Dimethoate Position Document 2/3
Dimethoate Support Team
EPA /sf*2> - Zc/iJi
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302-2-101
REPORT DOCUMENTATION 1 report no.
FAGE " , EPA/SPRD-80/32
4. Title find Subtitl*
Dimethoate: position Document 2/3
3. Recipient's Accession No.
80 21384 6
5. R«port 0»t«
11/19/79
7. Author(s)
! 8. Performing Organization Rept. No
9. Performing Or^erniatlon Name and Address
Special Pesticide Review Division
Environmental Protection Agency
Crystal Mall ?2
Arlington VA
10. Proj»ct/Task/Work Unit No.
11. Contract(C) or Grant(G) No
(C)
(G)
12. Sponsoring Organisation Name and Address
Environmental Protection Agency
401 M St S.W.
Washington, D.C. 20460
13. Typ« of Report & Penod Covered
14.
15. Supplementary Notes
16. Abstract (Limit- 200 words)
Risk/benefit analysis: qualitative 8c quantitative risks of a pesticide,
value of crop uses, availability of alternative pesticides, exposure to
man and environment. Identification of risk reducing regulatory options
and proposed Agency action.
17. Document Analysis a. Descriptors
0504 ,0606
b. Identifiars/Ooen-Ended Terms
c. COSATI Field/Group
16, Availability Stctamon*
Release Unlimited
19. Security Clssa (Thin Report)
Unci assified_
20. Security Class (This P*3o)
21. No. of Pzgts
22. Price
Unclassified
(See ANSI-Z39 18)
Sot Instructions on ftoverte
/
OVriOKAL FORM 272 (4-77)
(Formerly NTIS-3S)
Department ol Commerce
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Acknowledgements
W. T. Waugh, Project Manager, SPRD, OPP
Edward Thomas, Project Manager, SPRD, OPP
Patrick Miller, Project Manager, SPRD, OPP
EPA Project Support Te*am
E. David Thomas, BFSD, OPP
Padma Datta, HED, OPP
Bill Burnam, HED, OPP
Bill Schneider, HED, OPP
Roger Hogan, HED, OPP
Irving Mauer, HED, OPP
Cara Jablon, OGC
Harry Gaede, BFSD, OPP
EPA Pesticide Chemical Review Committee (PCRC)
Marcia Williams, Chairperson, SPRD, OPP
Elizabeth L. Anderson, CAG, ORD
Richard N. Hill, OTS
Allen L. Jennings, SRD, 0PM
Donna R. Kuroda, OHEE, ORD
John J. Neylan, PED, OE
Michael Winer, OGC
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Dimethoate: Position Document 2/3
CONTENTS
Page
I. Background 1
A. Introduction 1
(1) Chemical and Physical Character-
i 2 11C 3 ¦ • ¦ ¦ * . • • ¦ • « • « « « . ¦ . . . 1
(2) Registered Uses and Production..... 2
(3 ) Tolerances.. 2
B. Applicable Sections^ of FIFRA 3
C. The "RPAR" Process.*.... 4
D. Bases for the Rebuttable Presumption.... 5
E. Organization of Position Document 6
II. Risk Analysis and Assessment 7
A.. Rebuttal Analysis 7
(1) Rebuttals Relating to the
Presumption of Oncogenicity 7
(a) Gibel et al. (1973) 9
(i) Source and Composition
of Test Compound 9
(ii) Abnormal Pattern of
Mortality 9
(iii) Insufficient Data 10
(iv) Method of Administration. 11
(v) Incorrect Dosage Data..., 11
(vi) Low Exposure from Food
Residues. 12
(vii) Lack of Tumors in
Controls 13
(b) New Study Offered in
Rebuttal..... .#...•« 1^4
(c) Steiglitz et al. (1974).; 15
(i) Lack of Information........ 15
(ii) Source of Test Compound.... 16
(2) Rebuttals Relating to the Pre-
sumption of Reproductive and
Fetotoxic Effects.. 17
(a) Rebuttals Relating to More
Than One Study 18
(i) Type of Effects Observed. 18
(b) Budreau and Singh (1973)...... 20
(i) Inconsistent Data 20
(ii) Drowning of Litters..... 21
(iii) Dam Transfer Experiment. 21
(iv) Contaminated Drinking
Water.... 22
iŁ
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(v) Nutritional Difficulties. 22
(vi) Lowered Mating Success... 22
(vii) Condition of Test
Animals 23
