not induce gene mutation in Z^ coli (WP2). The bioassay was
designed to monitor induced genetic alteration in E. coli at the tryptophan
locus. However, tests in ]S. coli are not as sensitive as tests in
Salmonella and, therefore,"positive findings may not be manifested through
experiments in this organism (Sandhu, 1978).
Diallate's potential to cause primary DNA damage was studied
in two strains of Saccfaaromyces cerevisiae. SRI International (Simon,
1978) employed strain D, to measure induced mitotic recombination and LBI
(Brusick, 1977a) used strain D. to measure gene conversion. While posi-
tive results were reported for mitotic recombinations in the SRI study, the
iai study results were negative. However, this mixed finding does not
detract from the finding of induction of mitotic aberrations, a supportive
finding for mutagenesis.
Monsanto submitted a dominant lethal study in mice in 1975
(Xeplinger, 1974). This study done by 1ST was reported by Monsanto as a
negative study. The TDAP program reviewed this study and found it to be
invalid because of the lack of raw data.
2. Neurotoxicity
The Agency concluded in the PD 1 that diallate is neurotoxic
at the dose levels tested. This conclusion was based on an IBT study in
chickens (Keplinger, 1976b). That study did not provide a dose-response
relationship nor a no observable effect level which is needed to determine
a margin of safety.
In the diallate PD 1, published on May 31, 1977,
registrants were given 180 days to complete appropriate neurotoxicity
studies and submit the results to the Agency or face possible cancellation
under the provisions of FIFRA Section 6(b)(1)— . Monsanto submitted an
— In 1978 FIFRA was amended to provide for suspension under Section
3(c)(2)(B).
11-16
-------
1ST study in which diallate was administered to chickens—' at dose
levels ranging from 0.01 to 0.32 gmAg which were administered twice daily
for 3 consecutive days (Phillips, 1977). Twenty days following the initial
dose, alX surviving birds were again given the same dose regimen. Controls
were dosed with 0.32 got/kg corn oil and positive controls received 500 mg/
kg TOCP on day 0.
All positive controls exhibited lesions typically associated
with delayed neurotoxicity (Phillips, 1977). No such lesions were found in
the negative controls.
Two test birds, one in the 0.04 gmAg and one in the 0.16
gmAg group showed focal lesions of axonal degeneration and secondary
demyelination in the sciatic nerve. While these lesions were described as
morphologically indistinguishable from those observed in the positive
control birds, the affected birds showed no clinical signs which could be
characterized as delayed neurotoxicity prior to sacrifice. Ho dose
response relationship was established nor were there any reasons given for
the absence of lesions at the highest dose.
Both of these IBT studies were reviewed by the TDAP. The
original study, discussed in PD1, was validated and therefore does demon-
strate that diallate given at 312 mgAg causes neurotoxic effects. How-
ever, as stated in TO 1, this study does not show any dose response with
which to determine ultimate safety. The second IBT study on neurotoxicity
was declared invalid. TDAP found that raw data were totally missing on
this experiment.
The Agency1s concerns on neurotoxic effects of diallate have
not been addressed by the registrant. While attempting to satisfy the
needs of EPA, Monsanto has failed to take adequate precautions to insure
validity of their data. Therefore, although the Agency does not have
enough data to quantify the potential neurotoxic risks of diallate, it has
calculated the annual applicator exposure. The Agency has determined that
the effect level is 600 times greater than the exposure level.
3. Reproductive Effects
Prior to the RPAR review the Agency requested Monsanto to
perform a 3-generation reproduction study in rats. However, no time limit
was imposed on the registrant. At the time of PD 1 only the data in the
F° (parental) generation had been submitted. The final report is
expected in 1980. This study will be evaluated by the Agency and its
results will be included in PD 4.
— The study used 5 birds per dose group with dose given at 0.01,
0.02, 0.04, 0.08, 0.16, and 0.32 gmAg.
H-17
-------
C. Exposure Analysis
The Agency analyzes, exposure to a pesticide as part of the
overall risk assessment. The complete exposure analysis includes
incremental exposures to various populations depending on the route of
exposure (e.g. dietary exposure to the general population, occupational
exposure to applicators, drift to farm families, etc.). In compiling the
analysis, the Agency takes into account the use patterns and methods of
application so all populations likely to receive exposure are included in
the analysis.
1. Spray Applicator Exposure
a. Spray Applicators
Information concerning spray applicator exposure was
provided by the Environmental Fate Branch of the Agency's Hazard Evaluation
Division (BED) (Selim, 1978). Diallate is applied primarily as an emulsi-
fiable concentrate with ground equipment by boom sprayer. Spray applica-
tors are exposed to diallate by 1) dermal exposure during the loading of
the sprayer *i\* during the application process, and 2) inhalation of the
volatilized compound.
Exposure from diallate has not been measured, conse-
quently the Agency used published data on triallate to prepare exposure
analysis for diallate (the mode of application and chemical-physical
properties of triallate are similar to diallate). To further check these
results, the Agency validated the assumptions used for diallate by an
exposure analysis which was published for paraquat. The pattern of
exposure to paraquat is similar for the applicator working with diallate.
Therefore, the Agency felt justified in utilizing the paraquat data for
extrapolation to diallate. Both of these extrapolations produced very
similar results.
The estimated dosages were reported in mg/hr, then
converted to mg/kg/year. The conversion from dermal exposure expressed in
mgAg/year to equivalent lifetime dietary exposure expressed in ppm in the
diet is as follows:
X » 60 kg (worker dermal exposure in mg/kg/yr) x 40 yr
365 d/yr x2?0 yr x 1.5 kg/d
* 6.26x10 x (worker dermal exposure in mg/kg/yr)
m lifetime dietary exposure in ppm
where X is ppm in diet, 60 is average body weight in kg, and 1.5 kg is the
average daily dietary intake. A 40-year working history and a 70-year
lifetime is assumed for the applicators. This value (X) will be used to
calculate lifetime probability in the Risk Assessment Section (II.0.1).
11-18
-------
Table II-7 presents data on the absorbed dose in mg/kg/
year and parts per tiHii-jrm for spray applicators exposed to diallate.
Rubber gloves and coveralls were considered as protective clothing when
calculating the exposure reduction levels.
The annual exposure to applicators of diallate is 0.516
agAg/y* (.0323 ppm) and 0.018 mgAg/yr (0.0011 ppm) from dermal and
inhalation exposure respectively (Selim, 1978). These estimates are based
on 10% absorption from both routes (Gardner, 1980). Based on the assump-
tion that dermal exposure would be reduced by a factor of 4 if protective
clothing is used, the dermal exposure level can be reduced to 0.13 mg/kg/yr
(8.1 x 10 ppm) (Selim, 1978).
b. Granular Applicators
An applicator's exposure from granular diallate
applications would be lower than an applicator's exposure using the
emulsifiable concentrate formulations. With the granular formulation there
is no chance of exposure from spray drift or from spray splash as there is
with the emulsifiable concentrate formulations. The granules do not
adhere to the skin as the emulsifiable concentrates would. Additionally,
because diallate is applied during the late fall or early spring in the
northwestern states, it is likely that most diallate applicators would be
wearing clothing such as long sleeved shirts and trousers to protect
themselves from the cold as well as protect themselves against the
diallate. However, for the brief period of loading the (pre-mixed)
granular diallate formulations there is a potential dermal and inhalation
exposure hazard to the applicator due to dust from the granules. To
mitigate this potential hazard, the Agency suggests the use of rubber gloves
and cloth face masks for applicators during the loading process.
2. Dietary Exposure
The human population encounters direct dietary exposure to
diallate residues through consumption of the following foods: barley,
lentils, peas, soybeans, sugar beets, corn (grain), and flax (seed).
worst-case exposure was developed from tolerances
established for residues of diallate in foods. The FDA, in its Market
Basket Survey, has not analyzed raw agricultural commodities specifically
for diallate. It is assumed that residues are present in all individual
raw agricultural commodities to the extent permitted by the tolerances and
that the commodities are uniformly distributed throughout the country.
Table II -8 presents the dietary exposure of the entire U.S. population to
diallate.
A second set of estimates were developed which were based on
available information concerning the percentage of crops treated and were
provided by the Agency's Benefits and Field Studies Division (Lewis, 1978).
Table II -8 presents the exposure estimates when the percentage of crop
treated is considered.
11-19
-------
D. Risk Assessment
1. Oncogenie Effects
The cancer risk assessment of diallate is based on the
principles and procedures outlined in the EPA interim cancer risk assessment
guidelines (41 FR 21402, May 25, 1976). These guidelines specify that a
substance will be considered a "presumptive cancer risk when it causes a
statistically significant excess incidence of benign or malignant tumors in
humans or animals." Current and anticipated exposure levels are appro-
priate considerations for establishing cancer risk estimates. These
estimates may be derived from a variety of risk extrapolation models such
as the log-probit and linear non-threshold models.
11-20
-------
Table II-7 Diallate Dermal and Inhalation Exposure to Spray
Applicators and Equivalent Lifetime Dietary Exposure
Estimated
Route of Dose
Exposure mq/hr
DEHMAL
Absence of
protective cloth-
ing (Assuming 2.58
10% dermal ...
absorption)—
With protec-
tive clothing
(Assuming 10% .65
dermal .
absorption )— —
INHALATION
Without mask .09
With mask
(10% of .009
exposure
without
mask)
Duration
of
Exposure
6-12
hr/yr.
6-12
hr/yr.
6-12
hr/yr.
6-12
hr/yr.
Dose
in
mg/kq/yr
.258
.516
0.065
.13
.009
.018
.0009
.0018
Dose in
ppm
-
2 x 10
3 x 10*
_3
4 x 10"
8 x 10"
6 x 10__
1 x 10
-5
6 x 10 .
1 x 10
1/ 10% absorption is assumed in absence of data on diallate (Gardner,
1980).
2/ Assuming that protective clothing provides a four fold reduction in
"" exposure. (Selim, 1973)
11-21
-------
Table II-8. Annual U.S. Population Dietary Exposure to Diallate, Based
On Tolerance Levels and Percent of Crop Treated
Exposure Based on
100% of Crop Treated
with Residues at
Tolerance Levels
Source
Percent of Crop
Treated with
Diallate
Exposure Based on Actual
Percent of Crop Treated
with Residues at
Tolerance Levels
pom
Barley
Lentils
Peas
Potatoes
Safflower*
Soybeans
Sugar beets
Corn, grain
Flax, seed
0.000013
0.00002
0.00035
0.00271
0.000013
0.00046
0.00001
0.0005
0.000013
0.10
38
10
0.46
100
0.20
14.3
0.009
3
0.00000
0.00001
0.00005
0.00002
0.00002
0.00000
0.00012
0.00000
0.00000
**
**
Total
0.004089
0.00022
* 100% is assumed in the absence of data .
** Mot actually "0", remaining significant figures truncated.
11-22
-------
In accordance with these principles, the EPA Cancer
Assessment Group (GAG) (Albert, 1979b) developed risk estimates based on
several different models and a range of exposure estimates. After
reviewing the data sources- and the preliminary risk estimates, the GAG
concurred in recommendations that the final quantitative risk estimates be
based on data from the MCI mouse study (Innes study) using the one-hit
model. The CAG used the Innes data because animals in the Innes study were
fed the compound beginning at a younger age *>»«« were animals in the. NCI
(rat.) or IBT studies, and therefore provided the most sensitive animal upon
which to base the conservative analysis.
To develop a risk estimate, CAG evaluated the animal test
data and the human exposure data using several different models. They
selected the one-hit model because it provided the most conservative
estimate of potential risk to humans.
As explained above, the animal bioassay data used for the
quantitative risk assessment were based on the Innes oral feeding study in
mice. In this study one treated group of mice were fed 560 ppm diallate in
the diet. A statistically significant higher incidence of hepatomas in
males of both strains X and Y was observed, as compared to matched controls
(see Table II-9).
The proportion of hepatomas observed in Strain X males was
used to calculate the slope parameter for the one-hit model, adjusting for
background tumor incidence. Therefore, using the proportion of hepatomas
in the matched control 97oup and the treated group, the one-hit slope
parameter is as follows:—
B - - In [(1-Pt)/M-Pc)] /y
B - - In [{1- 13/16)/(1-0/16)J/570
» 2.989. x 10
From the slope, the estimate lifetime probability can be estimated from
the following equation.
P » BX - (2.989 x 10~3)X
(where X is the ppm in the diet from actual exposure
and from equivalent dermal exposure as calculated in
Section II.C.1.)
— Where: B * slope coefficient of the one-hit model
P » (Pt-Pc)d-Pc)
PC * Incidence of hepatomas in control animals
Pt * Incidence of hepatomas in test animals
7 * Test animal exposure (ppm)
x * Potential human exposure (ppm)
11-23
-------
Table II-9. NCI House Study (Innes Study): Liver Tumors (Hepatomas) in
Mice Ingesting Diallata
Dose Group
Matched Control (vehicle)
negative Control
Pooled Control
560 ppm
Strain
X
Male Female
0/16*
1/17*
8/79*
13/16
0/16
0/18
0/87**
2/16
Strain
Male
1/18*
3/18**
5/90*
10/18
Y
Female
0/17
0/17
1/82
1/15
* Statistically significant when p is £ .01.
** Statistically significant when p is £ .05.
11-24
-------
The exposure estimates for dietary and applicator exposure
were factored into the above equation. Risks from these exposures.are
shown in Tables II-10 and 11-11. A dietary worst-case risk of 10
occurs at tolerance levels assuming that 100% of the crops are treated. It
is not likely that 100% of the crops will be treated with diallate. There-
fore using the projected percentages of treated crops from Section III,
results in a reasonable worse case risk of 10
Risk to applicators without protective clothing is estimated
at 10~ , a relatively high risk. With protective clothing, risk to
applicators is improved to 10 (Table 11-11).
Aggregated, these risks imply that 1 in 10,000 applicators
might have a lifetime risk of developing a diallate induced tumor taking
into account both occupational and dietary exposure. It is estimated that
there are 2380 diallate applicators (Selim, 1978). The general population
would have a lesser risk (10-7), but this is based on current usage and
should any increase in usage occur, the dietary risks would increase.
2. Mutagenic Effects
While adequate evidence exists to establish the mutagenicity
of diallate in in vitro systems, no quantitative assessment of risk can be
made because of (1) insufficient data from-mammalian test systems(Mauer,
1978), and (2) no generally applicable method has been developed to
quantify mutagenic risk.—— Recent studies have established £ strong
correlation between a chemical's carcinogenic potential and its ability to
induce mitotic recombination (Sandhu, 1978).
— The Agency has not yet developed a standard procedure for
defining mutagenic risk in quantitative terms. At the present
time, much attention is being focused on developing a battery of
test systems and other data that are predictive of mutagenic risk
in humans. Until such time as more quantitative methods and
procedures for risk estimation are developed for each mutagenic
endpoint of concern, the Agency will evaluate each mutagenic
chemical on a case-by-case basis, taking into account all
available test data. The approach taken by the Agency will of
necessity be conservative in order to assure that man and the
environment are protected from the risk of "unreasonable adverse
effects" through the action of mutagenic agents. The evolving
nature of methodology in the field of mutagenicity testing
dictates that the Agency will revise its risk estimation
procedure for future chemicals under evaluation as superior risk
predictive models and other relevant information become
available. As well, the Agency will revise its risk estimates
for chemicals which have previously been subjected to risk
assessments if additional more relevant test data and other
predictive information are developed.
11-25
-------
Table 11-10. Lifetime Spray Applicator Cancer Risk from Dermal and
Exposure to Diallate
Equivalent Lifetime
Dietary Dose Assuming
12 Hour *!«««« i Exposure Lifetime Probability of
Route (ppm)
DERMAL
Without protective 3 x 10~
clothing*
With protective
clothing (10% _3
absorption)* 8 x 10~
INHALATION
Without mask 1 x 10
With mask ( 10%
of exposure _4
without mask)* 1 x 10
Cancer Due to Diallate
1 x 10~4
2 x 10~5
3 x 10"6
3 x 10~?
* 10% absorption is assumed in the absence of data on diallate (Gardner
1980).
11-26
-------
Table 11-11. Cancer Risk to D.S. Population from Dietary
Exposure to Diallate
Source
Lifetime Probability
of Cancer Based on
100% of Crop Treated
Residues at Tolerance
Levels
Lifetime Probability
of Cancer Based on
Estimated Percent of Crop
Treated with Residues
at Tolerance Levels
Barley
Lentils
Peas
Potatoes
Safflower
-
Soybeans
Flax seed
Beet Sugar
Corn
Total
4
6
1
8
4
1
4
1
1
1
x 10~8
x 10~8
-6
x 10
X10-6
x 10~8
-6
x 10
-6
.9 x 10
-6
x 10
-6
x 10 *
X10-5
4 x ID'11
2 x 10~8
-7
1 x 10
-8
4 x 10
4 x 10~8
-9
3 x 10
Negligible
2 x 10~7
Negligible
4 x 10~?
11-27
-------
E. Risks Associated with Alternative Chemicals
Several chemicals have been proposed as alternatives should
diallate become unavailable. In non-irrigated areas, eptam would be the
major substitute with barban and dalapon used to a lesser extent. In
irrigated areas cycloate and barban are the major substitutes. Eptam and
barban are substitutes used on flax. Triallate, propham and barban are
alternative chemicals for use on lentils and peas.
The data bases for the alternative chemicals are not complete. A
complete list indicating the studies which the Agency has on hand appears
in Table 11-12. Based on the studies reviewed for all alternatives other
<-h»ti triallate, no unreasonable adverse effects were found associated with
the proposed alternatives. Because of the lack of chronic studies no quali-
tative ranking of alternatives can be made with regard to their relative
toxicities.
The battery of toxicological tests performed on triallate include
mutagenic, chronic feeding, teratogenic, and neurotoxic studies. Triallate
was found to exhibit mutagenic activity in the Ames test in bacteria with
metabolic activation. It was also found to be positive in yeast when
tested for mitotic recombination. Negative findings were reported to gene
conversion in yeast, mouse lymphoma, and dominant lethal assays. When
triallate is compared to diallate in tests which are positive for both,
diallate is at least 3 times more active.
Negative findings for triallate were reported in a chronic
feeding study in rats. This study was evaluated by TDAP and found to be
valid only as an oncogenic screen test because of deficiences in the
experimental design.
The teratogenic and neurotoxic studies on triallate were
performed by IBT. These studies were evaluated by TDAP and found to be
invalid.
11-28
-------
Table 11-12
TOXICOLOGICAL DATA SUMMARY FOR DIALLATE ALTERNATIVES (CHROMIC DATA)
CHEMICAL ONCOGENICITY
Trial late **Rat
Barban N/A
Cycloate N/A
Dalapon N/A
i EPTC*
NJ
i /\ 1 n_ 4_ _ __ \
MUTAGENICITY
Gene Conversion (-)
Mitotic Recom-
bination ( + )
Bacteria 4+ (with
activation)
2- (no activation)
Dominant Lethal (-)
Mouse Lymphoma (-)
N/A
N/A
N/A
CHRONIC REPRODUCTIVE
FEEDING TBRATOGENICITY EFFECTS
"Rat (-) Rabbit (Invalid) N/A
Dog (-) N/A N/A
Rat (-) N/A N/A
Rat (-) Dog (-) N/A
Rat (-)
NEUROTOXICITY
Chicken (2 Inval
Studies)
N/A
N/A
N/A
(+) Positive Study
(-) Negative Study
* EPTC has negligible residue tolerances, therefore no chronic data have been
submitted.
** This IBT study listed under "Oncogenicity" and "Chronic Feeding," was
reviewed by TDAP. While the study was considered invalid as a chronic
feeding study, it was found valid as an oncogenic screening study.
-------
III. Benefit Analysis
As a pre-emergence selective herbicide, diallate is used as a soil
treatment on field crops for control of wild oats. Because Monsanto is the
sole producer of diallate, production and marketing data are confidential.
However, it is estimated that approximately 390,000 pounds active
ingredient of diallate were applied annually to 319,000 acres of sugar
beets, flax, lentils, and peas, the major use sites of diallate between
1976 and 1978. Small amounts of diallate are also applied to potatoes,
soybeans, barley, corn, and forage legumes.—
The Agency has received 16 submissions from registrants and interested
parties pertaining to the benefits of diallate, in particular as it is used
on sugar beets, lentils, and peas. The Agency considered this information
in analyzing the benefits of diallate.
For sugar beets, flax, lentils, and peas, the estimates of acreage
treated, the identification of biologically viable alternatives, and the
use data were based primarily on Assessment of the Meed for Diallate in
Agriculture, USDA/State Assessment Team on Diallate (September, 1977, and
1979 modifications). The economic analysis based on these biological data
was prepared by Development Planning and Research Associates, Inc. in March
of 1979.
However, lack of published data on yield changes limited certain
aspects of the analysis. Expert opinion was used in place of these data.