(viii) Selection of, Test
Animals 24
(ix) Definition of "Repro-
duction Time" 24
(x) Maternal Toxicity 25
(xi) Incorrect Dosage Data.... 25
(xii) Effect on Neuro and
Endocrine Systems 26
(c) Scheufler ( 1975a) 26
(i) Lack of Detail 26
(ii) Definition of "Nuclei"... 28
(iii) Total Loss Data 28
(iv) Route of Exposure 29
(d) Exposure Rebuttals 30
(e) Calculation of Margin of Safety 30
(3) Rebuttals Relating to the Pre-
sumption of Mutagenicity 32
(a) Rebuttals Relating to More
Than One Study 34
(i) Purity of Test Compound.. 34
(ii) Diverse Test Results 34
(iii)Dosage Levels 35
(iv) Bacterial Assays: Vari-
able Results 35
(b) Hanna and Dyer ( 1975) 36
(i) Control Plates 36
(ii) Dose Not Reported 37
( i ii) Incorrec t Protocol 37
(iv) Toxicity Estimate 38
(v) Confirmation of Pheno-
types 38
(c) Shirasu et al. ( 1976) 39
(d) Mohn ( 1973) 39
(i) Invalid Test System 39
(ii) Low Potency of Compound.. 40
• (iii)Liquid Suspension Assay. 40
(e) Agarwal et al. (1973) 41
(i) Phytotoxicity of
Dimethoate 41
(ii) Lack of Controls. 41
(iii)Variation in Results 41
(f) Amer and Farah ( 1974) 42
(i) Lack of Control Data and
Analyses of Results 42
(ii) Non-Heritable Abnor-
malities 42 '
ii
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(iii) Differences Between
Pure and Formulated
Dimethoate 43
Civ) Procedural Errors 43
(g) Fahrig ( 1973)
(i) Lack of Survival Data.... 44
(ii) Lack of Detail 44
(iii) Improper Handling of
Test Colonies 45
(h) Gerstengarbe ( 1975) 45
(i) Improper Controls 45
(ii) Route of Adminstration... 46
(iii) Source of Test Compound. 46
(iv) Incorrect Dosage Data.... 47
(v) Number of Animals Used... 47
(vi) Dose/Sperm Relationship.. 48
(i) Bhunya and Behera ( 1975) 49
(i) Lack of Control Data 49
(ii) Reversible Effects 49
(j). New Studies Offered in
. Rebuttal 50
(i) American Cyanamid Co.
. ( 1977) 50
(ii) Ashwood-Smith et al.
( 1972) 50
(4) Other Comments 51
(a) Delayed Neurotoxicity 51
(b) Synergism of Dimethoate
by Other Pesticides 52
B. Exposure Analysis 53
(1) Exposure Due to
Aerial Application 53
(a) Respiratory Exposure 54
(b) Dermal Exposure 55
(2) Exposure Due to
Ground Application: Dermal and
Respiratory Exposure 56
(i) Boom and Compressed Air
Application Situations.... 56
(ii) Air Blast Application
Situations 59
(3) Exposure to Farm Workers 59
(4) General Population Exposure 60
C. Risk Analysis 60
(1) Oncogenicity Risk Analysis 64
(2) Mutagenicity Risk Analysis 66
(a) Relevant Positive Tests 67
(i) Reverse Mutation
Bacterial Assays 67
(ii) Forward Mutation
Bacterial Assays 68
iii
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(iii) Dominant-Lethal
Assay (Mouse) 68
(iv) Yeast Gene
Conversion Assay 69
(v) Unscheduled DNA Synthesis
in Mammalian Cells 69
(b) Studies Suggestive
of Mutagenesis 70
(i) Plant Cytological
Analysis 70
(ii) Mammalian Cytogenetic
Analyses 71
(c) Negative Tests 71
(d) Summary 75
(3) Reproductive and Fetotoxic
Effects Risk Analysis 77
(a) New Data 77
(b) Teratogenic Risk 79
(i) General Population Risk.. 80
(ii) Applicator Risk 80a
(4) Fish and Wildlife
Risk Analysis 81
III. Benefit Analysis of Dimethoate 83
A. Introduction 84
B. Grains..... 84.1
C. Field Crops 85.1
D. Fruits and Nuts 86.1
E. Vegetables 88
F. Other Use Sites 89.1
IV. Development and Selection of
Regulatory Options 103
A. Introduction 103
B. Basis for Development of Options 103
C. Risk Reduction Methods 105
(1) Option #1 107
(2) Option #2 108
(3) Option #3 108
(a) Require Protective Clothing
For All Products For All Uses 109
(b) Require Respirators for
Pilots and Mixer/Loaders 119
(c) Require Automatic Flagging
for all Aerial Application
Situations 120
(4) Option #4 122
(5) Option #5 123
(6) Option #6 124
(a) Citrus 127
(b) Pome Fruit 128
(c) Pecans 129
iv
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(d) Dust Formulations 129.1
(7) Option in 134
V. Recommended Options 135
A. Comparison of Options 135
B. Recommended Options 138
(1) Generation of Additional Data 138
(2) Altering Selected Application
Practices 139
(3) Cancellation of Selected High Risk
Formulations 139
C. Use Situations Not Addressed in this
Analysis 139
VI. Additional Testing Requirements 140
A. Oncogenicity 141
B. Mutagenicity . 141
C. Delayed Neurotoxicity... 142
D. Applicator Exposure Data.... 142
References 144
9
V
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Dimethoate: Position Document 2/3
I. BACKGROUND
A. Introduction
(1) Chemical and Physical Characteristics
Dimethoate is an organophosphate insecticide and
acaricide. Its chemical name is 0,0-dimethyl S-(N-methyl-
carbamoylmethyl) phosphorodithioate.
Its chemical structure is:
S
n
(CH 0) P-S-CH CONHCH
3 2 2 3
Dimethoate is a white, crystalline solid with a camphorlike
odor; the technical grade material is a yellow-brown liquid.
The compound has a melting point of 51 to 52° C. It is
most soluble in alcohols and ketones; its solubility in
water is 2 to 31 (EPA 1977).
Dimethoate may be oxidized to a number of toxic
products (cholinesterase inhibitors) by air, oxidative
N-demethylation, and potassium permanganate. These toxic
products include dimethoxon (dimethoate's oxygen analog),
0,0-dimethyl S-(N-methylcarbamoylmethyl) thiophosphate , and
both the N-demethylated analogs and the N-hydrox-methyl
intermediates of dimethoate and dimethoxon. Dimethoxon, an
important toxic metabolite of dimethoate, is formed when the
sulfur in dimethoate is replaced by oxygen (EPA 1977).
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(2) Registered Uses and Production
Dimethoate has been produced as a pesticide since
1963; it is a contact, residual and systemic insecticide/
acaricide that is especially effective against rasping and
sucking insect pests. It is available in emulsifiable
concentrates, wettable powders, dusts and granules. Forty-
seven registrants hold Federal registrations for 99 products,
and 6 additional companies have applied for Federal registra-
tion. The most recent Agency records show that a total of
2,491,877 pounds of dimethoate were produced during 1976
(EPA 1979)
(3) Tolerances
Tolerances for total residues of dimethoate in
or on raw agricultural commodities are listed in 40 CFR
180.204 as follow: 2 parts per million (ppm) in or on
alfalfa, apples, beans (dry, lima, snap), broccoli, cabbage,
cauliflower, celery, collards, endive (escarole), grape-
fruit, kale, lemons, lettuce, mustard greens, oranges,
pears, peas, peppers, soybean forage, soybean hay, spinach,
Swiss chard, tangerines, tomatoes, turnips (roots and
tops), and wheat (green fodder and straw); 1 ppm in or on
corn fodder and forage, grapes, and melons; 0.2 ppm in or
on potatoes and sorghum forage; 0.1 ppm in or on cottonseed,
pecans, safflower seed, and sorghum grain; 0.1 ppm (negligible
residue) in or on corn grain; 0.05 ppm (negligible residue)
2
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in or on soybeans; 0.04 ppm (negligible residue) in or on
wheat grain; 0.02 ppm (negligible residue) in eggs and in
meat, fat, and meat byproducts of cattle, goats, hogs,
horses, poultry, and sheep; and 0.002 ppm (negligible residue)
in milk.