Alternate weed control strategies also lacked firm data, necessitating the
use of expert opinion to generate impacts of alternate control programs
(USDA/State Assessment Team, 1977).
The alternatives to diallate were selected on the basis of cost,
efficacy, and availability. Partial budgeting was employed to assess the
economic impacts of diallate cancellation.— The partial budgeting
methodology allowed the change in the cost of weed control to be measured,
together with the effect on gross returns associated with substituting
alternative weed control practices while all other inputs were held
constant. The economic analysis also assumed that in some instances the
cancellation of diallate would cause growers to shift production to
alternative crops. In these cases, net returns to the producer associated
with the production of alternative crops were evaluated.
J/ The USDA/State Assessment Team on Diallate (August 31, 1977) esti-
~~ mated that approximately 10,000 acres or less of each of these crops
were treated with diallate annually, accounting for 0.5% or less of
the total crop planting in each case. The Monsanto submission filed
September 9, 1977, did not address the benefits of diallate use on
any of these minor crops.
2/ The partial budgeting methodology allows the measurement of the
change in the cost of pest control and the effect on returns associated
with substituting alternative chemical and non-chemical pest control
practices into the budget with all other inputs held constant.
III-l
-------
If the major uses of diallate on sugar beets, flax, peas, and lentils
were cancelled, varied effects on producers would result. Because an
acceptable substitute herbicide is available, peas and lentils would
actually return more inmff" to producers if diallate were cancelled. The
positive economic impact is based on increased yields which are due to a
decrease in phytotoxicity and better wild oat control in some instances,
see further discussion in Section III.C. Sugar beet producers would suffer
an estimated adverse impact of $4.0 million. Flax producers are expected
to experience an estimated $0.4 million economic loss. The net adverse
impact upon all affected user groups is approximately $3.2 million
annually.— These aggregate economic impacts are summarized in Table
IXI-1. The following subsections (A through E) briefly explain the
economic impacts involved should the major and minor uses of diallate be
cancelled.
A. Sugar Beets
Sugar beet production subject to wild oat infestation is located
in the non-irrigated acreage of Minnesota and North Dakota, and irrigated
acreage in Montana, Wyoming, Idaho, Utah, Washington, Oregon, and
California. As an average for the period 1976-1978, see Tables III-2 and
III-3, these nine states planted 995,000 acres of sugar beets annually or
72.6% of the U.S. total acreage. Of the nine-state total, 418,000 acres,
or 42%, were in Minnesota and North Dakota; 577,000 acres, or 58%, were in
the seven western states subject to wild oat infestation.
Diallate is a major herbicide used to control wild oats in sugar
beets. It is most widely used in non-irrigated acres. As an average
during the 1976-1978 period, diallate was estimated to have been applied to
185,175 acres of non-irrigated beets, and to 35,800 acres of irrigated
beets. In total, diallate was applied to 220,975 acres, or 22% of the
total sugar beet acreage subject to wild oat infestation.
Annual use of diallate to control wild oats in sugar beets, as an
average for the period 1976-1978, was estimated to have been 231,470 pounds
(active ingredient basis) in non-irrigated areas and 44,750 pounds in
irrigated areas. Total estimated use of diallate on sugar beets is thus
276,220 pounds.
Two formulations of diallate are used on sugar beets. Granular
diallate is applied to approximately 15% of the treated acreage while the
emulsifiable concentrate is applied to approximately 85% (Lewis, 1979).
The degree control of wild oats provided by each of these formulations
appears to be the same for the fall application. There is some decrease in
control of wild oats when the granular is substituted for the emulsifiable
concentrate in the spring application.
3/ This reflects an estimated 1.2 million net increase in revenues when
triallate is substituted for diallate where it is also registered for
these uses.
IXX-2
-------
Table III-1. Annual Economic Impact of Cancellation of Dial late
on the Maj or Use Sites -
H
H
H
A
Site
Sugar
beets
Flax
Lentils
Peas
Maj or use
total
Extent
of Use
( thousand
pounds )
276.2
38.4
43.3
30.4
388.3
Units
Treated
( thousand
acres)
221.0
30.7
43.3
24.3
319.3
Percent of Aggregate Economic Impacts
Total Units User Market & Consumer
(million (million dollars)-'
dollars)
16.7 4.0 loss none
3.0 .4 loss none
38.0 .7 gain none
10.5 .5 gain none
Total Market Value
(million dollars)
500
59
34
23.6
- Sourcei Economic Analysis of Effects of Restricting Use of
Diallate on Sugar Beets, Flax, Lentils, and Dry Peas.
Development Planning & Research Associates, Inc.
March, 1979.
-^ 1978 price levels
-------
Table Hl-2. Eatlaiated Annual aggregate MM coata Cot eliminating diallata on irrigated augar beat*, 1978-1978
H
H
Coati
Aaroe* Material Application Yield ioai** Other ooata
With dlallata
Without dlallata
Cycloate
Prophaa
Dalapon
Barban
Paraquat
Untreated
Hand weeding a/
Added cultivation to/
Delayed aaedlng
Shift to other crops
Cub-total w/o dlallata
Mat change w/o dlallata
• USDA/Stata aeaaaeaont Study,
•* Utea per acre Iron USDA/Stata
a/ Charge at (20 per acre, baaed
33.800
8.200
300
1.800
1,800
1,800
3,600
8,200
10,700
900
6,400
43,700
percentage of
(I)
223,940
192.336
3.960
8.262
20,318
36,000
»__
— _
-._
361,076
33.536
original acreage
Aasaeamer.ti Study, 1977. Sugar
on interview
information from
W
125,658
28.782
1,053
2.862
2,862
2,862
»_.
38,421
(87,237)
eatiMted
W III
—
167,132
43,660
42,660
122,860
133,100
663,350
164,000
129.418 27,713
42,660
1.632,000
1,343,840 1,843,713
1,343,840 1,843,713
to be treated with diallata.
Total coate
(1)
331.198
388.430
47,673
33,784
146.040
171.962
663,330
164.000
137.111
42.660
1,652,000
9,489.040
3,117,852
baeta valued at >23.70/ton.
augar boat
proceaaora.
b/ North Dakota Crop and Livestock Reporting Service. 1977.
-------
Tabla III-J. EatiiMted annual aggregate uaac Impacta for alienating dlallata on non-lxvlgata* aug«r
a
n
H
1
**t
HSU
jlarbiotda Kit act
a. with diallata
b. diallata nubutltutaa
1 . <>|>ton
Cultural Uffttut
a. with diallata
1 . uaud
2. cultivate OK)
b. without diallata
I . 61!•• Total ooat Qtanga in poat
(fl " ill <«t (f)
+ 116,292
1.166.608 649.964 1,816,572
1.932.064
345.960 133.520
1.104,060 154,659
152.419 42,218
+ 321,847
4,466.420
2.401.145 546,266
1,430,009
4.700,267
2,503,107 551.075 65,052*
1,430,009
--- 224.344
* 430,126
4,710,060
1,917.672
2.793,108.
5,140,906
2,051.739
2,900,177
101.070
yi.ild of 2 Toii/aoru at $2O.2il j.ur ton (aoucau of yield loua uatlMta, USUA/Stata Auuaatinant Toon, 1977)
-------
Should diallate use on sugar beets be cancelled, procedures will
substitute an integrated chemical and cultural strategy for wild oat
control. In non-irrigated areas, eptam is a major substitute for diallate,
with barban and dalapon also used for wild oat control. In irrigated
areas, cycloate and barban are the major substitute herbicides. Sugar beet
producers would also need to increase the amount of mechanical and hand
labor used to cultivate their beets. Some producers may experience yield
losses with alternative weed control strategies (including use of
alternative herbicides and delayed seeding), while other producers may
shift to alternate crops.
Economic impacts would result from changes in herbicide costs,
increased mechanical and hand cultivation costs, additional reseeding
costs, decreased yields, and shifts to other crops. Should diallate be
cancelled, sugar beet producers may experience estimated economic losses
potentially as high as $4.0 million (Tables III-2 and III-3). Of that $4.0
million impact, approximately $3.1 million would result from adverse
effects in the irrigated sugar beet areas of the Western U.S., and $0.9
million would be attributed to ramifications in the non-irrigated Red River
Valley area of Horth Dakota and Minnesota. In the Red River Valley most of
the adverse impact would derive from possible increased hand labor costs
and possible increased mechanical cultivation costs. In irrigated areas,
losses would be nearly equally divided between yield losses and lost
revenue resulting from changes in crop production from sugar beets to other
crops.
The effect of diallate cancellation on a typical Red River Valley
farm with 185 acres of sugar beets would be increased costs of $870
annually. The average cost increase per acre of sugar beets is $4.69.
This, of course, assumes the typical farm would make all herbicide,
cultural, and labor adjustments in the same proportions as the entire
Valley area. Changes in net yield are not anticipated. The average
producer could expect his net returns to land, management, and labor to
decrease by only 2.1%, from $41,102 to $40,232.
The effect of diallate cancellation on a typical irrigated sugar
beet farm would be much more severe, with an average impact of $87.65 per
acre of sugar beets. On a farm which ordinarily treated 100 acres of sugar
beets with diallate, the adverse annual effects would amount to $8,765,
most of which would be due to reductions in net returns (over variable
cost). For a typical farm, crop returns over variable cost would be
reduced nearly 18%. This loss, however, is to the individual farmer.
There is little overall yield loss since diallate is not used extensively
in irrigated plantings. In a switch to the granular formulation of
diallate alone for the control of wild oats in sugar beets, the increased
cost to growers in the short run will be approximately $6-$7 per acre
treatment, given currentprices.
While the cancellation of diallate may pose significant problems
to the local grower, this effect will not seriously reduce total U.S.
III-6
-------
production because the sugar from sugar beets represents only a small
percentage of total U.S. sugar consumed. Over 50% of the U.S. sugar is now
imported due to the favorable tariff for imports. A decline in profit
because of sugar imports is already reducing sugar beet acreages.
B. Flax
United States flax production is concentrated in the states of
Minnesota, North Dakota, and South Dakota. This area produced 98% of U.S.
flax on an average of 1,025,000 acres between 1976 and 1978. Approximately
3% of the total flax acreage (30,750 acres) was estimated to have been
treated with diallate during this period - an estimated 38,440 pounds
(active ingredient basis) of diallate annually. The emulsifiable concen-
trate formulation is the only form of diallate currently registered for use
on flax; however, granular diallate could be used on flax if it were
registered, but at slightly higher costs. Herbicide use on flax is very
limited because of the extreme phytotoxic reaction of flax to any herbi-
cide, including diallate. Diallate is, however, used in preference to
other herbicides.
Eptam and barban are the most common herbicides which can be
substituted for diallate to control wild oats in flax; however, both of
these chemicals have characteristics which limit their use on flax. Eptam
is phytotoxic in flax, and barban can only be applied when the wild oats
are at the two leaf stage (2-4 days). If weather is bad for that period
the effectiveness of the chemical is lost. A cultural method of wild oat
control is delayed seeding; however, this non-chemical method of weed
control reduces flax yields by about 33%.
Cancelling the use of diallate on flax is anticipated to result
in annual losses of approximately $0.4 million to flax producers. The
economic impacts result from a combination of changes in herbicides costs,
shifts in production from flax to alternative crops, and yield losses
resulting from delayed seeding. The average loss in returns per acre of
flax treated with diallate substitutes would be $13.59. This loss
represents 25% of the expected returns to land, labor, and management with
diallate available.
Since only 3% of the total flax acreage is estimated to be
treated with diallate, the cancellation of diallate would not have a sig-
nificant effect on total flaxseed supplies or established marketing systems
or patterns. Moreover, some shift in production away from flax is already
occurring because of decreasing demand for flaxseed and flax straw. (USDA,
Crop Production Annual Summary, 1978.)
C. Lentils
Conmercial lentil production is located almost entirely in
Washington and Idaho. During the 1976-1978 period, an average of 114,000
acres of lentils were planted annually in these two states. Both states
III-7
-------
are subject to wild oat infestations, and diallate is a major herbicide
used to control wild oats in lentil plantings. It is estimated that 43,320
acres or 38% of the total lentil acreage were treated with diallate. With
a normal use rate of one pound (active ingredient basis) of diallate
applied per acre, this would require 43,320 pounds of diallate.
Use of triallate provides an excellent substitute for diallate
use on lentils. Triallate, although increasing the overall costs of wild
oat control, offers increased yields which more than offset the increase in
costs. The positive economic impact is based on increased yields resulting
from triallate being less phytotoxic and in some cases better control of
the pest. Triallate would pick up an estimated 93% of the diallate usage
if diallate were cancelled. Therefore, cancellation of diallate and a
shift to triallate would have a positive impact to growers by increasing
returns by $512,000 annually, with an increase in production of 1.6%.
The growers reluctance to switch to triallate may be 1) unfamil-
iarity with triallate, 2) inconvenience of stocking additional chemicals
when diallate can treat all crops, and 3) marketing preferences.
Other herbicides which are expected to offset the impact of
diallate's cancellation on lentils include propham and barban. However,
these two herbicides are not as useful as triallate because of altered
efficacy characteristics (e.g. critical timing for effectiveness and rapid
biodegradation in soil). Therefore, these herbicides are not considered as
complete alternatives for diallate.
D. Peas
Dry peas (including Austrian winter peas and wrinkled seed peas)
are produced primarily in Washington and Idaho. During the 1976-1978
period, an average of 231,000 acres of dry peas were produced in these two
states. Wild oats are a major pest in dry pea production. Approximately
11% of the total acreage is treated with diallate for wild oat control,
using 30,375 pounds (active ingredient basis) of diallate.
Triallate is considered the primary substitute for diallate.
Triallate is already used on 45% of the dry peas produced and offers
growers a larger return on the land through increased yields (see
discussion in III.C.), so that the total return to the grower increases by
nearly $730,000 annually.
Propham and barban are also registered for use in dry peas.
However, these two chemicals have limitations which preclude their total
effectiveness as alternatives. Upon diallate's cancellation, the usage of
both propham and barban would increase above the current 2% (propham) and
6% (barban) usage on dry peas.
The cancellation of diallate is anticipated to result in U.S. dry
pea production increases of less than 0.01%. Therefore no economic impacts
would occur at either the market or consumer levels.
III-8
-------
5. Minor Uses
Diallate, in addition to the foregoing major uses, is also
registered for use on soybeans, corn, barley, potatoes, safflower, and
alfalfa. The percentage of use on each of the above crops is quite small;
thus, use of diallate has been determined to be minor on these crops. Use
of diallate on these crops is basically limited to North Dakota, Minnesota,
Montana, and Idaho.
The estimated use of diallate on potatoes is 0.5% of the total
potato acreage. For all other minor crops except safflower and alfalfa,
the total treated acreage is thought to be 0.1% or less. Data are not
available to show the total amount of diallate used on safflower and
alfalfa acreage.
If diallate becomes unavailable, barban would be used to control
wild oats on soybeans, and eptam would be the chemical of choice in corn
and potatoes. Triallate is registered for use on barley. Monsanto has
expressed a desire to register triallate for all crops for which diallate
is now registered (Spurrier, 1979).
The cancellation of diallate on the crops discussed in this
section is not expected to have any economic impact upon the grower or
market prices. Only in the case of potatoes does the use approach 0.5% of
the total acreage. In other cases, diallate treated acreage amounts to
0.1% or less of the total acreage.
III-9
-------
IV. Development of Regulatory Options
A. Introduction
The risks and benefits associated with the uses of diallate have
been identified in Sections II and III. As explained in Section I, FIFRA
mandates that the Agency achieve a balance between the competing considera-
tions of risks and benefits. In order to carry out that mandate, the
Agency has developed various regulatory options and has evaluated each
option for its impact on both sides of the risk/benefit equation.
This section of Position Document 2/3 briefly summarizes the
salient risks and benefits associated with the uses of diallate and
describes the process by which the Agency developed potential courses of
action.
B. Salient Risk/Benefit Considerations
In performing a risk/benefit analysis of the uses of diallate,
the Agency identified several salient factors, on both sides of the risk/
benefit equation, which became determining considerations in the
development of regulatory options. These considerations are reviewed below.
1. Salient Risk Considerations
As detailed in Section II of this document the original risk
criteria cited in the RPAR notice as the basis for the Agency's presumption
against diallate stands unrebutted. The principal risk associated with the
use of diallate is oncogenicity. This risk manifests itself in the general
population through dietary exposures at very low levels and to pesticide
applicators through dermal and inhalation exposures when applying diallate
as an emulsifiable concentrate.
It is estimated that there are approximately 24004pesticide
applicators currently at risk. This risk is estimated to be 10 and is
of primary concern to the Agency (Table 1^-10). The dietary risk to the
general population is estimated to be 10 based on tolerance levels
adjusted to reflect the percent of crop treated (Table 11-11). The Agency
considers the dietary risks of diallate to be low and not of primary
concern when compared to the benefits associated with its use.
Since the original RPAR notice was published the Agency
received additional evidence to support the conclusion that diallate is a
mutagen. Although quantitative estimates of the mutagenic risk to
applicators are not possible at this time, any risk reduction procedures
proposed to reduce the oncogenic risks of diallate will concomitantly
reduce mutagenic risks.
There is also evidence that diallate causes neurotoxic
effects. As in the case of mutagenic risks quantitative estimates of risk
IV-1
-------
are not presently possible. However, based on current exposure estimates
there is a 600-fold span between the observed effect level and the exposure
level.
2. Salient Benefit Considerations
The benefits of diallate were assessed in terms of the
economic impacts which would result if its uses were cancelled and users
were thereby forced to employ available alternatives. As detailed in
Section III, the economic impacts associated with the cancellation of
diallate total just over $3 million (Table III-1).
Sutjar Beets
The total annual market value of sugar beets is $500
million. Should diallate become unavailable, growers are expected to
experience an annual loss of $4 million. More than 60% of the diallate
used in this country is applied to sugar beets. Presently the emulsifiable
concentrate formulation is applied to 85% of the treated acreage while the
granular formulation is applied to the remaining 15%. The degree control
of wild oats provided by each of these formulations appears to be the same.
Several alternative chemicals were identified in Section III
of this document. Specifically mentioned were, 1) cycloate for control in
irrigated areas, and 2) eptam for control in non-irrigated areas, and 3)
barban which can be used in both areas. However, due to certain limita-
tions (see Section III.A) none of these chemicals provide adequate
protection against wild oats.
In changing to granular diallate alone for control of wild
oats in sugar beets, the increased cost to growers in the short run will be
approximately $6-$7 per acre-treatment given current prices.
Flax
Approximately 3% of the total flax acreage is treated with
diallate. If all forms of diallate should become unavailable for use in
the control of wild oats in flax, growers are expected to experience a
$400,000 annual loss. The emulsifiable concentrate is the only formulation
presently registered for this use.
Eptam and barban are the most commonly used alternatives for
diallate. Both of these chemicals have limitations which reduce their
desirability and effectiveness in the control of wild oats (see Section
III.B). Granular dialiate is anticipated to provide effective control of
wild oats in flax; however, this formulation is not currently registered
for this use.
IV-2
-------
Lentils
Thirty-eight percent of the total lentil acreage is treated
with diallate. Lentil production is basically limited to two western
states, Idaho and Washington. It is estimated that more than 43,000 pounds
of diallate are applied to lentil acreage annually. The emulsifiable
concentrate is the only diallate formulation presently registered for this
use.
The major alternate chemical used to control wild oats in
lentils is triallate. Triallate has proven to be an effective alternate
and provides control of wild oats equal to or greater than that provided by
diallate. Triallate is also less phytotoxic to lentils than diallate.
Propham and barban are alternative chemicals but do not provide acceptable
control of wild oats.
Peas
Dry peas, like lentils, are primarily grown in Idaho and
Washington. Currently, approximately 11% of the dry pea acreage is treated
with diallate. Only the emulsifiable concentrate formulation of diallate
is registered for use on peas for the control of wild oats.
Triallate is the priory alternate chemical for diallate on
peas. Presently, triallate is used on 45% of the dry pea acreage.
Triallate is less phytotoxic to peas than diallate.
Minor Uses (Alfalfa, Barley, Corn, Potatoes, Safflower,
and Soybeans)
The total percent of minor crop acreage treated annually
with diallate ranges from <0.1% to 0.5%. More specifically, it is
estimated that 0.5% of the potato acreage is treated, whereas the
percentage of treated acreage for all other crops is 0.1% or less. No
economic impacts are expected if diallate is cancelled. Only the
emulsifiable concentrate formulation is registered for the minor uses.
Barban and eptam are considered as possible substitute
chemicals. Triallate is now registered for use on barley.
C. Risk/Benefit Analysis
1. Dietary Risk/Benefit Analysis
As indicated in Section II.D.1. the dietary risk from
diallate is estimated as 10 . This estimate is based on assuming
residues exist on treated crops at the tolerance level. This is a worst
case assumption and to date, residues have not been found on any crops at
the level of detection (.02 ppm). More than 60% of the dietary risk is
attributable to the use of diallate on sugar beets. The dietary risk is
IV-3
-------
considered to be low and the benefits of diallate use are moderate for
sugar beets and flax, and low for lentils, peas, and minor crops. In sugar
beets the average cost increase per acre will range from $4.69 to $87.65.