B. Applicable Sections of FIFRA
The Federal Insecticide, Fungicide, and Rodenticide
Act (7 U.S.C. 136 ej: 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 "unreason-
able adverse effects on the environment," defined in Section
2(bb) of FIFRA to mean "any 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 risks and benefits from the pesticide's
use.
Section 6(b) of FIFRA authorized 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
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causes unreasonable adverse effects on the environment."
Thus, the Administrator may cancel the registration of
a pesticide whenever he determines that it no longer satis-
fies 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 also does
not comply with the misbranding provisions of FIFRA which
requires the labeling to contain certain language "adequate
to protect health and the environment" (FIFRA 2(g)).
C. The "RPAR" Process
The Agency has designed a process, known as the
Rebuttable Presumption Against Registration (RPAR) process,
to gather risk and benefit information about pesticides
which appear to pose adverse health or environmental
effects. This process allows an open, balanced decision
and invites participation by all interested groups.
This process is set forth in 40 CFR 162.11. These
regulations describe various risk criteria and provide
that an RPAR shall arise if the Agency determines that
any of these criteria have been met. Once a rebuttable
presumption has arisen, registrants, applicants, and
interested persons may submit evidence in rebuttal or
in support of the presumption. These people may also
submit evidence on the economic, social, and environmental
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benefits of any use of the pesticide. If the presumptions
of risk are not rebutted, the benefits evidence submitted is
considered with the risk information. Various risk reduction
methods and their costs are then analyzed. The Agency then
determines whether the pesticide may be regulated so as to
achieve a balance between risks and benefits. If the risks
outweigh the benefits of use, the registrations for that use
must be cancelled; conversely, if benefits exceed risk,
registration will be continued.
D. Bases for the Rebuttable Presumption
The dimethoate RPAR notice cited three risk criteria
which dimethoate had met or exceeded. [All such risk
criteria are listed in the Code of Federal Regulations, 40
CFR Section 162.11(a)(3).] These three risk criteria were
oncogenic effects in test animals, mutagenic effects
(multi-test evidence) [40 CFR 162. 11(a)(3)(ii)(A) ], and
reproductive and fetotoxic effects in test animals [40 CFR
l62.11(a)(3)(ii)(B)].
5
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In addition to these risk criteria, the RPAR notice
listed two other possible adverse effects of dimethoate for
which insufficient evidence existed to initiate a rebuttable
presumption. The Agency requested registrants and other
interested parties to submit data on these effects: delayed
neurotoxicity and synergism of dimethoate by other pesticides.
E. Organization of Position Document
This Position Document contains six parts. Part I is this
introductory section. Part II contains an evaluation of the
potential risks of dimethoate. It includes descriptions of
the relevant data on risks, exposure data, and the Agency's
present risk assessment. Part III is a description of the
potential economic benefits of dimethoate. Part IV describes
the range of the regulatory options identified for the
reduction of risks. Part V is the Agency's recommended
option and a comparison of the regulatory options identified
in Part IV. Finally, Part VI delineates additional testing
requirements.
6
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11• RISK ANALYSIS AND ASSESSMENT
A. Rebuttal Analysis
The Agency has received comments concerning the
oncogenic, mutagenic, and reproductive and fetotoxic effects
studies which were the basis for issuing a rebuttable
presumption. The Agency has reviewed these studies again
in the light of the rebuttal comments and has concluded that
comments submitted to date fail to rebut the presumptions
and that dimethoate continues to exceed the risk criteria
outlined in UO CFR Section 162.11 based on the chemical's
ability to induce oncogenic, mutagenic, and reproductive and
fetotoxic effects. Rebuttal comments received and the
Agency's response to those comments are set forth below.