For flax the loss in returns per acre would be about $14. For all other
uses economic benefits would accrue due to minor production increases from
either more effective control of wild oats or decreased phytotoxic effects
of alternate chemicals. Therefore, the Agency concludes that the benefits
(low to moderate) outweigh the dietary risk (low). In view of this,
regulatory action on the basis of dietary risk alone is not warranted. As
indicated above the principal risk of diallate is to pesticide applicators
through dermal and inhalation exposure when applying diallate as an
emulsifiable concentrate.
2. Applicator Risk/Benefit Analysis
The applicator risk/benefit matrix for diallate, expressed
in qualitative terms, is shown in Table IV-1. For all presently registered
use patterns the applicator risks are high for the emulsifiable concentrate
formulations while the risks associated with the granular formulation are
no greater than the general populations risk from dietary exposure. The
benefits of diallate use (either formulation) on sugar beets and flax are
moderate and all other uses are low.
Applicators of the emulsifiable concentrate formulation may
be exposed both dermally and via inhalation as the result of splashing,
vaporization, or accidental spills. Likewise during application, exposure
may occur both dermally and via inhalation. Table 11-10 identifies the
dermal risk to applicators of the emulsifiable concentrate formulation as
10 .
One potential risk reduction measure is to require applica-
tors using emulsifiable concentrate diallate to wear protective clothing.
Protective clothing in this instance is defined as rubber gloves and
coveralls. These items would reduce the exposure level by a factor_pf 4
(see Section II.C.1.). This reduction would result in a risk of 10
which the Agency still considers unreasonable when compared to the low and
moderate benefits and, therefore, unacceptable. Therefore, a protective
clothing requirement will not be considered as a viable risk reduction
measure in this analysis.
Thus the risk/benefit picture for the emulsifiable concen-
trate formulation is essentially the same for all uses. The applicator
risk is high and the benefits are, at best, moderate. Since the risks out-
weigh the benefits in every case, the Agency must consider regulatory
options for reducing the risks associated with the emulsifiable concentrate
formulation, in particular, the high applicator risks.
From this analysis the Agency concludes that the high risk
involved in the use of the emulsifiable concentrate is unacceptable when
considered against the low to moderate benefits of all emulsifiable
IV-4
-------
Table IV-1. Applicator Risks versus Economic Benefits of Diallate
Uses
Sugar Beets
Flax
Lentils
Dry ?eas
Minor Uses
Barley,
Potatoes ,
Saf flower,
Soybeans ,
Corn, Alfalfa
Applicator Risk
Smulsifiable Granular Economic Benefits (c)
Concentrate
High (a) Low Moderate
High (a) {b) Moderate
High (a) (b) Low
High (a) {b) Low
High (a) (b) Low
(a) High Risk _> 10~4
(b) Although not registered for these uses the applicator risks would remain
low if registered.
(c) Benefits analysis did not evaluate the individual benefits of the two
formulations.
IV-5
-------
concentrate uses. It also concludes that this risk can be reduced to the
acceptably low dietary level if the emulsifiable concentrate formulation is
replaced by the granular formulation. Therefore, the Agency will examine
the feasibility of cancelling all diallate emulsifiable concentrate
formulations in its regulatory options.
For sugar beets (the only use for which the granular formula-
tion is also registered), the risk/benefit balance for the granular formula-
tion is shifted favorably. Risks become low because of significantly
decreased applicator exposure and benefits remain moderate because the cost
and effectiveness of granular diallate are approximately the same as the
emulsifiable concentrate. Based on this finding for sugar beets, the
Agency assumes that this more favorable risk/benefit balance could be
achieved if the granular formulation were registered for all of the other
uses.
D. Regulatory Options
With regard to the emulsifiable concentrate products of diallate,
three basic regulatory options have been developed for consideration:
1. Continue emulsifiable concentrate registrations.
2. Cancel emulsifiable concentrate registrations immediately.
3. Cancel emulsifiable concentrate registrations effective in
two years.
Options 1 and 2 represent an absolute regulatory response.
For Option 1 it means that sale and distribution of diallate emulsifiable
concentrate products are unconditionally continued. Option 2 on the other
hand means that sale and distribution of these products are prohibited
effective as soon as the decision becomes final. Option 3 represents a
decision to phase out the emulsifiable concentrate formulations to permit
time to extend the registrations of granular diallate to uses where it is
not presently registered.
1. Option 1; Continue Emilsifiable Concentrate Registration
This option would return emulsifiable concentrate formula-
tions of diallate to the registration process, and they would be retained
as effective means to control wild oats in sugar beets and other crops. By
adopting Option 1, the Agency would conclude that the benefits associated
with the use of emulsifiable concentrate diallate outweigh the risks and
that allowing its use would not result in 'unreasonable adverse effects.
-4
Under this option, the potential applicator risks of 10
resulting from inhalation and dermal exposure would not be reduced. There
would be no adverse economic impacts associated with Option 1 because use
of emulsifiable concentrate formulations would continue. By choosing this
IV-6
-------
option the Agency would conclude that the benefits would outweigh the risks
of continued use.
2. Option 2: Cancel Smulsifiable Concentrate Registrations
Immediately
This option would eliminate all uses of emulsifiable
concentrate diallate thirty days after the final Agency decision. 3y
adopting Option 2 the Agency would conclude that the risks associated with
the use of emulsifiable concentrate diallate exceed the benefits, and
result in unreasonable adverse effects.
Under this option, applicator risks resulting from
inhalation and dermal exposure would be reduced to the same magnitude of
risk as the general dietary risk. Cancelling all emulsifiable concentrate
registrations iaanediately would imply that risks outweigh benefits.
Hie economic impact which result from the immediate
cancellation of diallate emulsifiable concentrate formulations on sugar
beets is estimated to be more than $3 million (Table III-1). The benefit
analysis did not attempt to identify the impact of the individual formula-
tions. Bowever, most of the impact will result from the cancellation of
the emulsifiable concentrate formulations. This is based on the fact that
the emulsifiable concentrate accounts for approximately 85% of the diallate
presently used on sugar beets. Flax growers are expected to suffer a
$400,000 annual loss while growers of lentils and peas are anticipated to
receive an economic gain as expressed in Table III-1.
This option would ignore such factors as availability of
alternatives including granular diallate since time would have to be
allowed to produce adequate quantitites of this material. It also ignores
the time necessary to register granular diallate on flax and other crops
for which the emulsifiable concentrate is now registered if the markets
demand such action. Lastly, this option neglects to allow time for growers
to modify or acquire the necessary equipment to apply the granular
formulation.
3. Option 3; Cancel Bmulsifiable Concentrate Registrations
Effective Two Years After the Decision Becomes Final
This option is essentially the same as Option 2. It differs
in that it would eliminate all uses of emulsifiable concentrate diallate
two years after the decision becomes final. By adopting Option 3, the
Agency would indicate its unwillingness to accept the applicator risks
associated with the use of the emulsifiable concentrate formulation
indefinitely. This option would lessen the impact of immediate cancel-
lation by 1) allowing time to produce the necessary granular diallate to
control wild oats in sugar beets, 2) allowing time to register granular
diallate on crops where only the emulsifiable concentrate is now registered
and where other registered alternatives are not desirable, and 3) allowing
time for growers to make necessary equipment adjustments.
IV-7
-------
Some granular diallate formulations are presently registered
for use on sugar beets only in Minnesota and North Dakota. It will be
necessary to allow sufficient time to extend the registration of these
granular formulations to the western states. While the registered granular
formulation with diallate as the sole active ingredient is only registered
for use in the non-irrigated areas, other granular formulations with
diallate as one of the active ingredients are registered in other geo-
graphical areas (western states). Two years should also provide ample time
to register the granular formulation on crops now being treated with the
emulsifiable concentrate formulation if the market demands it.
The Agency, based on the information available, believes 1)
that a two-year tinif frame is sufficient *-im«» for the company to produce
the granular diallate required to maintain control of wild oats in sugar
beets, and 2) that two years is ample *-inu» for growers to make adjustments
in equipment necessary to apply the granular formulation (Lewis, 1980).
Because there is no acceptable alternative chemical
presently registered for use on flax, cancellation of the emulsifiable
concentrate is a major concern. The expected annual economic impact to
flax growers is $400,000. The Agency believes that the granular
formulation will provide excellent wild oat control with little or no
phytotoxicity and is willing to consider a proposal for this use.
Registrants of the emulsifiable concentrate and granular
formulations may submit an application for amended registration to
1) convert their emulsifiable concentrate formulation to granular, and
2) expand their granular registrations to crops for which only the
emulsifiable concentrate is now registered. The review of these actions
will be expedited and should not require additional data.
IV-8
-------
V. Proposed Regulatory Decision
The Agency proposes to implement Option 3 which is to cancel the
emulsifiable concentrate formulations of diallate effective two years from
the date the decision becomes final.
Option 1 is unacceptable because the level of risk Jo applicators of
the enmlsifiable concentrate formulations remains at 10 which the
Agency is unwilling to permit considering the low and moderate benefits.
Option 2 is also unacceptable. While under this Option the risk to
applicators is reduced to the general dietary risk level, it does not take
into account the potential impacts that may occur due to the unavailability
of adequate supplies of granular diallate currently registered for sugar
beet use. In addition it does not permit any opportunity for the
registrant to extend the use of granular diallate to those uses where only
the enmlsifiable concentrate is currently registered prior to complete
cancellation.
Option 3 would overcome the disadvantages of both Options 1 and 2.
The Agency would welcome applications to extend the use of granular
diallate as a replacement for the emulsifiable concentrate and EPA
considers a two-year time frame appropriate to accomplish this. At the
same time, the two-year time frame permits the production of adequate
supplies of granular diallate to meet expected market demand.
Also under Option 3 registrants would be allowed to convert
emulsifiable concentrate formulations to granular and expand granular
registrations to crops for which only the emulsifiable concentrate is
presently registered.
V-l
-------
VI. References
Albert, R.E., 1979a. Diallate RPAR Rebuttal Response. Carcinogen
Assessment Group, EPA, 1979.
Albert, R.E., 1979b. Risk Assessment of Avadex. Carcinogen Assessment
Group, EPA, 1979.
Brusick, D.J. 1977a. Mutagenicity Evaluation of CP15336, BIO-77-166 (Final
Report July, 1977) submitted to Monsanto, Co, Inc., by Litton
Bionetics, Inc., Project No. 2683. 9pp.
Brusick, D.J. 1977b. Mutagenicity evaluation of CP15336 in the mouse
lymphoma v-ssay, BIO-77-171 (Final 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.
Carcinogenesis Bioassay Data Systems, 1975. Preliminary Analysis Report
for Avadex. Prepared for the National Cancer Institute by EG&G/Mason
Research Institute.
Development Planning and Research Associates, Inc., March, 1979. Economic
Analysis of Effects of Restricting Use of Diallate on Sugarbeets,
Flax, Lentils and Dry Peas; to Environmental Protection Agency.
Gardner, R., 1980. Estimates of human exposure to diallate. Memo to James
Wilson, SPRD (TS-791), Project Manager.
Innes, J.R.M., B.M. Ulland, M.G. Valeno, L. Petrucrlli, L. Fishbein,
E.R. Hart, A.J. Pollotta, R.R. Bates, H.L. Falk, J.J. Gart, M. Klein,
I. Mitchell and J. Peters. 1969. Bioassay of Pesticides and
Industrial Chemicals for Tumorigenicity in Mice: A Preliminary Note.
J. Nat. Cancer Inst. 42:1101.
Jensen, J. 1980. Applicator Exposure to Diallate While Using the Granular
Formulation. Memo to J. E. Wilson, Jr., Project Manager for Diallate,
April 23, 1980.
Keplinger, M.L. 1974. Mutagenic Study with Avadex Technical in Albino
Mice. BTL-74-13. Industrial Bio-Test Laboratories, Inc., August 20,
1974. IBT No. 622-05252. Submitted to EPA by Monsanto Company on
October 14, 1976. 14 pp.
Keplinger, M.L. 1976a. Two-year Chronic Oral Toxicity Study with Avadex
Technical in Albino Rats BTL-74-12. Industrial Bio-Test
Laboratories, Inc., December 17, 1976. IBT No. 622-05250. Submitted
to EPA by Monsanto Company on February 4, 1977. EPA Accession No.
228094.
Keplinger, M.L. 1976b. Neurotoxicity Study with Avadex in Chickens,
BTL-76-84. Industrial Bio-Test Laboratories, Inc., December 28,
1976. %IBT No. 8580-09119. Submitted to EPA by Monsanto Company on
February 16, 1977. EPA Accession No. 226094.
VI-1
-------
Lewis, C., 1980. Additional information on use of granular diallate.
Memo to James Wilson, SPRD Project Manager.
Mauer, I., 1978. Ph.D., Geneticist, Toxicology Branch, EPA, November 28,
1978. Diallate: Preliminary Assessment of Mutagenicity, Regulatory
Options, and Alternatives, Memorandum to Roger Gardner, Toxicology,
EPA.
Monsanto Agricultural Products Co., 1977. Rebuttal to the Rebuttable
Presumption Against Registration and Continued Registration of
Pesticide Products Containing Diallate. I1A [30000/15].
Pesticide Residues Committee, 1965. NAS-NRC Report on "No Residue" and
"Zero Tolerance,1* June 1965.
Phillips, B.M. 1977. Final Report to Monsanto Company 42-day Neurotoxicity
Study with Diallate in Chickens. (f1B(30000/15) attachment A)
Rinkus, S.J. and M.S. Legator, 1977. Mutagenicity of Diallate. Submitted
to EPA (FRS/TSD). July 6, 1977. 5 pp.
Sandhu, S.S., Ph.D., Biochemistry Branch, EPA, August 30, 1978. Evaluation
of the Data for the Mutagenicity of Diallate and Ti Lallate.
Memorandum to William F. Durham, Ph.D., Director, Environmental
Toxicology Division (HERL/RTP), EPA.
Selim, S. October 16, 1978. Exposure Analysis for Diallate. Proprietary
Environmental Fate Branch, Hazard Evaluation Division, OPP, EPA.
SikJca, J.C. and P. Florczyk. 1978. Mutagenic Activity of Thiocarbamate
Pesticides in a Microbial Test System. J. Agr. Food Chem. 26:146-.
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. 23 pp.
Sochard, M.R. 1980. Editing of Diallate PD 2/3 Pursuant to Memo From J.
Jensen, EFB, to J. E. Wilson, Jr., Project Manager for Diallate,
May 14, 1980.
Spurrier E. , 1979. Memo of telephone conversation with R. Troast.
Olland, B., E.K. Weisburger, and J.H. Weisburger. 1973. Chronic Toxicity
and Carcinogenicity of Industrial Chemicals and Pesticides.
Toxicol. Appl. Pharmacol. 25:446.
USDA/State Assessment Team on Diallate, 1977. Assessment of the Need for
Diallate in Agriculture #10A[30000/15].
U.S. Department of Health Education and Welfare. 1969. Report of the
Secretary's Commission on Pesticides and Their Relationship to
Environmental Health. U.S. Government Printing Office, Washington,
D.C.
VI-2
-------
UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
OFFICE 3F =E3~!CIO£S ANO TOXiC 3U3STANCSS
ENVIRONMENTAL PROTECTION AGENCY
(OPP-30000/153)
DIALLATS
PRELIMINARY NOTICE OF DETERMINATION CONCLUDING
THE REBUTTA3LE PRESUMPTION AGAINST REGISTRATION
OF PESTICIDE PRODUCTS AND NOTICE OF
AVAILABILITY OF POSITION DOCUMENT
AGENCY: Environmental Protection Agency (SPA)
ACTION: Notice of Availability
SUMMARY: The Environmental Protection Agency issued
a notice of rebuttable presumption against registration
and continued registration of pesticide products containing
diallate on May 31, 1977. This notice announces the Agency's
oreliminary regulatory position pursuant to 40 CFR 152.11(a)
(5) and makes the document available to registrants, users,
and other interested parties.
DATES: Written comments are due on or before (insert
date 30 days after date of publication in the FEDERAL
REGISTER).
ADDRESS: Document Control Office
Chemical Information Division
SPA (TS-793)
Room E447
401 M Street, S.W.
Washington, DC 20460
-------
FOR FURTHER INFORMATION CONTACT:
James Wilson, Project Manager
Special Pesticide Review Division
401 M Street, S.W.
Washington, B.C. 20460 (TS-791)
SUPPLEMENTARY INFORMATION: The Agency's Position Document
(?D 2/3) reviews the risks and benefits of the pesticide
products containing diallate and discusses various regulatory
options available. The preliminary findings will be reviewed
by the FIFRA Scientific Advisory Panel and the Secretary of
Agriculture as required under the amended FIFRA.
I. INTRODUCTION
The Environmental Protection Agency issued a notice of
rebuttable presumption against registration and continued
registration ("SPAR") of pesticide products containing
diallate published in the FEDERAL REGISTER of May 31, 1977
(42 FR 27669), a thiocarbamate herbicide, thereby initiating
the Agency's public review of the risks and benefits of
diallate. The rebuttable presumption was issued on the
basis of oncogeniciry. The Agency also requested registrants
and other interested parties to submit data on the effects
that diallate may have on plant and animal ceil division.
This notice constitutes the Agency's Notice of Deter-
mination (Notice) pursuant to 40 CFR 162.11(a)(5). This
determination is preliminary at this point pending external
review through submission to, and review by, the United
States Department of Asriculture and the Scientific Advisorv
-------
Panel, pursuant to sections 6(b) and 25(d) of the Federal
Fungicide, Insecticide, and Rodenticide Act (FIFRA) as
amended. The action does not become final until the Agency
has reviewed these comments and issued a final notice.
In broad summary, the Agency has determined that diallate
continues to exceed the risk criteria outlined in 40 CFR
162.11 for cncogenicity. The risks that diallate poses to
applicators of the emulsifiable concentrate formulation are
of sufficient concern to require the Agency to consider
whether these risks can be reduced. The Agency has considered
benefits information including that submitted by registrants,
interested persons, and the United States Department of
Agriculture and has analysed the economic, social, and
environmental benefits of the uses of diallate. The Agency
has weighed risks and benefits together, in-order to determine
whether the risks of each diallate use are warranted by the
benefits of the use. In weighing risks and benefits, the
Aaencv considered what risk reductions could be achieved and
how risk reduction measures would affect the benefits of the
use.
The Agency has determined that the risks of certain uses
of diallate are greater than the social, economic, and
environmental benefits of these uses, unless risk reductions
are accomplished by modifications in the terms and conditions
of registration. Accordingly, the Agency is proposing to
initiate action to cancel or deny registrations for all of
the uses of diallate which involve the emulsifiable concentrate
formulation. The Agency has further determined that these
-------
cancellations will accomplish significant risk reductions,
and that these risk reductions can be achieved without
significant impacts on the benefits of the continued use of
the granular formulation of diallate. The remainder of this
Notice and the accompanying Position Document set forth in
detail the Agency's analysis of comments submitted during
the rebuttal phase of the diallate RPAR, the Agency's
reasons and factual bases for the regulatory actions it is
initiating.
II. LEGAL BACKGROUND
In order to obtain a registration for a pesticide under
?I?RA, a manufacturer must demonstrate that the pesticide
satisfies the statutory standard for registration. Section
3(c)(5) of FIFRA requires, among other things, that the
pesticide perform its intended function without causing
"unreasonable adverse effects on the environment". The term
"unreasonable adverse effects on the environment" is defined
in FIFRA section 2(bb) as "any unreasonable risk to man or
the environment, taking into account the economic, social,
and environmental costs and benefits of the use of any
oesticide". In effect, this standard requires a finding
that the benefits of each use of the pesticide exceed the
risks of use, when the pesticide is used in accordance with
commonly recognized practices. The burden of proving that a
pesticide satisfies the registration standard is on the
proponents of registration and continues as long as the
recistra'cion remains in effect. Under section 6 of FIFRA,
-------
the Administrator is required to cancel the registration of
a pesticide or modify the terms and conditions of registration
whenever he determines that the pesticide no longer satifies
the statutory standard for registration.
The Agency generally announces that an RPAR has arisen
by publishing a notice in the FEDERAL REGISTER After an
RPAR is issued, registrants and other interested persons
are invited to review the data upon which the presumption is
based and to submit data and information to rebut the
presumption. Respondents may rebut the presumption of risk
by showing that the Agency's initial determiation of risk
was in error, or by showing that use of the pesticide is not
likely to result in any significant exposure to humans or to
the animal or plant of concern with regard to the adverse
effect in cues-ion. See 40 CFR 162.11(a)(4). Further, in
addition to submitting evidence to rebut the risk presumption,
respondents may submit evidence^ as to whether the economic,
social, and environmental benefits of the use of the pesticide
subject to the presumption outweigh the risks of use.