(1) Rebuttals Relating to the Presumption of Onco-
genicity
The Agency received responses from five commentors
on the oncogenicity risk criterion. The Agency's Carcinogen
Assessment Group (CAG) has reviewed the rebuttals and
additional information submitted (Memo 1978a). Based on
this evaluation, the Agency has concluded that these rebuttals,
taken individually, do not invalidate the oncogenicity risk
criterion cited in the RPAR notice. However, based on a
re-analysis of the studies involved and the rebuttal comments
as a whole, the EPA Carcinogen Assessment Group has concluded
that the weight of evidence for dimethoate's carcinoge-
nicity is only suggestive, that the evidence warrants
7
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further studies, and that the evidence is inadequate to
justify a quantitative assessment of cancer risk (Memo 1979g)
[see also Section II.C].
The Agency cited three studies in its discussion
of the possible oncogenic effects of dimethoate. The
first study (Gibel et al. 1973) showed positive oncogenic
effects. Ten-week-old Wistar rats of both sexes were
administered doses of dimethoate, twice weekly by gavage,
of 5, 15, and 30 mg/kg. One other group of animals was
given 15 mg/kg intramuscularly. There was a significant
increase of malignant tumors at 30 mg/kg (oral route)
and 15 mg/kg (intramuscu1ar route). In addition, there
was a significant linear trend (p<0.01) for the oral
route. The second study (NCI 1977) was negative for
oncogenic effects. Osborne-Mendel rats of both sexes,
35 days old, were administered 250 and 125 ppm dimethoate
in the diet. After 19 days, the doses were halved and
continued for 61 weeks. The animals were observed for
115 weeks. Statistical analysis of tumor incidence by
site and type showed neither an excess incidence of any
specific tumor type nor any increase in total tumors.
The third study (Steiglitz et al. 1974) indicated that
dimethoate may cause hematotoxic effects in Wistar rats,
including hyperplasia of the hematopoietic parenchyma
in the bone marrow and extraosseous myeloid metaplasia.
The Agency did not base its RPAR on this third study
because the study lacked sufficient detail. However,
8
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the Agency requested registrants and other interested
parties to submit to the Agency information on these, or
v
similar, effects of dimethoate.
(a) Gibel et al. (1973)
(i) Source and Composition of Test Compound
Several commentor3 questioned the source of dimethoate
used by Gibel et al. (1973)» pointing out that the physical
and chemical properties of Gibel's test material are different
from those of dimethoate marketed in the U.S. (30000/16:#5A;
#13; #25A; #35; #36).
The Agency has rejected these rebuttal attempts. The
source of the material was the Bitterfeld Chemical Co.
(Letter 1975). According to Dr. Gibel, the material was
obtained from the Bitterfeld Co. and was recrystallized for
use in the study. The recrystallized product was 99%
pure, which implies that the crystallized product was
similar in purity to that marketed in the U.S. (The Agency
notes that the study by Lewerenz et al. (1970), which was
submitted as a negative study for carcinogenicity by American
Cyanamid Co. and Montedison USA, Inc., was also conducted
with dimethoate obtained from the Bitterfeld Chemical Co.
[see Section II.A.(1)(b)] for a discussion of the Lewerenz
et. al. study.)
(ii) Abnormal Pattern of Mortality
Two commentors (30000/16:#5A, #13) pointed out that
the Gibel et al. study does not show the normal pattern of
9
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mortality, because the high-dose group survived longer than
the low-dose group.
The Agency has rejected this rebuttal attempt. The
Agency acknowledges that mean survival time in days for each
group in the Gibel et al. study appears to be inconsistent
with normal toxicological responses, i.e., the high-dose
group survived longer than the low-dose group. This pattern
of mortality, however, has also been observed in other
carcinogenic bioassay studies, including the NCI dimethoate
study (NCI 1977). In the NCI dimethoate bioassay, both the
high and low-dose male rats survived longer than the controls.
The Agency concludes it is unlikely that differences between
mean survival times of the high- and low-dose groups would
account for the tumor incidences in the Gibel study.
(iii) Insufficient Data
American Cyanamid Co. (30000/16:#5A) and Menzer
(30000/16:035) pointed out that Gibel et al. did not report
either the lifespan of individual animals or the sex of the
animals in each dose group.