The regulations require the Agency to conclude an RPAR
bv issuing a Notice of Determination in which the Agency
states and explains its position on the question of whether
the risk ^resumptions have been rebutted. If the Agency
determines that the presumption is not rebutted, it will
then consider information relating to the social, economic,
and environmental costs and benefits which registrants and
other interested oersons submitted to the Agency, and any
other benefits information known to the Agency.
-------
After weighing the risks and the benefits of a pesticide
use, the Administrator may conclude the RPAR process by
issuing a notice of intent to cancel or deny registration,
pursuant to FIFRA section 6(b)(1) and section 3(c)(6) or
by issuing a notice of intent to hold a hearing pursuant to
section 6(b)(2) of FIFRA to determine whether the registra-
tions should be cancelled or applications for registration
denied.
In determining whether the use of a pesticide poses risk
which are greater than benefits, the Agency considers
modifications to the terms and conditions of registration
which can reduce risks, and the impacts of such modifications
on the benefits of the use. Among the risk reduction
measures short of cancellation which are available to the
Agency are changes in the directions for use on the pesticide's
labeling and classification of the pesticide for "restricted
use" pursuant to FIFRA section 3(d).
FIFRA requires the Agency to submit notices issued
pursuant to section 6 to the Secretary of Agriculture
for comment and to provide the Secretary of Agriculture
with an analysis of the impact of the proposed action on
the agricultural economy under section 6(b) of FIFRA. The
Agency is required to submit these documents to the Secretary
at least 60 days before making it public. If the Secretary
of Agriculture comments in writing within 30 days after
receiving the notice, the Agency is required to publish
the Secretary's comments and the Administrator's response
-------
with the notice. FIFRA also requires the Administrator to
submit section 6 notices to a Scientific Advisory Panel for
comment on the impact of the proposed action on health and
the environment, at the same time and under the same proce-
dures as those described above for review by the Secretary
of Agriculture under section 25(d) of FIFRA.
Although not required to do so under the statute, the
Agency has decided that it is consistent with the general
theme of the RPAR process and the Agency's overall policy of
open decision making to afford registrants and other interest-
ed persons an opportunity to comment on the bases for the
proposed action during the time that the proposed action in
under review by the Secretary of Agriculture and the Scien-
tific Advisory Panel. Accordingly, appropriate steps: will
be taken to make copies of the Position Document available
to registrants and other interested persons at -the time the
decision documents are transmitted for formal external
review, through publication of a notice of availability in
the Federal Register, or by other means. Registrants and
other interested person will be allowed the same 30 day com-
ment period that the statute provides for receipt of comments
from the Secretary of Agriculture and the Scientific Advisory
Panel.
After completing these external review procedures and
making any changes in the proposed action which are deemed
appropriate as a result of the comments received, the Agency
will proceed to implement the desired regulatory action by
preparing appropriate documents and releasing them in the
manner prescribed by the statute and by the Agency's rules.
-------
III. DETERMINATION AND INITIATION OF REGULATORY ACTION
The Agency has considered information on the risks
associated with the uses of diallate including information
submitted by registrants and other interested persons in
response to the diallate RPAR. The Agency has also considered
information on the social, economic, an environmental
benefits of the uses of diallate subject to the RPAR,
including benefits information submitted by registrants and
other interested person in conjunction with their rebuttal
submissions, and information submitted by the United States
Department of Agriculture.
The Agency's assessment of the risks and benefits of the
uses of diallate subject to this RPAR, its conclusions and
determinations whether any uses of diallate pose unreasonable
adverse effects on the environment, and its determinations
whether modifications in terms of conditions of registration
reduce risks sufficiently to eliminate any unreasonable
adverse effects are set forth in detail in the Position
Document. This Position Document is hereby adopted by the
Agency as its statement of reasons for the determinations
and actions announced in this Notice and as its analysis of
the impacts of the proposed regulatory actions on the
agricultural economy. For the reasons summarized below and
developed in detail in the Position Document, the Determina-
tions of the Agency with respect to diallate are as follows:
-------
A. Determination of Risk
The diallate RPAR was based on information indicating
that diallate posed oncogenic risks to humans. As developed
fully in the Position Document (PD 2/3), the Agency has
determined that the information submitted to rebut the risk
criteria for oncogenicity was insufficient to overcome the
presumption against diallate for this effect.
Since the original RPAR notice was published the
Agency received additional evidence to support the conclusion
that diallate is a mutagen. Although quantitative estimates
of the mutagenic risk to applicators are not possible at
this timef any risk reduction procedures proposed to reduce
the oncogenic risks of diallate will concomitantly reduce
mutagenic risks.
There is also evidence that diallate causes neuro-
'toxic effects. As in the case of mutagenic risks quantitative
estimates of risk are not presently possible. However,
based on current exposure estimates there is a 600-fold span
between the observed effect level in chickens and the
estimated human exposure level.
The principal risk associated with the use of
diallate is oncogenicity. This risk manifests itself in the
general population through dietary exposures at low levels
and to pesticide applicators through dermal and inhalation
exposures before and/or during application of diallate as an
emulsifiable concentrate at high levels.
-------
It is estimated that there are approximately 2400
pesticide applicators currently at risk. This risk is
—4
estimated to be 10 and is of primary concern to the
Agency. The dietary risk to the general population is
estimated to be 10~ based on tolerance levels adjusted to
reflect the percent of crop treated. Since residues have
not been detected on diallate treated foods, these risk
estimates are almost certainly overstated. The Agency
considers the dietary risks of diallate to be low and not of
primary concern when compared to the benefits associated
with its use.
B. Determinations of Benefits
Diallate is used primarily to control wild oats in
sugar beets, flax, lentils and peas. It has minor use with
alfalfa, barley, corn, potatoes, safflower and soybeans.
1. Sugar Beets. The total annual market value of sugar
beets is $500 million. Should diallate become unavailable,
growers are expected to experience an annual loss of $4
million. More than 60 percent of the diallate used in this
country is applied to sugar beets. Presently the emulsifiable
concentrate formulation is applied to approximately 85
percent of the treated acreage while the granular formulation
is applied to the remaining 15 percent. The degree of
control of wild oats provided by each of these formulations
appears to be the same for fall applications but slightly
less for the granular formulation in spring applications.
-------
2. Flax . Approximately 3 percent of the total flax
acreage is treated with diallate. If diallate should become
unavailable for use in the control of wild oats in flax,
growers are expected to experience a $400,000 annual loss.
The emulsifiable concentrate is the only formulation presently
registered for this use. However, the granular is expected
to be as effective.
3. Lentils. Thirty-eight percent of the total lentil
acreage is treated with diallate. Lentil production is
basically limited to two western states, Idaho and Washington.
It is estimated that more than 43,000 pounds of diallate are
applied to lentil acreage annually. The emulsifiable
concentrate is the only diallate formulation presently
registered for this use.
4* Peas. Dry peas, like lentils, are primarily grown
in Idaho and Washington. Currently, approximately 11 percent
of the dry pea acreage is treated with diallate. Only the
emulsifiable concentrate formulation of diallate is registered
for use on peas for the control of wild oats.
5. Minor uses including alfalfa, barley, corn, potatoes,
safflower, and soybeans. The total percent of minor crop
acreage treated annually with diallate ranges from <0.1
percent to 0.5 percent. More specifically, it is estimated
that 0.5 percent of the potato acreage is treated, whereas
the percentage of treated acreage for all other crops is 0.1
percent or less. No economic impacts are expected if
diallate is cancelled. Only the emulsifiable concentrate
formulation is registered for the minor uses.
-------
C. Determinations of Unreasonable Adverse Effects
For the reasons set forth in the accompany-
ing Position Document, the Agency has made the following
determinations about the unreasonable adverse effects
associated with the continued use of the eraulsifiable
concentrate formulations of diallate.
The Agency has determined that the risks arising
from the use of emulsifiable concentrate formulations of
diallate to control wild oats are greater than its social,
economic, and environmental benefits.
The Agency has further determined that modifications
in the terms and conditions of registration of the emulifi-
able concentrate formulation of diallate will not accomplish
significant risk reductions. Accordingly, the Agency has
determined that, unless these formulations are cancelled,
the uses of these formulations will continue to cause
unreasonable adverse effects in the environment, when used
in accordance with widespread and commonly recognized prac-
tices. The Agency has also determined that benefits derived
from uses of granular formulations of diallate are greater
than its social, economic, and environmental risks. Therefore,
these formulations will not be cancelled.
D. Initiation of Regulatory Action
Based upon the determinations summarized above and
set out in detail in the Position Document, the Agency is
initiating a regulatory action which would cancel the use of
all diallate emulsifiable concentrate formulations two years
after this decision becomes final. Diallate registrants may
-------
apply for amended registration to convert from emulsifiable
to granular formulations as well as expanded registrations
of the granular to crops for which only the emulsifiable
concentrate is now registered. Review of the amended
registrations will be expedited and may not require more
data.
V. PROCEDURAL MATTERS
This Notice of Determination notifies the United States
of Agriculture, the Scientific Advisory Panel, pesticide
registrants and users, and other interested parties of the
Agency's preliminary determinations relating to the risks
and benefits to the uses of diallate and provides these
entities and individuals with the opportunity to comment on
these determinations.
The Agency's decision to initiate regulatory action
must be referred for review by^the Secretary of Agriculture
and the Scientific Advisory Panel. The EPA position document
setting forth the reasons and factual bases for the regulatory
actions which the Agency proposes and this Notice of Deter-
mination are being transmitted immediately to the Secretary
of Agriculture and the Scientific Advisory Panel for comments.
The Agency also will offer registrants and other interested
persons an opportunity to comment on the bases for the
Agency's action by making copies of the Position Document
available upon request.
-------
Interested persons may receive copies of the documents
by communicating their requests to James Wilson, Project
Manager, Special Pesticide Review Division, Office of
Pesticide Programs, EPA (TS-791), 401 M Street SW, Washington,
DC 20460 (703) 557-7420. Registrants and other interested
persons have the same period of 30 day comment period
that the statute provides for the Secretary of Agriculture
and the Scientific Advisory Panel.
All comments on the proposed actions should be sent to
the Document Control Office, Chemical Information Division,
EPA (TS-793), Room E-447, 401 M Street S.W., Washington, DC
20460. In order to facilitate the work of the Agency and of
others inspecting the comments, registrants and other interested
persons should submit three copies of their comments. The
comments should bear the the identifying notation 30000/15B and
f V
should be submitted on or before e>£
After completion of these review procedures, the Agency
will consider the comments received and publish an analysis
of them, together with any changes in the regulatory actions
announced in this Notice which it determines are appropriate.
Until this final review phase is concluded in this manner,
it is not necessary for registrants or other interested
persons to request a hearing to contest any regulatory
action resulting from the conclusion of this RPAR.
Dated:
SXe-ven D. Jellijnek
Assistant Administrator
for Pesticides
and Toxic Substances
-------
DIALLATE
Position Docunent 2/3
April, 1980
Office of Pesticides and Toxic Substances
Environmental Protection Agency
401 'M' Street, S.W.
Washington, D.C. 20460
-------
ACKNOWLEDGEMENTS
EPA Proj eet Support Team
James E. Wilson, Jr., Senior PM, SPRD
Minnie R. Sochard, Ph.D., PM, SPRD
Karl 0. Bayer, OGC
Tom Edwards, HED
Roger Gardiner, HED
Janice Jensen, HED
Dave Johnson, HED
Charles Lewis, BFSD
Richard Stevens, HED
Linda V. Zygadlo, BFSD
-------
TABLE OF CONTENTS
Page Number
I. Background 1-1
A. Introduction 1-1
1. Organization of Position Document 1-1
2. Chemical and Physical Characteristics 1-1
3. Registered Uses 1-1
4. Tolerances 1-2
B. Applicable Sections of FIFRA . 1-2
C. The "•RPAR" Process 1-3
D. Regulatory History 1-3
E. Basis for the Rebuttable Presumption 1-4
II. Analysis and Assessment of Risk II-1
A. Analysis of Rebuttal Arguments
for Oncogenicity - II-1
1. Rebuttal Pertaining to National
Cancer Institute (NCI) Rat
Study (Litton-Bionetics) II-1
2. Rebuttal Pertaining to Industrial
Bio-Test (IBT) Rat Study
(Sponsored by Monsanto Company) II-5
3. Rebuttal Pertaining to NCI
Mouse Study (Innes Study) 11-11
B. Analysis of Data Submitted Since PD 1
for Other Possible Adverse Effects 11-14
1. Mutagenicity 11-14
2. Neurotoxicity 11-16
3. Reproductive Effects 11-17
C. Exposure Analysis 11-18
1. Spray Applicator Exposure 11-18
a. Spray Applicators 11-18
b. Granular Applicators 11-19
2. Dietary Exposure 11-19
D. Risk Assessment 11-19
1. Oncogenic Effects 11-19
2. Mutagenic Effects 11-24
E. Risks Associated with Alternative Chemicals 11-27
III. Benefit Analysis III-1
A. Sugar Beets III-2
B. Flax III-7
C. Lentils III-7
D. Peas IH-8
E. Minor Uses III-9
IV. Development of Regulatory Options IV-1
A. Introduction IV-1
B. Salient Risk/Benefit Considerations IV-1
1. Salient Risk Considerations IV-1
2. Salient Benefit Considerations IV-2
-------
C. Risk/Benefit Analysis Options IV-3
1. Dietary Risk/Benefit Analysis IV-3
2. Applicator Risk/Benefit Analysis IV-4
0. Regulatory Options IV-6
1. Option 1 IV-6
2. Option 2 IV-7
3. Option 3- IV-7
V. Proposed Regulatory Decision V-1
VI. References
-------
DLALLATE: POSITION DOCUMENT 2/3
I« Background
A. Introduction
1 • Organization of Position Document
This Position Document contains five parts. Part I is the
introductory section. Part II is an evaluation of the risk of diallate.
It includes descriptions of the relevant data on toxicity, exposure, and
the Agency's present risk assessment. Part III is a summary of the
economic benefits of diallate. Part IV describes the range of the
regulatory options considered by the Agency. Part V puts forward the
Agency's recommended option.
2. Chemical and Physical Characteristics
Diallate (S-(2,3-Dichloroallyl)diisopropylthiocarbamate) is
a thiocarbamate which is also known by the trade name AVADEX®. Diallate
acts as a pre-emergence selective herbicide. It is an amber-colored liquid
which is formulated as an emulsifiable concentrate (4 pounds/ gallon ) and as
a granular (10%).— Its molecular weight is 270.2. Its structural
formula is as follows:
trans isoner ds isoaer
H Cl CH3 Cl Cl CH
Gl .
* ^CH— CH
-
3
Foraula
Formula Weight
3. Registered Uses
Monsanto Agricultural Products Company is the sole producer
of technical-grade diallate. As a registered pesticide, diallate is cur-
rently used to control wild oats in sugar beets, flax, barley, corn (grain
and silage), forage legumes (alfalfa, sweet, red and alsike clover),
— As a granular, diallate is registered for use on sugar beets only.
i-r
-------
lentils, peas, potatoes, safflower, and soybeans. In combination with
pebulate or cycloate, it is used also to control other grasses and broad-
leaf weeds in sugar beets. Diallate is incorporated into the soil in the
fall before the freeze or in the spring, either before or after seeding,
but before emergence. Usually only one application is made by the user per
season.
Eight federal registrations of products containing diallate
are held by three registrants.
4. Tolerances
Tolerances for diallate in or on raw agricultural
commodities are listed in 40 CFR 180.277 as follows: negligible residues
on alfalfa (fresh and hay), barley (grain, forage, and straw), clover
(fresh and hay), field corn grain, fodder"and forage, flaxseed, lentils,
peas, pea forage and hay, potatoes, safflower seed, soybeans, soybean
forage and hay, and sugar beet roots and tops at 0.05 part per million.
B. Applicable Sections of FIFRA
The Federal Insecticide, Fungicide and Rodenticide Act (7 O.S.C.
136 et seq.) , as amended, confers authority on EPA to regulate pesticide
products. Section 3 (a) of the Act requires all pesticide products to be
registered by the Administrator before they may be sold or distributed.
Before the Administrator may register a pesticide, however, he must
determine that its use will not result in "unreasonable adverse effects on
the environment," defined in Section 2(bb) of FIFRA to mean "unreasonable
risk to man or the environment, taking into account the economic, social,
and environmental costs and benefits of the use of any pesticide." In
other words, any registration decision must .take into account both risk and
benefits from the pesticide's uses.
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 to him that che 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
may cancel the registration of a pesticide whenever he determines that it
no longer satisfies the statutory standard for registration; this standard
requires, among other things, that the pesticide "perform its intended
function without unreasonable adverse effects on the environment" [FIFRA
3(c)(5)(C)]. He may also cancel the registration of a pesticide if its
labeling does not comply with the misbranding provision of FIFRA, which
requires the labeling to contain certain language "adequate to protect
health and the environment" (FIFRA 2(q)).
1-2
-------
C. The "RPAR" Process
To implement its authorized functions, the Agency has designed
the Rebuttable Presumption Against Registration (RPAR) process, which
involves gathering data on the risks and benefits associated with the uses
of suspect pesticides. By allowing all interested parties to participate by
submitting information, the process enables EPA to make balanced decisions
concerning problem pesticides.
If the presumptions of risk are not rebutted, the evidence
pertaining to benefits must be evaluated and considered together with the
evidence pertaining to risk. Various risk reduction methods and their
costs are analyzed. The Agency then determines whether the pesticide may
be regulated so that a balance is achieved between risks and benefits. If
the statutory balance cannot be reached for a use, the registrations for
that use must be cancelled.
0. Regulatory History
The first registration for a product containing diallate was
granted to Monsanto on December 9, 1960 (EPA Registration Number 424-119).
Use of diallate on corn, forage legumes, lentils, peas, potatoes,
safflower, and sugar beets was approved. Because no residues were detected
in or on these raw agricultural commodities the use of diallate was
accepted under the "no residue-zero tolerance" concept.
In 1954, the Food, Drug, and Cosmetic Act was amended to provide
for the establishment of tolerances or exemptions from tolerances for
pesticide chemicals in or on food crops. The amendments also provided for
the establishment of a tolerance "at zero level" if data showed that no
detectable residues were present in the treated crop at the time of
harvest. In 1965 the National Research Council of the National Academy of
Sciences recommended that the "no residue-zero tolerance" concept be
abandoned. This recommendation was based on the fact that this concept, as
applied in the registration and regulation of pesticides, had become
scientifically and administratively untenable. Among the reasons given by
the council were that analytical methodology had improved, and that small
levels of pesticide residues had become detectable (Pesticide Residues
Committee Report on "No Residue" and "Zero Tolerance", NAS-NRC, June 1965).
In 1966 the USDA began to phase-out this concept (FR April 13,
1966). Registrants of products under this concept were given (through a
series of 1 year extensions) until 1971 to convert the "no residue"
tolerances to finite tolerances.
The Council also recommended that pesticides previously regulated
under the "no residue" concept be regulated on the basis of "negligible
residue" tolerances. These tolerances could be established by supplying a
limited amount of data. It was concluded that a negligible residue is the
amount which will produce no effects in test animals, which (effects) are
1-3
-------
indistinguishable from control animals. The tolerance, in many cases, may
reflect the sensitivity of the method and require only two 90-day
(subacute) animal studies. Such was the case when the tolerance for
negligible residues was established for diallate.
During the phase-out period, Monsanto filed a petition (PP
7F0607) requesting a tolerance of 0.3 ppm on corn, forage legumes, lentils,
peas, potatoes, safflower, and sugar beets. That petition was subsequently
withdrawn and a second petition was filed (PP 9F832) requesting a tolerance
for negligible residues of 0.05 ppm on the above crops. Tolerances for
negligible residues of diallate were established in or on the above raw
agiicultural commodities on July 28, 1971 (40 CFR 180.277).
On May 31, 1977, the Agency issued in the Federal Register (42
FR 27669) a notice of rebuttable presumption against registration and
continued registration of pesticide products containing diallate.
Diallate: Position Document 1, published together with the RPAR notice,
explained the background and supporting data for the presumption of risk
cited in the RPAR notice.
Following the publication of the RPAR notice, Monsanto Company
requested and was given a 60-day extension of the rebuttal period. The
extension was granted to all registrants and interested parties.
E. Basis for the Rebuttable Presumption
The rebuttable presumption against registration and continued
registration of pesticide products containing diallate was issued on the
basis of oncogenic effects in test animals as a risk criterion [40 CFR
162.11 (a)(3)]. Specifically, the presumption was based on the following
three long-term feeding studies which indicated that diallate is poten-
tially oncogenic: 1) a National Cancer Institute (NCI) Ulland et al.,
1973) rat study (Litton Bionetics), 2) an Industrial Bio-Test (IBT)
(Keplinger. 1976a) rat study (sponsored by Monsanto Company), and 3) an NCI
mouse study (Innes et al., 1969).