The Agency has rejected these rebuttal attempts.
Gibel did not report individual survival days per animal but
did report mean survival days for the controls versus each
experimental group. These data permit evaluation of the
test results. While the Agency would be interested in
details of individual survival times, the study may be
evaluated in terms of mean survival times.
10
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The Gibel et al. study also did not distinguish
between the number of animals of each sex in each dose
group. While this is normally reported, the absence of this
information does not negate the test results as reported.
(iv) Method of Administration
American Cyanamid Co. (30000/16:#5A) and Menzer
(30000/16:#35) stated that Gibel used the gavage method to
administer the chemical for his carcinogenesis study and
concluded that this method of administration is not acceptable.
The Agency has rejected this rebuttal attempt.
Gavage is an acceptable method for administration of chemical
carcinogens in bioassays. The NCI frequently uses this
method in their bioassay program. While Gibel has not made
clear why this method was employed rather than the more
commonly used method of dietary intake, the results of this
study are not in question because of this route of
administration, especially since the target organ was not
the stomach. Since tumors were reported at remote sites,
the test material was obviously absorbed and disseminated.
(v)' Incorrect Dosage Data
American Cyanamid Co. (30000/16:#5A) indicated that
Gibel reported dosage information incorrectly. The registrant
stated that this represented a lack of organization in the
research program and concluded that: (1) the Gibel study
was poorly conceived; (2) it was executed in an inappropriate
fashion; and (3) it resulted in data that are not scien-
tifically useful or valid.
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The Agency has rejected this rebuttal attempt. The
dosage information incorrectly reported in Table 4 of
Gibel's study does not by itself negate the significance of
the study. Similar problems are apparent in the report by
Lewerenz et al. (1970). For example, Lewerenz et al.
reported that 75 ppm dimethoate in the diet was equal to 20
mg/kg per day. Data representing the average body weight
and feed consumption, however, indicated a true dose level
of 5.5 mg/kg per day in females and 5.88 mg/kg per day in
males. Apparently, Lewerenz reported a dose four times
higher than the data indicated.
(vi ) Low Exposure from Food Residues
American Cyanamid Co. (30000/16:#5A) and Montedison
USA, Inc. (30000/16:#25A) pointed out that, in two subsequent
papers (Oedek et al. 1975 and Gibe! et al. 1976), Gibel
concluded that the hazard to consumers (resulting from
dimethoate) "will probably not have to be expected in the
future." The registrants also stated that, considering both
the amount of dimethoate residues on agricultural crops and
the legally established waiting periods between use of
dimethoate and harvest, there is little or no danger of
cancer formation.
The Agency has rejected these rebuttal attempts.
The Agency is concerned about the hazard to the applicators
of dimethoate as we 11 as to the consumer exposed to dimethoate-
9
treated commodities. Gibel stated that, in his opinion,
12
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exposure to dimethoate in food will not pose a cancer risk.
The Agency notes, however, that Dr. Gibel expressed his real
concern when discussing potential oncogenic risk to workers
involved in the production and application of dimethoate.
Dedek et al. (1975) stated, "The results of these studies
should be taken into consideration in optimizing safety
measures, both for pesticide production and agricultural
workers handling pesticides." In a subsequent paper (Gibel
et al. 1976), Gibel warned that "the groups of persons
coming into direct contact with such pesticides as phosphoric
acid esters (Dimethoate) - workers in production and in
agriculture - must therefore be subjected to particularly
careful preventive-medical control and must be held to very
vigorous worker-protection guidelines."
(vii) . Lack of Tumors in Controls
American Cyanamid (30000/16:#5A) and Montedison USA,
Inc. (30000/16:#25A) indicated that it is extremely unusual
that no malignant and very few benign tumors were found in
the Wistar rat control group. The previous record of the
Wistar rat group is not the low spontaneous tumor rate of
8.7% cited by Gibel. This gross difference could indicate
that the control rats were not thoroughly examined. Addi-
tional tumors in the control animals would have radically
altered their conclusions.