Data from the rat study conducted by Ulland and coworkers at
Litton Sionetics were verified by the NCI and reviewed by the EPA
Carcinogen Assessment Group (GAG). The GAG concluded that the Litton
Bionetics study showed a statistically significant increase in malignant
tumors at the highest dose in male rats and in carcinomas at the higher
dose in female rats.
Industrial Bio-Test concluded from its rat study "that the
neoplastic lesions noted in the test and controls were considered normal
for rats of this age and strain." In its evaluation, the CAG concluded
that "the Industrial Bio-Test study in rats showed a statistically
significant excess of mammary carcinomas in•females."
1-4
-------
The CAG also concluded that the mouse study conducted by Innes
and coworkers showed an increased incidence of liver-cell and pulmonary
tumors. This study was the basis for the Mrak Commission Report recommen-
dation that human exposure to diallate be minimized because there was
evidence of tumor induction in mice.
Respondents were given an opportunity to rebut the presumption
against diallate by showing (1) that the Agency's initial determination of
risk was in error, or (2) that given current use patterns, exposure to
diallate is not likely to result in any significant chronic adverse effects
[40 CFR 162.11(a)(4)]. Respondents were also invited to submit evidence on
behalf of the social, economic, and environmental benefits of the use of
the pesticide [40 CFR 162.11(a)(5)(iii)].
1-5
-------
II. Analysis and Assessment of Risk
A. Analysis of Rebuttal Arguments - for Oncogenicity
The Agency has analyzed the rebuttal-comments submitted to it in
response to to the presumption of oncogenicity— and responded to these
comments in this section. From the analysis of rebuttal comments, the
Agency has concluded that the oncogenic presumption against diallate has
not been rebutted and that humans are subj ect to the risk of developing
cancer from the use of diallate.
1. Rebuttal Pertaining to National Cancer Institute (NCI) Rat
Study (Litton Bionetics)
a. Errors in Tabulated Data
Monsanto Company nateu errors in the data cited in the
EPA's Carcinogen Assessment Group (CAG) (Albert, 1979) report and in
rebuttal presented a retabulation of the raw data (Monsanto Co.,
#1A[30000/15]).
The Agency acknowledges Monsanto's rebuttal on this
point. The CAG has re-evaluated the raw data and has corrected its report
accordingly. However, these corrections do not change the Agency's
interpretations of the study.
The CAG's revised tabulation of the data (shown in
Tables II-1 and II-2) differs somewhat from the data presented by Monsanto.
Most of these differences are due to the classification of gliomas and
leukemias as sarcomas by the CAG and as carcinomas by Monsanto. These
differences in classification are unimportant since the Agency bases its
regulatory decisions on oncogenic risks which include all turners (Albert,
1979a).
b. Statistical Difference in the Malignant Tumors in Males
Monsanto Company contended that according to their
analysis- of the data, there is no statistical difference in the number of
malignant tumors in the diallate-treated male rats (both dose groups
combined) compared to pooled controls (13/52 treated vs. 11/64 controls,p =
.21). Monsanto asserted further that there is no statistical difference in
the number of malignant tumors or of sarcomas in either treated group of
male rats (high or low dose) as compared ta control groups (Monsanto Co.,
#1A[30000/15]).
The respondent acknowledged an increased incidence of
carcinomas in the high-dose male group as compared to the controls, but
submitted that the incidence in the low-dose male group was not different
from either control group (Monsanto Co., #1A[330000/15]).
2/ In addition to the above-mentioned rebuttals, the Agency received
16 responses pertaining to the benefits of diallate. Comments
submitted on benefits are addressed in Section III, "Benefit Analysis."
II-l
-------
Table II-1. NCI Rat Study, Incidence of Malignant Tumors in
Male Rats Ingesting Avadex (Diallate)—
Comparison of Low- and High-Dose Groups to Pooled Controls
No. of Rats with No. of Rats, with Total No. of Rats
Dose Group Carcinomas Sarcomas" with Malignant Tumors£/—/
Pooled Control
Low Dose
High Dose
4/64 (6%) .
3/26 (12%)-
4/26 (15%)
7/64 (11%)
1/26 (4%)
4/26 (15%)
11/64 (17%)
4/26 <15%lf/ /
10/26 (38%)-:i
a/
-' Revised CAG tabulation. (Albert, 1979a)
— , Gliomas and leukemias were counted as sarcomas.
c/
— Rats with carcinomas did not have sarcomas.
—/ Corrected for survival.
—' Two of these rats with carcinomas had metastases (carcinomas of the
prostate metastatic to lung and lymph nodes; islet cell carcinomas of
_. the pancreas with metastases to the heart).
— The tumor incidence in the high dose group compared to the pooled
control group is statistically significant (p = .032) (Fisher Exact
Test).
-* The total incidence of 10/26 includes 2 unclassified malignant
tumors in the subcutaneous tissue.
II-2
-------
Table II-2. NCI Rat Study, Incidence of Malignant Tumors in
Female Rats Ingesting Avadex (Diallate)—
Comparison of Low- and High-Dose Groups to Pooled Controls
No. of Rats with No. of Rats .with Total No. of Rats
Dose Group . Carcinomas Sarcomas— with Malignant Tumors
Pooled Control
Low Dose
High Dose
— Revised CAG
— , Gliomas and
3/64 (Si).,
2/26 (8%)-/
5/26 (19%)-/
tabulation . (
leukemia s were
4/64 (6%)
2/26 (8%)
0/26 (0%)
Albert, 1979a).
counted as sarcomas .
7/64
4/26
5/26
(11%)
(15%)
(19%)
— The two rats with carcinomas of the mammary gland had metastases to
, the lungs.
— The tumor incidence in the high dose group compared to the pooled
control group is statistically significant (p = .042) (Fisher Exact Test)
II-3
-------
The Agency rej ects Monsanto's rebuttal on this point.
The GAG analyzed tumor incidence from each treatment group individually,
whereas Monsanto Company combined the data from the high- and low-dose
groups and in combining the data the significance found in the high dose
group was masked. The GAG re-evaluation of the data demonstrated a statis-
tically significant increase in total malignant tumors in male rats of the
high-dose group as compared to pooled controls (10/26 treated vs.11/64
controls; p = .032) (Refer to Table II-1) {Albert, 1979a).
c. Statistical Significance of Carcinomas, Sarcomas,
and Total Malignant Tumors in Females
From their analysis of the data on female rats,
Monsanto Company concluded that there is no statistically significant
increase in carcinomas, sarcomas, or total malignant tumors in either
treated group (Monsanto Co., #1A[30000/15]) .
The Agency rej ects this rebuttal attempt. From the
GAG's revised tabulation of the data, it is apparent that there is a
•statistically significant increase of carcinomas in the female rats of the
high-dose group as compared to pooled controls (5/26 treated vs. 3/64
controls; p = .042). (Albert, 1979a.) (Refer to Table II-2.)
d« Low Number of Tumors in High-Dose Male Rats
Monsanto Company asserted that the number of tumor-
bearing rats in each diallate-treated group is lower than in either control
group, and emphasized that the high-dose group has the lowest number of
animals with tumors (Monsanto Co., #1A[30000/15]).
The Agency rej ects this point of rebuttal. The number
tabulated by the GAG for the controls was 11/64 (17%) as compared with 10/
26 (38%) and 4/26 (15%) in the high-and low^-dose male groups, respectively.
The individual numbers of animals possessing tumors is not relevant. The
appropriate comparison is the percentage of animals which have tumors. The
percentage of animals with tumors in the high-dose v,roup is statistically
greater than the percentage of animals with tumors in the control group.
(Albert, 1979a.)
e. No Apparent Effect of Piallate on the Formation of
Individual Tumor Types
Monsanto contended that an evaluation of individual
tumor types/sites is necessary to conclude that a compound is carcinogenic,
and that there was no apparent effect of diallate on the formation of
individual tumor types (Monsanto Co., #1A[30000/15]) .
The Agency rej ects this rebuttal attempt. Although
there was no statistically significant incidence of individual tumor types,
there was a statistically significant increase of total malignant tumors in
H-4
-------
male rats of the high-dose group relative to pooled controls. Moreover,
there was a statistically significant increase of carcinomas in female rats
of the high-dose group compared to pooled controls. The use of total tumor
data in evaluating carcinogenicity is discussed in a recent Interagency
Regulatory Liaison Group (IRLG) document as follows:
"At the present time there is considerable
uncertainty about the interpretation of carcinogenic
responses in terms of the total tumor yield in contrast
to the response in terms of a statistically significant
increase of tumors in specific target organs or
tissues. Traditionally, carcinogens have been
recognized in human and animal studies by a decisive
increase in tumors of target organs. However, it is
conceivable that a generalized increase in total tumor
yield, in the absence of an excess incidence in one or
more target tissues, could occur, for example by a
promoting effect that generally increases the
spontaneous incidence of tumors in test animals or by
the action of a multipotent carcinogen whose response
did not reach statistical significance in any one organ
even at the maximum tolerated dose.— "
2. Rebuttal Pertaining to Industrial Bio-Test (IBT) Rat
Study (Sponsored by Monsanto Co.)
The existing registrations and tolerances for diallate were
established and supported by data contained in studies conducted by
Industrial 3io-Test Laboratories (IBT) for Monsanto.
In 1977, subsequent to the publication of Position Document
1, the Agency, in the Office of Pesticide Programs, established a
Toxicology Data Audit Program (TDAP) to assure the reliability and
integrity of data supplied to the Agency by pesticide manufacturers. These
data are the integral component of the information upon which pesticides
are registered and tolerances are established in the United States.
Industrial Bio-Test Laboratories (IBT) was one of the
initial laboratories audited jointly with the Food and Drug Administration.
The IBT laboratory performed a large volume of testing utilized by the
Agency in its regulatory decision-making. During an audit at the facility,
numerous significant departures from acceptable laboratory practice were
noted. As a result, the Agency decided to reevaluate all pivotal IBT
studies used in support of tolerances. The workload of this evaluation
program was shared with the Canadian Government in cases where chemicals
were registered on identical data bases. The IBT studies for diallate were
evaluated by Canada and the results are shown in Table II-2a.
3/ IRLG (February 6, 1979), Scientific Bases for Identifying Potential
Carcinogens and Estimating Their Risks.
II-5
-------
Table II-2a. Diallate IBT Studies
Type of Study
IBT No.
Status
Remarks
Fish & Wildlife
8-Oay LC Mallard Duck
8-Day Dietary LC5Q Bob-
white Quail
8-Day Dietary LC5Q Bob-
white Quail
8-Day Dietary LC^Q Bob-
white Quail
4-Day Fish Tox
Fish & Wildlife
Fish S Wildlife
Fish & Wildlife
Acute Studies
4-week Pilot oral study
Pilot feeding study/mice
Acute Inhalation
Acute cholinesterase
651-3026
J-6672
J-6673
651-3025
Valid
Valid
Valid
Valid
665-3027
A-6675
A-6674
A-6849
3531-9714
8532-9820-
59-13-3
8530-9030
Valid
Invalid No raw data
Invalid No raw data
Invalid No raw data
Valid
Invalid Incomplete raw data
Invalid No raw data
Valid
II-6
-------
Table II-2a. (continued). Diallate 1ST Studies
Type of Study
Subacute Studies
Subchronic oral
Subchronic oral
Subchronic oral
Subchronic oral
Chronic Studir.s
Teratogenicity/rabbits
Mutageni city/mi ce
Neurotoxicity/ chicken
Neurotoxicity/ chicken
Chronic feeding/rats
IBT No.
59-13A
59-13-2
59-13
59-13-1
651-5254
622-5252
8580-9119
8580-10813
622-5250
Status
Invalid
Invalid
Invalid
Invalid
Invalid
Invalid
Valid
Invalid
Invalid
Remarks
No raw data
No raw data
No raw data
No raw data
Deficiencies in
exper imental
design
No raw data
No raw data
Incomplete raw
data
IX-7
-------
TDAP Evaluation of 1ST Rat Study
The IBT study sumitted by Monsanto was evaluated by the
Office of Pesticide Program's Toxicology Data Audit Program (TDAP). The
analysis of the study indicates that the 2-year feeding study is invalid
because of the lack of histopathology data, food consumption data, organ
weight data on surviving animals, and dietary preparation data to show
unequivocally that doses were correctly prepared. Therefore, no scientific
conclusions can be drawn from this study.
a. Errors in Tabulated Data
Monsanto observed errors in the data cited in the CAG
report and in their rebuttal submitted a retabulation of the raw data.
Monsanto contended there are no statistically significant differences in
the number of animals with tumors in the diallate-treated groups as
compared to the controls (Monsanto Co.,- #1A[30000/15]).
The CAG has re-evaluated the raw data and has corrected
its report accordingly. The revised CAG tabulation (shown in Tables II-3
and II-4) now agrees with the retabulation submitted by Monsanto Company.
The data indicate that there is no statistically significant increase
either of total tumors (benign and malignant) or of tumors of any
anatomical site in any diallate-treated group of male rats as compared to
controls.
As Table II-5 indicates, however, female rats treated
with 100 ppm diallate (middle dose) showed a statistically significant
increase of benign mammary tumors (p = .021) and hence of total mammary
gland tumors (Albert, 1979). Therefore, the last portion of this rebuttal
is rej ected.
b. No Statistical Increase in Mammary Tumors
The incidence of mammary tumors in diallate-treated
female rats is shown in Table II-5. Monsanto Company pointed out that
there was no statistically significant increase in the number of mammary
tumors in the treated female rats of the high- or low-dose groups as
compared to the controls. The respondent argued that the admittedly
statistically significant increase in mammary tumor among the middle-dose
groups represents a random event, since there was no dose response.
Monsanto pointed out further that there is no statistically significant
increase of mammary carcinomas. (Monsanto Co., #1A[30000/15])
As Monsanto noted, the female rats of the middle dose
group exhibited a statistically significant increase of total mammary
tumors (p = .021), which was attributable to the statistically significant
increase in benign mammary tumors (p = .021). This increase of benign
mammary tumors in the middle-dose group may indicate an adverse effect,
although the possibility that this response may be a random event cannot be
11-8
-------
Table II-3. IBT Rat Study, Incidence of Benign and Maligngnt
Tumors in Male Rats Ingesting Diallate
Dose Group
No. of Rats with
Benign Tumors
No. of Rats with , .
Malignant Tumors
Total No. of Rats
with Tumors
Control
50
100
200
1/50 (2%)
0/50 (0%)
2/49 (4%)
1/50 (2%)
4/50 (8%)
7/50 ( 14% )
4/49 (8%)
6/50 (12%)
5/50 (10%)
7/50 (14%)
6/49 (12%)
7/50 (14%)
Revised GAG tabulation (Albert, 1979a).
— Rats with endocrine tumors are not included.
— Rats with both benign and malignant tumors were tabulated as having
malignant tumors.
II-9
-------
Table 11-4.
1ST Sat Study, Incidence of Carcinomas and., .
Sarcomas in Male Rats Ingesting Diallate^ — —
Dose Group
No. of Rats with
Carcinomas
No. of Rats with
Sarcomas"
Total No. of Rats
with Malignant Tumor
Control
50
100
200
0/50 (0%)
3/50 (6%)
1/49 (2%)
2/50 (4%)
4/50 (8%)
4/50 CS.%) ,
3/49 (6%)~
4/50 (8%)
4/50 (8%)
7/50 (14%)
4/49 (8%)
6/50 (12%)
^' Revised CAG tabulation (Albert, 1979a).
— Table II-4 is an elaboration of Total Malignant Tumors column in
, Table II-3.
— Rats with ondocrine tumors are not included.
— Rats with both benign and malignant tumors were tabulated as having
malignant tumors.
S/
One rat had metastatic fibrosarcoma to the lung and liver, another
to the lung. No primary sarcomas were found in the two rats.
11-10
-------
unequivocally refuted (Albert, 1979a). However, the high percentage of
test animals with tumors in the high dose group strongly suggests that
there is an adverse effect.
c. Spontaneous Pituitary Adenomas
Monsanto Company pointed out that there is -a high
spontaneous- incidence of pituitary adenomas in the I3T rat study. The
respondent pointed out further that there is no apparent significant
increase in the incidence of this tumor in any treated group, nor any
linear increase by dose observed (Monsanto Co., *1A[30000/15] ).
The Agency agrees with this conclusion (Albert, 1979) .
3. Rebuttal Pertaining to the NCI Mouse Study (Innes Study)
a. Study Invalid
Monsanto Company claimed that the Innes study is
invalid for the following two reasons:
1) Only one dose level, the maximum tolerated dose
(MTD), was used in the study. The rebuttal contended that the MTD has been
redefined, thereby making the doses used in the study higher than what is
now considered the MTD and invalidating the experiment.
2) The experimental design necessitated the dosing
of litter-mates. The rebuttal contended that biological and statistical
significance cannot be drawn from this inferior experimental design.
Monsanto suggested that a bias of inherited tendencies (e.g., predisposi-
tion to hepatoma formation) cannot be eliminated because the litter mates
were not randomly distrihnted among the test groups (Monsanto Co.,
*1A[30000/15).
The Agency rej ects this rebuttal argument.
Concerning Monsanto's point 1) above, the Agency points out that the MTD is
defined in the NCI Guidelines as "... the highest dose of the test agent
given during the chronic study that can be predicted not to alter the
animal's normal longevity from effects other than carcinogenicity."—
Innes et al. reported that the MTD was
selected on the basis of a series of studies in which the maximal level
given in a5single dose, in 6 daily and in 19 daily doses, resulted in zero
mortality.—
— NCI Guidelines for Carcinogen Bioassay in Small Rodents, NCI Tech.
Report Ser. No. 1, Feb., 1976, p. 14. U.S. Dept. of Health, Education
and Welfare, PHS, NIH, NCI-CG-TR-1.
—^ Innes, J.R.M. et al (1969) Bioassay of Pesticides and Industrial
Chemicals for Tumorigenicity in Mice: A Preliminary Note. J. Nat.
Cancer Inst. Vol. 42, p. 1102.
H-11
-------
Table II-5.
IBT Rat Study, Incidence of Benign and Malignant Tumors of
the Mammary Gland in Female Rats Ingesting Diallate—
Dose Group'(pom)
No. of Rats with
D/
Benign Tumors—
No. of Rats with
Malignant Tumors
Total No. of Rats
with Tumors
Control
50
100
200
14/50 (28%)
19/49 (39%)
24/48 (50%)
15/46 (33%)
5/50 (10%)
4/49 (8%)
5/48 (10%)
10/46 (22%)
19/50 (38%)
23/49 (47%)
29/48 (60%)-
25/46 (54%)
~' Revised CAG tabulation (Albert, 1979a) .
— Rats with both benign and malignant tumors were counted as
malignant.
— The tumor incidence in the 100 ppm dose group compared to the
control group is statistically significant (p = .021) (Fisher Exact Test),
11-12
-------
A comparison of the survival data in the carcino-
genicity study indicates that the number of 18-month survivors in the
diallate-treated groups was similar to that of the vehicle (0.5% gelatin)
and untreated control groups for each respective species/sex. Hence the
doses given in the study were tolerated by the treated animals and
therefore did not exceed the MTD.
. In reference to Monsanto's point 2) above, Innes
administered diallate to mice (in 0.5% gelatin) by stomach tube from 7 days
to 4 weeks of age. Thereafter, the mice were weaned and were given
diallate (without a vehicle) in the diet. Since the study began prior to
weaning, each test group (e.g., diallate-treated, positive or negative
control group) was comprised of litter-mates instead of a random assortment
of litter-mates, which was precluded by the study design.
During the MRAK Gommission review of this study,
which recommended that human exposure to diallate be minimized,— Mr.
Carrol Weil presented a dissenting opinion which included criticism of the
non-random allocation of animals. Monsanto cited Mr. Weil's criticism in
its rebuttal.
In response to Mr. Weil's criticism on non-
randomization, the MRAK Commission reported that "...the data were
reexamined on a litter basis, in keeping with the Epstein-Mantel approach,
rather than on the single-animals basis employed in the Journal of the
National Cancer Institute report. All compounds which had been judged
positive for tumor ^nduction (significant at the 0.01 level, or stronger),
remained positive."— Thus, although non-randomization of litter-mates
is not the optimal experiment design, there is no evidence in this study
that a bias existed for a genetic predisposition to tumor occurrence
(Albert, 1979a).
b. Sex Specificity—•Increased Hepatomas in Male Mice
Monsanto Company acknowledged the statistically
significant increase in hepatomas in male mice in the Innes study, but
contended that the apparent sex-specificity is unusual (Monsanto Co.,
* 1A[30000/15]).
The Agency rejects this rebuttal point. The data from
the Innes study indicate a statistically significant increase in hepatomas
in both strains of male mice when compared with either their respective
matched (vehicle) control, negative control, or pooled negative control
6/
— Report of the Secretary's Commission of Pesticides and Their
Relationship to Environmental Health, Parts I and II. U.S. Dept. of
Health, Education and Welfare, Washington, D.C. (1969), p. 470.
— Ibid p. 483.
11-13
-------
groups; and a statistically significant incidence in female mice of strain
X when compared with the pooled negative control group only. Contrary to
Monsanto's assertion, hepatic tumors are known to occur raore frequentlv in
male mice than in females.— (Albert, 1979a).
c. No Statistically Significant Increase in Pulmonary
Adenomas
Monsanto Company argued that there was no statistically
significant increase in pulmonary adenomas in either sex of either strain
of mouse, whereas the CAG report indicated a small statistically
significant increase of .lung adenomas in both sexes of strain X and in
males of strain Y (Monsanto Co., #1A[30000/15]).
The Agency rejects this point of rebuttal. Having re-
analyzed the data, the CAG finds a borderline statistically significant
increase of pulmonary adenomas in the diallate-treated males of strain X as
compared with the matched (vehicle) control group (p = .051) and with
the pooled control groups (p » .041). (See Table II-6) (Albert, 1979a).
B. Analysis of Data Submitted Since PP 1 for Other Possible
Adverse Effects
1. Mutaqenicity
In PD 1 the Agency, based on the two available studies,
stated that it had insufficient data to indicate diallate is mutagenic.
The two studies were one, an Ames test in bacteria, and the second, a
dominant lethal study in rice (Keplinger 1974). On the basis of this
conclusion, the Agency requested comments and information on diallate's
mutagenic potential. Additional studies were submitted and evaluated, and
the Agency now concludes that diallate meets the criteria stated in 40 CFR
162.11 for mutagenicity by multi-test evidence. The additional studies
which led to the Agency1 s finding are discussed below.
In response to the Agency's request for additional
information with regard to the possible mutagenic properties of diallate,
Rinkus and Legator (1977) submitted a study entitled "Mutagenicity of
Diallate." This study, an Ames test, investigated the mutagenic effects of
diallate in five strains of Salmonella. Diallate exhibited mutageni:
activity in strains TA 1535 and TA 100 which exceeded the mutation
frequency of controls by factors of approximately 20 and 12 respectively.
This activity was only observed in the presence of a microsomal activation
system. No activity was observed in strains TA 1537, TA 1538, and TA 98 in
identical tests.
8/
— Stewart, H. I>. (1976). Comparative aspects of certain cancers.
Chpt. 10 in Cancer, A Comprehensive Treatise, Vol. 4, F. F. Becker
(ed.), Plenum Press, New York.
H-14
-------
Table II-6. NCI Mouse Study (Innes Study): Lung Tumors in Mice
Ingesting Avadex (Diallate)
Dose
Group
Strain X
Strain Y
Male
Female
Male
Female
Pulmonary Adenoma Matched Control
Pulmonary Carcinoma
0/16*(0%) 0/16 (0%)2/18 (11%) 1/17(5%)
0/16 (0%) 0/16 (0%)0/18 (0%) 0/17(0%)
Pulmonary Adenoma Negative Control
Pulmonary Carcinoma
2/17 (12%) 1/18 (5%)2/18 (11%) 0/17(0%)
0/17 (0%) 0/18 (0%)0/18 (0%) 0/17(0%)
Pulmonary Adenoma Pooled Control
Pulmonary Carcinoma
5/79**(6%) 3/87 (3%)10/90(11%) 3/82(4%)
0/79 (0%) 0/87 (0%) 0/90 (0%) 0/82(0%)
i
t~*
in
Pulmonary Adenoma 560 ppm
Pulmonary Carcinoma
4/16 (25%) 2/16 (13%)4/18 (22%]
0/16 (0%) 0/16 (0%0 0/18 (0%) 0/15(0%)
* p = .051 (Fisher Exact Test) for the incidence of pulmonary adenomas in
the treated group compared with the matched control.
**
p = .041 (Fisher Exact Test) for the incidence of pulmonary adenomas in
the treated group compared with the pooled control.
-------
In PD 1 an unevaluated study by Sikka and Florczyk (1978)
was mentioned. The study investigated the ability of diallate to induce
mutations in four strains of Salmonella typhimurium (TA 100, TA 1535, TA
98, and TA 1538) with and without a rat-liver microsomal activation system.
The study has now been evaluated and found to show activity at the 1 ug per
plate level in the TA 100 and TA 1535 strains indicating base-pair substi-
tutions with metabolic activation. Diallate did not cause mutation in
strains TA 98 and TA 1538 {frameshift mutants). These results confirm the
findings of Rinkus and Legator.
Litton Bionetics, Inc. (LSI) (Brusick, 1977b) investigated
the effects of diallate in the L5178Y mouse lymphoma cell. Ths study
concluded that "The test compound, CP 15336, induced forward mutation at
the TK locus in L5178Y mouse lymphoma cells in the presence of an uninduced
mouse liver S-9 metabolic activation system." No dose-related effects were
observed in the absence of metabolic activation.
Studies by SRI International (Simon, 1978) for EPA show that
diallate does not induce gene mutation in £_._ coli (WP2). The bioassay was
designed to monitor induced genetic alteration in E. coli at the tryptophan
locus. However, tests in JE. coli are not as sensitive as tests in
Salmonella and, therefore, positive findings may not be manifested through
experiments in this organism (Sandhu, 1978).
Diallate's potential to cause primary DNA damage was studied
in two strains of Saccfaaromyces cerevisiae. SRI International (Simon,
1973) employed strain D_ to measure induced mitotic recombination and LSI
(Brusick, 1977a) used strain D to measure gene conversion, while posi-
tive results were reported for mitotic recombinations in the SRI study, the
LSI study results were negative. However, this mixed finding does not
detract from the finding of induction of mitotic aberrations, a supportive
finding for mutagenesis.
Monsanto submitted a dominant lethal study in mice in 1975
(Keplinger, 1974). This study done by 1ST was reported by Monsanto as a
negative study. Th*» TDAP program reviewed this study and found it to be
invalid because of the lack of raw data.
2. Neurotoxicity
The Agency concluded in the PD 1 that diallate is neurotoxic
at the dose levels tested. This conclusion was based on an IBT study in
chickens {Keplinger, 1976b). That study did not provide a dose-response
relationship nor a no observable effect level which is needed to determine
a margin of safety.
In the diallate PD 1, published on May 31, 1977,
registrants were given 180 days to complete appropriate neurotoxicity
studies and submit the r-.suits to the Agency or face possible cancellation
under the provisions of FIFRA Section 6(b)(1)— . Monsanto submitted an
9/
— In 1978 FIFRA was amended to provide for suspension under Section
3(c)(2)(B).
11-16
-------
IBT study in which diallate was administered to chickens—' at dose
levels ranging from 0.01 to 0.32 gm/kg which were administered twice daily
for 3 consecutive days (Phillips, 1977). Twenty days following the initial
dose, all surviving birds were again given the same dose regimen. Controls
were dosed with 0.32 gm/kg corn oil and positive controls received 500 mg/
kg TOCP on day 0.
All positive controls exhibited lesions typically associated
with delayed neurotoxicity (Phillips, 1977). No such lesions were found in
the negative controls.
Two test birds, one in the 0.04 gm/kg and one in the 0.16
gm/kg group showed focal lesions of axonal degeneration and secondary
demyelination in the sciatic nerve. While these lesions were described as
morphologically indistinguishable from those observed in the positive
control birds, the affected birds showed no clinical signs which could be
characterized as delayed neurotoxicity prior to sacrifice. No dose
response relationship was established nor were there any reasons given for
the absence of lesions at the highest dose.
Both of these I3T studies were reviewed by the TDAP. The
original study, discussed in PD1, was validated and therefore does demon-
strate that diallate given at 312 mg/kg causes neurotoxic effects. How-
ever, as stated in PD 1, this study does not show any dose response with
which to determine ultinate safety. The second IBT study on neurotoxicity
was declared invalid. TDAP found that raw data were totally missing on
this experiment.
The Agency's concerns on neurotoxic effects of diallate have
not been addressed by the registrant. While attempting to satisfy the
needs of EPA, Monsanto has failed to take adequate precautions to insure
validity of their data. Therefore, although the Agency does not have
enough data to quantify the potential neurotoxic risks of diallate, it has
calculated the annual applicator exposure. The Agency has determined that
the effect level is 600 times greater than the exposure level.
3. Reproductive Effects
Prior to the RPAR review the Agency requested Monsanto to
perform a 3-generation reproduction study in rats. However, no time limit
was imposed on the registrant. At the time of PD 1 only the data in the
F° (parental) generation had been submitted. The final report is
expected in 1980. This study will be evaluated by the Agency and its
results will be included in PD 4.
—/ The study used 5 birds per dose group with dose given at 0.01,
0.02, 0.04, 0.08, 0.16, and 0.32 gmAg-
H-17
-------
C. Exposure Analysis
The Agency analyzes exposure to a pesticide as part of the
overall risk assessment. The complete exposure analysis includes
incremental exposures to various populations depending on the route of
exposure (e.g. dietary exposure to the general population, occupational
exposure to applicators, drift to farm families, etc.). In compiling the
analysis, the Agency takes into account the use patterns and methods of
application so all populations likely to receive exposure are included in
the analysis.
1. Spray Applicator Exposure
a. Spray Applicators
Information concerning spray applicator exposure was
provided by the Environmental Fate Branch of the Agency's Hazard Evaluation
Division (HfiD) (Selim, 1978). Diallate is applied primarily as an emulsi-
fiable concentrate with ground equipment by boom sprayer. Spray applica-
tors are exposed to diallate by 1) dermal exposure during the loading of
the sprayer and during the application process, and 2) inhalation of the
volatilized compound.
Exposure from diallate has not been maasurad, conse-
quently the Agency used published data on triallate to prepare axposur-3
analysis for diallate (the mode of application ar.d chemical-physical
propertiss of triallate are similar to diallate). To further check these
results, the Agency validated the assumptions used for diallate by an
exposure analysis which was published for paraquat. The pattern of
exposure to paraquat is similar for the applicator wording with diallate.
Therefore, the Agency felt justified in utilizing the paraquat data for
extrapolation to diallate. Both of these extrapolations produced very
similar results.
The estimated dosages were reported in mg/hr, then
converted co mgAg/year. The conversion from dermal exposure expressed in
mg/kg/year to equivalent lifetime dietary exposure expressed in ppm in the
diet is as follows:
60 kg (worker dermal exposure- in mg/kg/yr) x 40 yr
365 d/yr ^70 yr x 1.5 kg/d
6.26 x 10 x (worker dermal exposure in mg/kg/yr)
lifetime dietary exposure in ppm
where X is ppm in diet, 60 is average body weight in kg, and 1.5 kg is the
average daily dietary intake. A 40-year working history and a 70-year
lifetime is assumed for the applicators. This value (X) will be used to
calculate lifetime probability in the Risk Assessment Section (II.D.1).
11-18
-------
Table II-7 presents data on the absorbed dose in mg/kg/
year and parts per million for spray applicators exposed to diallate.
Rubber gloves and coveralls were considered as protective clothing when
calculating the exposure reduction levels.
The annual exposure to applicators of diallate is 0.516
mg/kg/yr (.0323 ppm) and 0.018 mg/kg/yr (0.0011 ppm) from dermal and
inhalation exposure respectively (Selim, 1978). These estimates are based
on 10% absorption from both routes (Gardner, 1980). Based on the assump-
tion that dermal exposure would be reduced by a factor of 4 if protective
clothing is used, the dermal exposure level can be reduced to 0.13 mg/kg/yr
(8.1 x 10 ppm) (Selim, 1978).
b. Granular Applicators
An applicator's exposure from granular diallate
applications would be lower than an applicator's exposure using the
emulsifiable concentrate formulations. With the granular formulation there
is no chance of exposure from spray drift or from spray splash as there is
with the enulsifiable concentrate formulations. The granules do not
adhere to the skin as the emulsifiable concentrates would. Additionally,
because diallate is applied during the late fall or early spring in the
northwestern states, it is likely that most diallate applicators would be
wearing clothing such as long sleeved shirts and trousers to protect
themselves from rhe cold as well as protect uhemselves against the
diallate. However, for the brief period of loading the (ore-mixed)
granular diallate formulations there is a potential dermal and inhalation
exposure hazard to the applicator due to dust from the granules. To
mitigate this potential hazard, the Agency suggests the use of rubber gloves
and cloth face masks for applicators during the loading process.
2. Dietary Exposure
The human population encounters direct dietary exposure to
diallate. residues through consumption of the following foods: barley,
lentils, peas, soybeans, sugar beets, corn (grain), and flax (seed).
Maximum worst-case exposure was developed from tolerances
established for residues of diallate in foods. The FDA, in its Market
Basket Survey, has not analyzed raw agricultural commodities specifically
for diallate. It is assumed that residues are present in all individual
raw agricultural concnodities to che extent permitted by the tolerances and
that the commodities are uniformly distributed throughout the country.
Table II-8 presents the dietary exposure of the entire U.S. population to
diallate.
A second set of estimates were-developed which were based on
available information concerning the percentage of crops treated and were
provided by the Agency's Benefits and Field Studies Division (Lewis, 1978).
Table II-8 presents the exposure estimates when the percentage of crop
treated is considered.
11-19
-------
D. Risk Assessment
1. Oncoqenic Effects
The cancer risk assessment of diallate is based on the
principles and procedures outlined in the EPA interim cancer risk assessment
guidelines (41 FR 21402, May 25, 1976). These guidelines specify that a
substance will be considered a "presumptive cancer risk when it causes a
statistically significant excess incidence of benign or malignant tumors in
humans or animals." Current and anticipated exposure levels are appro-
priate considerations for establishing cancer risk estimates. These
estimates may be derived from a variety of risk extrapolation models such
as the log-probit and linear non-threshold models.
11-20
-------
Table II-7 Diallate Dermal and Inhalation Exposure to Spray
Applicators and Equivalent Lifetime Dietary Exposure
Route of
Exposure
Estimated
Dose
mg/hr
Duration
of
Exposure
Dose
in
mg/kg/yr
Dose in
ppm
DERMAL
Absence of
protective cloth- __
ing (Assuming 2.58 6-12 .258 2 x 10
10% dermal . hr/yr. .516 3 x 10
absorption)—
With protec-
tive clothing _
(Assuming 10% .65 6-12 0.065 4 x 10
dermal ^. . hr/yr. .13 8 x 10~
absorption)— —
INHALATION
-4
Without mask .09 6-12 .009 6 x 10
hr/yr. .018 1 x 10
With mask _5
(10% of .009 6-12 .0009 6 x 10_4
exposure hr/yr. .0018 1 x 10
without
mask)
1/ 10% absorption is assumed in absence of data on diallate (Gardner,
~" 1980).
2/ Assuming that protective clothing provides a four fold reduction in
~ exposure. (Selim, 1978)
11-21
-------
Table II-8.
Annual tJ.S. Population Dietary Exposure to Diallate, Based
On Tolerance Levels and Percent of Crop Treated
Exposure Based on
100% of Crop Treated
with Residues at
Tolerance Levels
Source ppm
Barley 0.000013
Lentils 0.00002
Peas 0.00035
Potatoes 0.00271
Saf flower* 0.000013
Soybeans 0.00046
Sugar beets Q. 00001
Corn, grain 0.0005
Flax, seed 0.000013
Percent of Crop
Treated with
Diallate
0.10
33
10
0.46
100
0.20
14.3
0.009
3
Exposure Based on Actual
Percent of Crop Treated
with Residues at
Tolerance Levels
ppm
0.00000
0.00001
0.00005
0.00002
0.00002
0.00000
0.00012
0.00000 **
o.ooooo **.
Total
0.004089
0.00022
* 100% is assumed in the absence of data
** Not actually "0", remaining significant figures truncated.
11-22
-------
In accordance with these principles, the EPA Cancer
Assessment Group (GAG) (Albert, 1979b) developed risk estimates based on
several different models and a range of exposure estimates. After
reviewing the data sources and the preliminary risk estimates, the GAG
concurred in recommendations that the final quantitative risk estimates be
based on data from the NCI mouse study (Innes study) using the one-hie
model. The CAG used the Innes data because animals in the Innes study were
fed the compound beginning at a younger age than were animals in the NCI
(rat) or IBT studies, and therefore provided the most sensitive animal upon
which to base the conservative analysis.
To develop a risk estimate, CAG evaluated the animal test
data and the human exposure data using several different models. They
selected the one-hit model because it provided the most conservative
estimate of potential risk to humans.
As explained above/ the animal bioassay data used for the
quantitative risk assessment were based on the Innes oral feeding study in
mice. In this study one treated group of mice were fed 560 ppm diallate in
the diet. A statistically significant higher incidence of hepatomas in
males of both strains X and Y was observed, as compared to matched controls
(see Table II-9).
The proportion of hepatomas observed in Strain X males was
used to calculate the slope parameter, for the one-hit model, adjusting for
background tumor incidence. Therefore, using the proportion of hepatomas
in the matched control 9TT°up and the treated group, the one-hit slope
parameter is as follows:—
B - • In [(1-Pt)/(1-Pc)] /y
B - - In [(1- 13/16)/(1-0/16)1/570
» 2.989. x 10
Prom the slope, the estimate life-time probability can be estimated from
the following equation.
P » BX * (2.989 x 10~3)X
(where X is the ppm in the diet from actual exposure
and from equivalent dermal exposure as calculated in
Section II.C.1.)
— Where: B * slope coefficient of the one-hit model
P * (Pt-Pc)(1-Pc)
PC * Incidence of hepatomas in control animals
Pt » Incidence of hepatomas in test animals
Y » Test animal exposure (ppm)
x * Potential human exposure (ppm)
11-23
-------
Table II-9. NCI Mouse Study (Innes Study): Liver Tumors (Hepatomas) in
Mice Ingesting Diallate
Dose Group
Matched Control (vehicle)
Negative Control
Pooled Control
560 ppm
Strain
Male
0/16*
1/17*
8/79*
13/16
X
Female
0/16
0/18
0/87**
2/16
Strain
Male
1/18*
3/18**
5/90*
10/18
Y
Female
0/17
0/17
1/82
1/15
* Statistically significant when p is £ .01,
** Statistically significant when p is £ .05,
11-24
-------
The exposure estimates for dietary and applicator exposure
were factored into the above equation. Risks from these exposures are
shown in Tables 11-10 and 11-11. A dietary worst-case risk of 10
occurs at tolerance levels assuming that 100% of the crops are treated. It
is not likely that 100% of the crops will be treated with diallate. There-
fore using the projected percentages of treated crops from Section III,
results in a reasonable worse case risk of 10
Risk to applicators without protective clothing is estimated
at 10 , a relatively high risk. With protective clothing, risk to
applicators is improved to 10 (Table 11-11).
Aggregated, these risks imply that 1 in 10,000 applicators
might have a lifetime risk of developing a diallate induced tumor taking
into account both occupational and dietary exposure. It is estimated that
there are 2380 diallate applicators (Selim, 1978). The general population
would have a lesser risk (10-7), but this is based on current usage and
should any increase in usage occur, the dietary risks would increase.
2. Mutagenic Effects
While adequate evidence exists to establish the rtiutagenicity
of diallate in in vitro systems, no quantitative assessment of risk can be
made because of (1) insufficient data from mammalian test systems(Mauer,
1978), and (2) no generally, applicable method has been developed to
quantify autagenic risk.— Recent studies have established a strong
correlation between a chemical's carcinogenic potential and its ability to
induce mitotic recombination (Sandhu, 1978).
The Agency has not yet developed a standard procedure for
defining mutagenic risk in quantitative terms. At the present
time/ much attention is being focused on developing a battery of
test systems and other data that are predictive of mutagenic risk
in humans. Until such time as more quantitative methods and
procedures for risk estimation are developed for each mutagenic
endpoint of concern, the Agency will evaluate each mutagenic
chemical on a case-by-case basis, taking into account all
available test data. The approach taken by the Agency will of
necessity be conservative in order to assure that man and the
environment are protected from the risk of "unreasonable adverse
effects" through the action of mutagenic agents. The evolving
nature of methodology in the field of mutagenicity testing
dictates that the Agency will revise its risk estimation
procedure for future chemicals under evaluation as superior risk
predictive models and other relevant information become
- available. As well, the Agency will revise its risk estimates
for chemicals which have previously been subjected to risk
assessments if additional more relevant test data and other
predictive information are developed.
11-25
-------
Table 11-10. Lifetime Spray Applicator Cancer Risk from Dermal and
Inhalation Exposure to Diallate
Equivalent Lifetime
Dietary Dose Assuming
12 Hour Annual Exposure Lifetime Probability of
Route (ppm)
DERMAL
Without protective 3 x 10
clothing*
With protective
clothing (10% -
absorption)* 8 x 10
INHALATION
Without aask 1 x 10"
With aask (10%
of exposure .
without aask)* 1 x 10
Cancer Due to Diallate
1 x 10~4
2 x 10~5
3 x 10~6
3 x 10~?
* 10% absorption is assumed in the absence of data on diallate (Gardner
1980).
11-26
-------
Table 11-11. Cancer Risk to U.S. Population from Dietary
Exposure to Diallate
Source
Lifetime Probability
of Cancer Based on
100% of Crop Treated
Residues at Tolerance
Levels
Lifetime Probability
of Cancer Based on
Estimated Percent of Crop
Treated with Residues
at Tolerance Levels
Sarley
Lentils
Peas
Potatoes
Saf flower
Soybeans
Flax seed
Beet Sugar
Corn
Total
4
6
1
3
4
1
4
1
1
1
-8
x 10
-8
x 10
-6
x 10
-6
x 10
x 10~8
-6
x 10
-6
.9 x 10
-6
x 10
-6
X 10
-5
x 10
-11
4x10
-8
2 x 10
-7
1 x 10
-8
4 x 10
4 x 10~8
3 x 10~9
Negligible
-7
2 x 10
Negligible
-7
4 x 10
11-27
-------
E. Risks Associated with Alternative Chemicals
Several chemicals have been proposed as alternatives should
diallate become unavailable. In non-irrigated areas, eptam would be the
major substitute with barban and dalapon used to a lesser extent. In
irrigated areas cycloate and barban are the major substitutes. Eptam and
barban are substitutes used on flax. Triallate, prophaai and barban are
alternative chemicals, for use on lentils and peas.
The data bases for the alternative chemicals are not complete. A
complete list indicating the studies which the Agency has on hand appears
in Table 11-12. Based on the studies reviewed for all alternatives other
than triallate, no unreasonable adverse effects were found associated with
the proposed alternatives. Because of the lack of chronic studies no quali-
tative ranking of alternatives can be made with regard to their relative
toxicities.
The battery of toxicological tests performed on triallate include
mutagenie, chronic feeding, teratogenic, and neurotoxic studies. Triallate.
was found to exhibit mutagenic activity in the Ames test in bacteria with
metabolic activation. It was also found to be positive in yeast when
tested for mitotic recombination. Negative findings were reported to gene
conversion in yeast, mouse lymphoma, and dominant lethal assays. When
triallate is compared to diallate in tests which are positive for both,
diallate.is at least 3 times more active.
Negative findings for triallate were reported in a chronic
feeding study in rats. This study was evaluated by TDAP and found to be
valid only as an oncogenic screen test because of ieficiences in the
experimental design.
The teratogenic and neurotoxic studies on triallate were
performed by IBT. These studies were evaluated by TDAP and found to be
invalid.
11-28
-------
TOXXCOIXX3ICAI, DATA SUMMARY TOR DIALLATE ALTERNATIVES (CHRONIC DATA)
M
iD
CHEMICAL ONCOGENICITY
Trialiate **Rat
Barban N/A
Cycloate N/A
Oalapon N/A
EPTC*
CHRONIC REPRODUCTIVE
MUTAGENZCITY FEEDING TERATOGENICITY EFFECTS
Gene Conversion (-)
Mitotic Recom-
bination (t) **Uat (-) Rabbit (Invalid) N/A
bacteria 4+ (with
activation)
2- (no activation)
Dominant Lethal (-)
Mouse Lymphoma (-)
N/A Dog (-) N/A N/A
N/A Rat (-) N/A N/A
N/A Rat (-) Dog (-) N/A
Rat (-)
NEUROTOXICITY
Chicken (2 In\
Studies)
N/A
N/A
N/A
(+) Positive Study
(-) Negative Study
* EPTC has negligible residue tolerances, therefore no chronic data have been
submitted.
** This IBT study listed under "Oncogeniclty" and "Chronic Feeding," was
reviewed by TDAP. While the study was considered invalid as a chronic
feeding study, it was found valid as an oncogenic screening study.
-------
III. Benefit Analysis
As a pre-emergence selective herbicide, diallate is used as a soil
treatment on field crops for control of wild oats. Because Monsanto is the
sole producer of diallate, production and marketing data are confidential.
However, it is estimated that approximately 390,000 pounds active
ingredient of diallate were applied annually to 319,000 acres of sugar
beets, flax, lentils, and peas, the major use sites of diallate between
1976 and 1978. Small amounts of diallate are also applied to potatoes,
soybeans, barley, corn, and forage legumes.—
The Agency has received 16 submissions from registrants and interested
parties pertaining to the benefits of diallate, in particular as it is used
on sugar beets, lentils, and peas. The Agency considered this information
in analyzing the benefits of diallate.
For sugar beets, flax, lentils, and peas, the estimates of acreage
treated, the identification of biologically viable alternatives, and the
use data were based primarily on Assessment of the Need for Diallate in
Agriculture, USDA/State Assessment Team on Diallate (September, 1977, and
1979 modifications). The economic analysis based on these biological data
was prepared by Development Planning and Research Associates, Inc. in March
of 1979.
However, lack of published data on yield changes limited certain
aspects of the analysis. Expert opinion was used in place of these data.
Alternate weed control strategies also lacked firm data, necessitating the
use of expert opinion to generate impacts of alternate control programs
(USDA/State Assessment Team, 1977).
The alternatives to diallate were selected on the basis of cost,
efficacy, and availability. Partial budgeting was employed to assess the
economic impacts of diallate cancellation.— The partial budgeting
methodology allowed the change in the cost of weed crntrol to be measured,
together with the effect on gross returns associated with substituting
alternative weed control practices while all other inputs were held
constant. The economic analysis also assumed that in some instances the
cancellation of diallate would cause growers to shift production to
alternative crops. In these cases, net returns to the producer associated
with the production of alternative crops were evaluated.
1/ The OSDA/State Assessment Team on Diallate (August 31, 1977) esti-
"~ mated that approximately 10,000 acres or less of each of these crops
were treated with -diallate annually, accounting for 0.5% or less of
the total crop planting in each case. The Monsanto ;-ubmission filed
September 9, 1977, did not address the benefits of diallate use on
any of these minor crops.
2/ The partial budgeting methodology allows the measurement of the
"" change in the cost of pest control and the effect on returns associated
with substituting alternative chemical and non-chemical pest control
practices into the budget with all other inputs held constant.
III-l
-------
If the major uses of diallate on sugar beets, flax, peas, and lentils
were cancelled, varied effects on producers would result. Because an
acceptable substitute herbicide is available, peas and lentils would
actually return more income to producers if diallate were cancelled. The
positive economic impact is based on increased yields which are due to a
decrease in phytotoxicity and better wild oat control in some instances,
see further discussion in Section III.C. Sugar beet producers would suffer
an estimated adverse impact of $4.0 million. Flax producers are expected
to experience an estimated $0.4 million economic loss. The net adverse
impact upon all affected user groups is approximately $3.2 million
annually.— These aggregate economic impacts are summarized in Table
III-1. The following subsections (A through E) briefly explain the
economic impacts involved should the major and minor uses of diallate be
cancelled.
A. Sugar Beets
Sugar beet production subject to wild oat infestation is located
in the non-irrigated acreage of Minnesota and North Dakota, and irrigated
acreage in Montana, Wyoming, Idaho, Utah, Washington, Oregon, and
California. As an average for the period 1976-1978, see Tables III-2 and
III-3, these nine states planted 995,000 acres of sugar beets annually or
72.6% of the U.S. total acreage. Of the nine-state total, 418,000 acres,
or 42%, rfere in Minnesota and North Dakota; 577,000 acres, or 58%, were in
the seven western states subject to wild oat infestation.
Diallate is a major herbicide used to control wild oats in sugar
beets. It is most widely used in non-irrigated acres. As an average
during the 1976-1978 period, diallate was estimated to have been applied to
185,175 acres of non-irrigated beets, and to 35,800 acres of irrigated
beets. In total, diallate was applied to 220,975 acres, or 22% of the
total sugar beet acreage subject to wild oat infestation.
Annual use of diallate to control wild oats in sugar beets, as an
average for the period 1976-1978, was estimated to have been 231,470 pounds
(active ingredient basis) in non-irrigated areas and 44,750 pounds in
irrigated areas. Total estimated use of diallate on sugar beets is thus
276,220 pounds.
Two formulations of diallate are used en sugar beets. Granular
diallate is applied to approximately 15% of the treated acreage while the
eoulsifiable concentrate is applied to approximately 85% (Lewis, 1979).
The degree control of wild oats provided by each of these formulations
appears to be the same for the fall application. There is some decrease in
control of wild oats when the granular is substituted for the emulsifiable
concentrate in the spring application.
3_/ This reflects an estimated 1.2 million net increase in revenues when
triallate is substituted for diallate where it is also registered for
these uses.
IIX-2
-------
Table III-1. Annual Economic Impact of Cancellation of Diallate
on the Major Use Sites -
H
H
U)
Site
Sugar
beets
Flax
Lentils
Peas
Maj or use
i-nt-al
Extent
of Use
(thousand
pounds)
276.2
38.4
43.3
30.4
IPO ^
Units
Treated
( thousand
acres)
221.0
30.7
43.3
24.3
1 1Q 1
Percent of Aggregate
Total Units User
(million
dollars)
16.7 4.0 loss
3.0 .4 loss
38.0 .7 gain
10.5 .5 gain
Economic Impacts
Market & Consumer .
(million dollars)-7
none
none
none
none
Total Market Value
(million dollars)
500
59
34
23.6
— Source: Economic Analysis of Effects of Restricting Use of
Diallate on Sugar Beets, Flax, Lentils, and Dry Peas.
Development Planning & Research Associates, Inc.
March, 1979.
- 1978 price levels
-------
Table III-]. Katlaatad annual aggregate uae coat* tot eliwluattiui diallete on icclgalud aityar b««tB, 1»76-1»75
n
H
With dlellata
Without diallata
Cycloate
Propham
(ulapon
Bactan
Paraquat
t'nt rout t»l
tlauJ uoudinq a/
fJJcd cultivation b/
DuliycJ auciliny
St. k(t to othur crop*
tub-total w/o dlallate
kUt change w/o dtallate
Acrga*
35, 800
a, 200
300
1,800
MOO
1,000
5,600
8,200
10,700
900
6,400
45,700
Material
(1)
225,540
112.536
3,860
a, 262
20.118
36.000
...
— --
361.076
15,516
Coat*
Application
125,658
28,782
1,051
2,862
2,862
2.862
18.421
(87,217)
Yield loge* • Other coat a
<« (f)
167,112
42,660
42,660
122,860
111.100
665,350
164.000
129,418 27.711
42,660
1.652,000
1,145,840 1.841.711
1,145.840 1.841.711
Total cost*
(1)
151.198
388.450
47.671
51.784
146.040
171.962
665.350
164.000
157, 111
42,660
1,652,000
S, 489, 040
1,117.852
• USOA/Statu Kuei.ai.nunt Study, perc«itt«<)* of original acr«ag« ••tlmatad to IM treated with dlalUt*.
*• Loss (.ur *cr« tram USDA/Stat* Agtunamor.l; Study, 1977. Sugar boat* valued at $21.70/ton.
a/ Chaiq* at $20 pur acre, baaed on interview Information Cram augar bout proce*sora.
b/ north-Dakota Crop and Llvaatock Hcportlng Service, 1&J7.
-------
III-). KHtliMtud annual ai>n
165,175
30,040
97,270
25.565
Cultural i:ifuui —
..
b.
lUitU
a.
b.
with dial lale
1 . iiUU'l
2. culiivjlo (3x)
witliuui iliultatu
1 . btiuil
2. .ciiliiviitu (3x)
3. <;ullivulti (4xt
I^UM
with 'Hal Idtu
1 . I liinul ntj
2. (^C4lii,.j (2H)
uitti'»ji ilidltutu
I. iliiiiuiii'j
2. w.^Ji,,., |2x)
). ,x.,., w,.,ll^
- — —
1U-...175
1U5.175
IUL.OU5
IU5.175
00,550
74,070
in. \'<>
-',;I5
Couta
Hatorlal Application Yield loaa Total cost Clianga In cott
(() ($) (»> It)
* 116.292
1.166.60U 649,964 1.016,572
1,932,064
345,960 133,520
1.104,060 154,659
152.419 42,230
* 121,047
4.466.420
2.4U1.345 546,266
1,438.809
4,700,267
2.503.IU7 551.075 65,fl52*
1,430,009
—. 224,344
» 430,126
4,710,060
1,917.672
2.703,100
5,140.906
2.051.739
2,'JUU,177
K)J,070
* h(.Mluc..| yi.,|.| of 2 Tiiii/acru jl *.'<). ^ti (,ur ton (aoutco of ylaM louu tiul Iwatu, llSDA/Stato AnuoBsnont Tuam, 1977)
-------
Should diallate use on sugar beets be cancelled, procedures will
substitute an integrated chemical and cultural strategy for wild oat
control. In non-irrigated areas, eptant is a major substitute for diallate,
with barban and dalapon also used for wild oat control. In irrigated
areas, cycloate and barban are the major substitute herbicides. Sugar beet
producers would also need to increase the amount of mechanical and hand
labor used to cultivate their beets. Some producers may experience yield
losses with alternative•weed control strategies (including use of
alternative herbicides and delayed seeding), while other producers may
shift to alternate crops.
Economic impacts would result from changes in herbicide costs,
increased mechanical and hand cultivation costs, additional reseeding
costs, decreased yields, and shifts to other crops. Should diallate be
cancelled, sugar beet producers may experience estimated economic losses
potentially as high as $4.0 million (Table's III-2 and III-3). Of that $4.0
million inpact, approximately $3.1 million would result from adverse
effects in the irrigated sugar beet areas of the Western U.S., and $0.9
million would be attributed to ramifications in the non-irrigated Red River
Valley area of North Dakota and Minnesota. In the Red River Valley most of
the adverse impact would derive from possible increased hand labor costs
and possible increased mechanical cultivation costs. In irrigated areas,
losses would be nearly equally divided between yield losses and lost
revenue resulting from changes in crop production from sugar beets to other
crops.
The effect of diallate cancellation on a typical Red River Valley
farm with 135 acres of sugar beets would be increased costs of $870
annually. The average cost increase per acre of sugar beets is $4.69.
This, of course, assumes the typical farm would make all herbicide,
cultural, and labor adjustments in the same proportions as the entire
Valley area. Changes in net yield are not anticipated. The average
producer could expect his net returns to land, management, and labor to
decrease by only 2.1%, from $41,102 to $40,232.
The effect of diallate cancellation on a typical irrigated sugar
beet farm would be much more severe, with an average impact of $87.65 per
acre of sugar beets. On a farm which ordinarily treated 100 acres of sugar
beets with diallate, the adverse annual effects would amount to $8,765,
most of which would be due to reductions in net returns (over variable
cost). For a typical farm, crop returns over variable cost would be
reduced nearly 18%. This loss, however, is to the individual fanner.
There is little overall yield loss since diallate is not used extensively
in irrigated plantings. In a switch to the granular formulation of
diallate alone for the control of wild oats in sugar beets, the increased
cost to growers in the short run will be approximately $6-$7 per acre
treatment, given current prices.
While the cancellation of diallate may pose significant problems
to the local grower, this effect will not seriously reduce total U.S.
Ill-6
-------
production because the sugar from sugar beets represents only a small
percentage of total U.S. sugar consumed. Over 50% of the U.S. sugar is now
imported due to the favorable tariff for imports. A decline in profit
because of sugar imports is already reducing sugar beet acreages.
B. Flax
United States.flax production is concentrated in the states of
Minnesota, North Dakota, and South Dakota. This area produced 98% of U.S.
flax on an average of 1,025,000 acres between 1976 and 1978. Approximately
3% of the total flax acreage (30,750 acres) was estimated to have been
treated with diallate during this period - an estimated 38,440 pounds
(active ingredient basis) of diallate annually. The emulsifiable concen-
trate formulation is the only form of diallate currently registered for use
on flax; however, granular diallate could be used on flax if it were
registered, but at slightly higher costs. • Herbicide use on flax is very
limited because of the extreme phytotoxic reaction of flax to any herbi-
cide, including diallate. Diallate is, however, used in preference to
other herbicides.
Eptam and barban are the most common herbicides which can be
substituted for diallate to control wild oats in flax; however, both of
these chemicals have characteristics which limit their use on flax. Sptam
is phytotoxic in flax, and barban can only be applied when the wild oats
are at the - two leaf stage (2-4 days). If weather is bad for that period
the effectiveness of the chemical is lost. A cultural method of wild oat
control is delayed seeding; however, this non-chemical method of• weed
control reduces flax yields by about 33%.
Cancelling the use of diallate on flax is anticipated to result
in annual losses of approximately $0.4 million to flax producers. The
economic impacts result from a combination of changes in herbicides costs,
shifts in production from flax to alternative crops, and yield losses
resulting from delayed seeding. The average loss in returns per acre of
flax treated with diallate substitutes would be $13.59. This loss
represents 25% of the expected returns to land, labor, and management with
diallate available.
Since only 3% of the total flax acreage is estimated to be
treated with diallate, the cancellation of diallate would not have a sig-
nificant effect on total flaxseed supplies or established marketing systems
or patterns. Moreover, some shift in production away from flax is already
occurring because of decreasing demand for flaxseed and flax straw. (USDA,
Crop Production Annual Summary, 1978.)
C. Lentils
Commercial lentil production is located almost entirely in
Washington and Idaho. During the 1976-1978 period, an average of 114,000
acres of lentils were planted annually in these two states. Both states
III-7
-------
are subject to wild oat: infestations, and dial late is a major herbicide
used to control wild oats in lentil plantings. It is estimated that 43,320
acres or 33% of the total lentil acreage were treated with diallate. With
a normal use rate of one pound (active ingredient basis) of diallate
applied per acre, this would require 43,320 pounds of diallate.
Use of triallate provides an excellent substitute for diallate
use on lentils. Triallate, although increasing the overall costs of wild
oat control, offers increased yields which more than offset the increase in
costs. The positive economic impact is based on increased yields resulting
from triallate being less phytotoxic and in some cases better control of
the pest. Triallate would pick up an estimated 93% of the diallate usage
if diallate were cancelled. Therefore, cancellation of diallate and a
shift to triallate would have a positive impact to growers by increasing
returns by $512,000 annually, with an increase in production of 1.6%.
The growers reluctance to switch to triallate may be 1) unfamil-
iarity with triallate, 2) inconvenience of stocking additional chemicals
when diallate can treat all crops, and 3) marketing preferences.
Other herbicides which are expected to offset the impact of
diallate's cancellation on lentils include prophaa and barban. However,
these two herbicides are not as useful as triallate because of altered
efficacy characteristics (e.g. critical timing for effectiveness and rapid
biodegradation in soil). Therefore, these herbicides are not considered as
complete alternatives for diallate.
D. Peas
Dry peas (including Austrian winter peas and wrinkled seed peas)
are produced primarily in Washington and Idaho. During the 1976-1978
period, an average of 231,000 acres of dry peas were produced in these two
states. Wild oats are a major pest in dry pea production. Approximately
11% of the total acreage is treated with diallate for wild oat control,
using 30,375 pounds (active ingredient basis) of diallate.
Triallate is considered the primary substitute for diallate.
Triallate is already used on 45% of the dry peas produced and offers
growers a larger return on the land through increased yields (see
discussion in III.C.), so that the total return to the grower increases by
nearly $730,000 annually.
Propham and barban are also registered for use in dry peas.
However, these two chemicals have limitations which preclude their total
effectiveness as alternatives. Upon diallate's cancellation, the usage of
both propham and barban would increase above the current 2% (propham) and
6% (barban) usage on dry peas.
The cancellation of diallate is anticipated to result in U.S. dry
pea production increases of less than 0.01%. Therefore no economic impacts
would occur at either the market or consumer levels.
III-8
-------
E. Minor Uses
Diallate, in addition to the foregoing major uses, is also
registered for use on soybeans, corn, barley, potatoes, safflower, and
alfalfa. The percentage of use on each of the above crops is quite small;
thus, use of diallate has been determined to be minor on these crops. Use
of diallate on these crops is basically limited to North Dakota, Minnesota,
Montana, and Idaho.
The estimated use of diallate on potatoes is 0.5% of the total
potato acreage. For all other minor crops except safflower and alfalfa,
the total treated acreage is thought to be 0.1% or less. Data are not
available to show the total amount of diallate used on safflower and
alfalfa acreage.
If diallate becomes unavailable,- batban would be used to control
wild oats on soybeans, and eptam would be the chemical of choice in corn
and potatoes. Triallate is registered for use on barley. Monsanto has
expressed a desire to register triallate for all crops for which diallate
is now registered (Spurrier, 1979).
The cancellation of diallate on the crops discussed in this
section is not expected to have any economic impact upon the grower or
aarket prices. Only in the case of potatoes does the use approach 0.5% of
the total acreage. In other cases, diallate treated acreage amounts to
0.1% or less of the total acreage.
III-9
-------
IV. Development of Regulatory Options
A. Introduction
. The risks and benefits associated with the uses of diallate have
been identified in Sections II and III. As explained in Section I, FIFRA
mandates that the Agency achieve a balance between the competing considera-
tions of risks and benefits. In order to carry out that mandate, the
Agency has developed various regulatory options and has evaluated each
option for its impact on both sides of the risk/benefit equation.
This section of Position Document 2/3 briefly summarizes the
salient risks and benefits associated with the uses of diallate and
describes the process by which the Agency developed potential courses of
action.
B. Salient Risk/Benefit Considerations
In performing a risk/benefit analysis of the uses of diallate,
the Agency identified several salient factors, on both sides of the risk/
benefit equation, which became determining considerations in the
development of regulatory options. These considerations are reviewed below.
1. Salient Risk Considerations
As detailed in Section II of this document the original risk
criteria cited in the RPAR notice as the basis for the Agency's presumption
against diallate stands unrabutted. The principal risk associated with the
use of diallate is oncogenicity. This risk manifests itself in the general
population through dietary exposures at very low levels and to pesticide
applicators through dermal and inhalation exposures when applying diallate
as an emulsifiable concentrate.
It is estimated that there are approximately 2400 pesticide
applicators currently at risk. This risk is estimated to be 10 and is
of primary concern to the Agency (Table IJ-10). The dietary risk to the
general population is estimated to be 10 based on tolerance levels
adjusted to reflect the percent of crop treated (Table 11-11). The Agency
considers the dietary risks of diallate to be low and not of primary
concern when compared to the benefits associated with its use.
Since the original RPAR notice was published the Agency
received additional evidence to support the conclusion that diallata is a
mutagen. Although quantitative estimates of the mutagenic risk to
applicators are not possible at this time, any risk reduction procedures
proposed to reduce the oncogenic risks of diallate will concomitantly
reduce mutagenic risks.
There is also evidence that diallate causes neurotoxic
effects. As in the case of mutagenic risks quantitative estimates of risk
IV-1
-------
are not presently possible. However, based on current'exposure estimates
there is a 600-fold span between the observed effect level and the exposure
level.
2. Salient Benefit Considerations
The benefits of diallate were assessed in terms of the
economic impacts which would result if its uses were cancelled and users
were thereby forced to employ available alternatives. As detailed in
Section III, the economic impacts associated with the cancellation of
diallate total just over $3 million (Table III-1).
Sugar Beets
The total annual market value of sugar beets is $500
million. Should diallate become unavailable, growers are expected to
experience an annual loss of $4 million. More than 60% of the diallate
used in this country is applied to sugar beets. Presently the emulsifiable
concentrate formulation is applied to 85% of the treated acreage while the
granular formulation is applied to the remaining 15%. The degree control
of wild oats provided by each of these formulations appears to be the same.
Several alternative chemicals were identified in Section III
of this document. Specifically mentioned were, 1) cycloate for control in
irrigated areas, and 2) eptam for control in non-irrigated areas, and 3)
barban which can be used in both areas. However, due to certain limita-
tions (see Section III.A) none of these chemicals provide adequate
protection against wild oats.
In changing to granular diallate alone for control of wild
oats in sugar beets, the increased cost to growers in the short run will be
approximately $6-$7 per acre-treatment given current prices.
Flax
Approximately 3% of the total flax acreage is treated with
diallate. If all forms of diallate should become unavailable for use in
the control of wild oats in flax, growers are expected to experience a
$400,000 annual loss. The emulsifiable concentrate is the only formulation
presently registered for this use.
Eptam and barban are the most commonly used alternatives for
diallate. Soth of these chemicals have limitations which reduce their
desirability and effectiveness in the control of wild oats (see Section
III.B). Granular diallate is anticipated to provide effective control of
wild oats in flax; however, this formulation is not currently registered
for this use.
IV-2
-------
Lentils
Thirty-eight percent of the total lentil acreage is treated
with diallate. Lentil production is basically limited to two western
states, Idaho and Washington. It is estimated that more than 43,000 pounds
of diallate are applied to lentil acreage annually. The emulsifiable
concentrate is the only diallate formulation presently registered for this
use.
The major alternate chemical used to control wild oats in
lentils is triallate. Triallate has proven to be an effective alternate
and provides control of wild oats equal to or greater than that provided by
diallate. Triallate is also less phytotoxic to lentils than diallate.
Propham and barban are alternative chemicals but do not provide acceptable
control of wild oats.
Peas
Dry peas, like lentils, are primarily grown in Idaho and
Washington. Currently, approximately 11% of the dry pea acreage is treated
with diallate. Only the emulsifiable concentrate formulation of diallate
is registered for use on peas for the control of wild oats.
Triallate-is the primary alternate chemical for diallate on
peas. Presently, triallate is used on 45% of the dry pea acreage.
Triallate is less phytotoxic to peas than diallate.
Minor Uses (Alfalfa, Barley, Corn, Potatoes, Safflower,
and Soybeans)
The total percent of minor crop acreage treated annually
with diallate ranges from <0.1% to 0.5%. More specifically, it is
estimated that 0.5% of the potato acreage is treated, whereas the
percentage of treated acreage for all other crops is 0.1% or less. No
economic impacts are expected if diallate is cancelled. Only the
emulsifiable concentrate formulation is registered for the minor uses.
Barban and eptam are considered as possible substitute
chemicals. Triallate is now registered for use on barley.
C. Risk/Benefit Analysis
1. Dietary Risk/Benefit Analysis
As indicated in Section II.D.1. the dietary risk from
diallate is estimated as 10 . This estimate is based on assuming
residues exist on treated crops at the tolerance level. This is a worst
case assumption and to date, residues have not been found on any crops at
the level of detection (.02 ppm). More than 60% of the dietary risk is
attributable to the use of diallate on sugar beets. The dietary risk is
IV-3
-------
considered to be low and the benefits of diallate use are moderate for
sugar beets and flax, and low for lentils, peas, and minor crops. In sugar
beets the average cost increase per acre will range from $4.69 to $97.65.
For flax the loss in returns per acre would be about $14. For all other
uses economic benefits would accrue due to minor production increases from
either more effective control of wild oats or decreased phytotoxic effects
of alternate chemicals. Therefore, the Agency concludes that the benefits
(low to moderate) outweigh the dietary risk (low), in view of this,
regulatory action on the basis of dietary risk alone is. not warranted, ^s
indicated above the principal risk of diallate is to pesticide applicators
through dermal and inhalation exposure when applying diallate as an
emulsifiable concentrate.
2. Applicator Risk/Benefit Analysis
The applicator risk/benefit matrix for diallate, expressed
in qualitative terms, is shown in Table IV-1. For all presently registered
use patterns the applicator risks are high for the emulsifiable concentrate
formulations while the risks associated with the granular formulation are
no greater than the general populations risk from dietary exposure. The
benefits of diallate use (either formulation) on sugar beets and flax are
moderate and all other uses are low.
Applicators of the emulsifiable concentrate formulation nay
be exposed both derraally and via inhalation as the result of splashing,
vaporization, or accidental spills. Likewise during application, exposure
may occur both dermally and via inhalation. Table 11-10 identifies the
dermal risk to applicators of the emulsifiable concentrate formulation as
10 .
One potential risk reduction measure is to require applica-
tors using emulsifiable concentrate diallate to wear protective clothing.
Protective clothing in this instance is defined as rubber gloves and
coveralls. These item? would reduce the exposure level by a factor of 4
(see Section U.C.1.). ThJs reduction would result in a risk of 10
which the Agency still considers unreasonable when compared to the low and
moderate benefits and, therefore, unacceptable. Therefore, a protective
clothing requirement will not be considered as a viable risk reduction
measure in this analysis.
Thus the risk/benefit picture for the emulsifiable concen-
trate formulation is essentially the same for all uses. The applicator
risk is high and the benefits are, at best, moderate. Since the risks out-
weigh the benefits in every case, the Agency must consider regulatory
options for reducing the risks associated with the emulsifiable concentrate
formulation, in particular, the high applicator risks.
From this analysis the Agency concludes that the high risk
involved in the use of the emulsifiable concentrate is unacceptable when
considered against the low to moderate benefits of all emulsifiable
IV~4
-------
Table IV-1. Applicator Risks versus Economic Benefits of Diallate
Uses
Sugar Beets
Flax
Lentils
Dry Peas
Minor Uses
Barley,
Potatoes ,
Saf flower,
Soybeans ,
Corn, Alfalfa
Applicator
Emulsifiable
Concentrate
High (a)
High (a)
High (a)
High (a)
High (a)
Risk
Granular Economic Benefits (c)
Low Moderate
(b) Moderate
(b) Low
(b) Low
(b) Low
-4
(a) High Risk >_ 10
(b) Although not registered for these uses the applicator risks would remain
low if registered.
(c) Benefits analysis did not evaluate the individual benefits of the two
formulations.
IV-5
-------
concentrate uses. It also concludes that this risk can be reduced to the
acceptably Low dietary level if the emulsifiable concentrate formulation is
replaced by the granular formulation. Therefore, the Agency will examine
the feasibility of cancelling all diallate emulsifiable concentrate
formulations in its regulatory options.
For sugar beets (the only use for which the granular formula-
tion is also registered!, the risk/benefit balance for the granular formula-
tion is shifted favorably. Risks become low because of significantly
decreased applicator exposure and benefits remain moderate because the cost
and effectiveness of granular diallate are approximately the same as the
emulsifiable concentrate. Based on this finding for sugar beets, the
Agency assumes that this more favorable risk/benefit balance could be
achieved if the granular formulation were registered for all of the other
uses.
D. Regulatory Options
With regard to the emulsifiable concentrate products of diallate,
three basic regulatory options have been developed for consideration:
1. Continue emulsifiable concentrate registrations.
2. Cancel emulsifiable concentrate registrations immediately.
3. Cancel emulsifiable concentrate - registrations affective in
two years.
Options 1 and 2 represent an absolute regulatory response.
For Option 1 it means that sale and distribution of diallate emulsifiable
concentrate products are unconditionally continued. Option 2 on the other
hand means that sale and distribution of these products are prohibited
effective as soon as the decision becomes final. Option 3 represents a
decision to phase out the emulsifiable concentrate formulations to permit
time to extend the registrations of granular diallate to uses where it is
not presently registered.
1. Option 1; Continue Emulsifiable Concentrate Registration
This option would return emulsifiable concentrate formula-
tions of diallate to the registration process, and they would be retained
as effective means to control wild oats in sugar beets and other crops. 3y
adopting Option 1, the Agency would conclude that the benefits associated
with the use of emulsifiable concentrate diallate outweigh the risks and
that allowing its use would not result in unreasonable adverse effects.
-4
Under this option, the potential applicato- risks of 10
resulting from inhalation and dermal exposure would not be reduced. There
would be no adverse economic impacts associated with Option 1 because use
of emulsifiable concentrate formulations would continue. 3y choosing this
1V-6
-------
option the Agency would conclude that the benefits would outweigh the risks
of continued use.
2. Option 2; Cancel Smulsifiable Concentrate Registrations
Immediately
This option would eliminate all uses of emulsifiable
concentrate diallate thirty days after the final Agency decision. By
adopting Option 2 the Agency would conclude that the risks associated with
the use of emulsifiable concentrate diallate 'exceed the benefits, and
result in unreasonable adverse effects.
Under this option, applicator risks resulting from
inhalation and dermal exposure would be reduced to the same magnitude of
risk as the general dietary risk. Cancelling all emulsifiable concentrate
registrations immediately would imply that" risks outweigh benefits.
The economic impact which result from the immediate
cancellation of diallate emulsifiable concentrate formulations on sugar
beets is estimated to be more than $3 million (Table III-1). The benefit
analysis did not attempt to identify the impact of the individual formula-
tions. However, most of the impact will result from the cancellation of
the emulsifiable concentrate formulations. This is based on the fact that
the emulsifiable concentrate accounts for approximately 35% of the diallate
presently used on sugar beets. Flax growers are expected to suffar a
$400,000 annual Loss while growers of lentils and peas are anticipated to
receive an economic gain as expressed in Table III-1.
This option would ignore such factors as availability of
alternatives including granular diallate since time would have to be
allowed to produce adequate quantitites of this material. It also ignores
the time necessary to register granular diallate on flax and other crops
for which the emulsifiable concentrate is now registered if the markets
demand such action. Lastly, this option neglects to allow time for growers
to modify or acquire the necessary equipment to apply the granular
formulation.
3. Option 3; Cancel Emulsifiable Concentrate Registrations
effective Two Years After the Decision Becomes Final
This option is essentially the same as Option 2. It differs
in that it would eliminate all uses of emulsifiable concentrate diallate
two years after the decision becomes final. By adopting Option 3, the
Agency would indicate its unwillingness to accept the applicator risks
associated with the use of the emulsifiable concentrate formulation
indefinitely. This option would lessen the impact of immediate cancel-
lation by 1) allowing time to produce the necessary granulir diallate to
control wild oats in sugar beets, 2) allowing time to register granular
diallate on crops where only the emulsifiable concentrate is now registered
and where other registered alternatives are not desirable, and 3) allowing
time for growers to make necessary equipment adjustments.
IV-7
-------
Some granular diallate formulations are presently registered
for use on sugar beets only in Minnesota and North Dakota. It will be
necessary to allow sufficient time to extend the registration of these
granular formulations to the western states. While the registsrad granular
formulation with diallate as the sole active ingredient is only registered
for use in the non-irrigated areas, other granular formulations with
diallate as one of the active ingredients are registered in other geo-
graphical areas (western states). Two years should also provide ample time
to register the granular formulation on crops now being treated with the
emuisifiable concentrate formulation if the market demands it.
The Agency, based on the information available, believes 1)
that a two-year time frame is sufficient time for the company to produce
the granular diallate required to maintain control of wild oats in sugar
beats, and 2) that two years is ample time for growers to make adjustments
in equipment necessary to apply the granular formulation (Lewis, 1980).
Because there is no acceptable alternative chemical
presently registered for use on flax, cancellation of the emuisifiable
concentrate is a major concern. The expected annual economic impact to
flax growers is $400,000. The Agency believes that the granular
formulation will provide excellent wild oat control with little or no
phytotoxicity and is willing to consider a proposal for this use.
Registrants of -the emuisifiable concentrate and granular
formulations may submit an application for amended registration to
1) convert their emuisifiable concentrate formulation to granular, and
2) expand their granular registrations to crops for which only the
emuisifiable concentrate is now registered. The review of these actions
will be expedited and should not require additional data.
IV-8
-------
V. Proposed Regulatory Decision
Agency proposes tol implement Option 3 which is to/cancel the
emulsifiable concentrate formulations of diallate effectiveTwo years from
the date the decision becomes final. I
Option 1 is unacceptable because the level of risk to applicators of
the emulsifiable concentrate formulations remains at 10 which the
Agency is unwilling to permit considering the low and moderate benefits.
Option 2 is also unacceptable. While under this Option the risk to
applicators is reduced to the general dietary risk level, it does not take
into account the potential impacts that may occur due to the unavailability
of adequate supplies of granular diallate currently registered for sugar
beet use. In addition it does not permit any opportunity for the
registrant to extend the use of granular diallate to those uses where only
the emulsifiable concentrate is currently registered prior to complete
cancellation.
Option 3 would overcome the disadvantages of both Options 1 and 2.
The Agency would welcome applications to extend the use of granular
diallate as a replacement for the emulsifiable concentrate and EPA
considers a two-year time frame appropriate to accomplish this. At the
same time, the two-year time frame permits the production of adequate
supplies of granular diallate to meet expected market demand.
Also under Option 3 registrants would be allowed to convert
emulsifiable concentrate formulations to granular and expand granular
registrations to crops for which only the emulsifiable concentrate is
presently registered.
V-l
-------
VI. References
Albert, R.E., 1979a. Diallate RPAR Rebuttal Response. Carcinogen
Assessment Group, EPA, 1979.
Albert, R.E., 1979b. Risk Assessment of Avadex. Carcinogen Assessment
Group, EPA, 1979.
Brusick, D.J. 1977a. Mutagenicity Evaluation of CP15336, BIO-77-166 (Final
Report July, 1977) submitted to Monsanto, Co, Inc., by Litton
Bionetics, Inc., Project No. 2683. 9pp.
Brusick, D.J. 1977b. Mutagenicity evaluation of CP15336 in the mouse
Lymphoma assay, BIO-77-171 (Final Report, August, 1977) submitted to
Monsanto Co, Inc., by Litton Bionetics, Inc., Project No. 2584.
Submitted to EPA March 22, 1973. EPA Accession No. 233353.
Carcinogenesis Bioassay Data Systems, 1975. Preliminary Analysis Report
for Avadex. Prepared for the National Cancer Institute by EG&G/Mason
Research Institute.
Development Planning and Research Associates, Inc., March, 1979. Economic
Analysis of Effects of Restricting Use of Diallate on Sugarbeets,
Flax, Lentils and Dry Peas; to Environmental Protection Agency.
Gardner, R., 1980. Estimates of human exposure to diallate. Memo to James
Wilson, SPRD (TS-791), Project Manager.
Innes, J.R.M., B.M. Ulland, M.G. Valeno, L. Petrucelli, L. Fishbein,
E.R. Hart, A.J. Polxotta, R.R. Bates, H.L. Falk, J.J. Gart, M. Klein,
I. Mitchell and J. Peters. 1969. Bioassay of Pesticides and
Industrial Chemicals for Tumorigenicity in Mice: A Preliminary Note.
J. Nat. Cancer Inst. 42:1101.
Jensen, J. 1980. Applicator Exposure to Diallate While Using the Granular
Formulation. Memo to J. E. Wilson, Jr., Project Manager for Diallate,
April 23, 1980.
Keplinger, M.L. 1974. Mutagenic Study with Avadex Technical in Albino
Mice. 3TL-74-13. Industrial Bio-Test Laboratories, Inc., August 20,
1974. 1ST No. 622-05252. Submitted to EPA by Monsanto Company on
October 14, 1976. 14 pp.
Keplinger, M.L. 1976a. Two-year Chronic Oral Toxicity Study with Avadex
Technical in Albino Rats BTL-74-12. Industrial Bio-Test
Laboratories, Inc., December 17, 1976. 1ST No. 622-05250. Submitted
to EPA by Monsanto Company on February 4, 1977. EPA Accession No.
228094.
Keplinger, M.L. 1976b. Neurotoxicity Study with Avadex in Chickens,
BTL-76-84. Industrial Bio-Test Laboratories, Inc., December 28,
1976. %IBT No. 8580-09119. Submitted to EPA by Monsanto Company on
February 16, 1977. EPA Accession No. 226094.
VI-1
-------
Lewis, C., 1980. Additional information on use of granular diallate.
Memo to James Wilson, SPRD Project Manager.
Mauer, I., 1978. Ph.D., Geneticist, Toxicology Branch, EPA, November 28,
1978. Diallate: Preliminary Assessment of Mutagenicity, Regulatory
Options, and Alternatives, Memorandum to Roger Gardner, Toxicology,
EPA.
Monsanto Agricultural Products Co., 1977. Rebuttal to the Rebuttable
Presumption Against Registration and Continued Registration of
Pesticide Products Containing Diallate. £1A [30000/15].
Pesticide Residues Committee, 1965. NAS-NRC Report on *"No Residue" and
"Zero Tolerance," June 1965.
Phillips, B.M. 1977. Final Report to Monsanto Company 42-day Neurotoxicity
Study with Diallate in Chickens. . (*1B(30000/15) attachment A)
Rinkus, S.J. and M.S. Legator, 1977. Mutagenicity of Diallate. Submitted
to EPA (FRS/TSD). July 6, 1977. 5 pp.
Sandhu, S.S., Ph.D., Biochemistry Branch, EPA, August 30, 1978. Evaluation
of the Data for the Mutagenicity of Diallate and Tr.iallate.
Memorandum to William F. Durham, Ph.D., Director, Environmental
Toxicology Division (HERL/RTP), EPA.
Selim, S. October 16, 1978. Exposure Analysis for Diallate. Proprietary
Environmental Fare Branch, Hazard Evaluation Division, OPP, EPA.
Sikka, J.C. and P. Florczyk. 1978. Mutagenic Activity of Thiocarbamate
Pesticides in a Microfaial Test System. J. Aqr. Food Chem. 26:146-.
Simmon, V.F., E.S. Riccio, and A. Griffih. 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. 23 pp.
Sochard, M.R. 1980. Editing of Diallate PD 2/3 Pursuant to Memo From J.
Jensen, EFB, to J. E. Wilson, Jr., Project Manager for Diallate/
May 14, 1980.
Spurrier E., 1979. Memo of telephone conversation with R. Troast.
Ulland, 3., S.K. Weisburger, and J.H. Weisburger. 1973. Chronic Toxicity
and Carcinogenicity of Industrial Chemicals and Pesticides.
Toxicol. Appl. Pharmacol. 25:446.
USDA/State Assessment Team on Diallate, 1977. Assessment of the Meed for
Diallate in Agriculture *10A[30000/15].
U.S. Department of Health Education and Welfare. 1969. Report of the
Secretary's Commission on Pesticides and Their Relationship to
Environmental Health. U.S. Government Printing Office, Washington,
D.C.
71-2
------- | |