The Agency has rejected this rebuttal attempt. There
is no indication in the experimental report that the controls
13
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were examined differently than the treated animals. There-
fore, there is no basis for the statement. CAG was unable
to identify and agree upon a spontaneous tumor rate for the
Wistar rat since these rates seem to vary rather widely
among different laboratories, depending upon the husbandry.
(b) New Study Offered in Rebuttal
American Cyanamid (30000/16:#5A) and Montedison USA,
Inc. (30000/16:#25A) submitted an unpublished study by
Lewerenz et al. (1970), which was reported as negative for
carcinogenicity. The registrants pointed out that the same
strain of rat was used in both the Lewerenz and Gibel papers
and concluded that the Lewerenz study negates the positive
findings by Gibel. The registrants also pointed out
that the Lewerenz paper bridged the gap between the NCI
(negative) and.Gibel (positive) studies.
The Agency has rejected this rebuttal attempt.
The source of the test material for both the Lewerenz et al.
(1970) and Gibel et al. (1973) studies was the Bitterfeld
Chemical Company. The same strain of rat (Wistar) was used
in both studies, but the dose levels were substantially
different. Lewerenz et al. (1970) used lower doses than did
Gibel et al. (1973)- Based on average body weight and feed
consumption data presented, the male rats in the Lewerenz
study were given 5.5 mg/kg per day and females were given
5.88 mg/kg per day in the highest dose group (75 ppm).
Gibel, on the other hand, administered 30 mg/kg per day
twice weekly. This difference in dose could account for the
difference in response.
14
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CAG (Memo 1978a) has reviewed the Lewerenz et al.
(1970) data and found deficiencies in the pathology report,
since only the results of macroscopic examinations are
reported. The tumor sites are not specified, and it is
therefore not possible to fully evaluate the pathology. CAG
concludes that the Lewerenz study cannot be used to negate
the result of Gibel et al. (1973) nor to confirm the negative
NCI study.
(c) Stei glitz et a 1 . (1974 )
(i) Lack of Information
American Cyanamid Co. (30000/16:#5A) argued that
Steiglitz et al. (1974) provided very little information or
data about their study. Specifically, the registrant
pointed out that it was unclear whether the percentage
incidence of myeloproliferation and extra-osseous myeloid
metaplasia referred to the total of all animals and all
dosages or to one particular dosage; that no mention was
made of control animals; that leucocyte counts were compared
to unspecified control animals; and that the authors did not
Indicate when leucocyte counts were made.
The Agency has rejected this rebuttal attempt.
The papers by Steiglitz et al. (1974) and Gibel et al .
(1973) were based on a single experiment. The Steiglitz et
al. (1974) paper addressed the effect observed on the blood
and blood forming tissues while Gibel et al. (1973) addressed
the oncogenic effects of dimethoate. The controls for both
papers (Gibel et al. (1973) and Stleglitz et al. 1974) are
described in Gibel et al. (1973). Furthermore, the judgement
15
-------
of the frequency of myeloproliferation and extra-osseous
myeloid metaplasia is subjective and may not require a
control group. The Agency acknowledges, however, that
additional information concerning the control group would
have made the study more definitive. Although the authors
did not indicate when leucocyte counts were made, the count
was in the normal range for controls but was high in the
treated group.
(i i ) Source of Test Compound
The Calif. Dept. of Food and Agriculture (30000/16:#36)
commented that the compound used in this study was probably
the same as that used by Gibel et al. (1973).
The Agency notes that both Steiglitz et al. (1974)
and Gibel et al. (1973) reported on the same group of
test animals. Gibel reported on carcinogenic effects,
Steiglitz on hematological effects. The test compound
was the same for both papers (Letter 1975).
In summary, the comments submitted on the oncogenic
risk criterion do not rebut the Agency's original presumption
concerning the oncogenic potential of dimethoate. The Gibel
et al . study as reported in 1973 and subsequent information
submitted by Dr. Gibel (Letter 1975) still leave out many
details regarding the conduct of this study that the Agency
would be interested in reviewing. CAG has concluded,
however, that the available data are only suggestive of
oncogenicity (Memo 1979g). The Agency's discussion of
oncogenic risk from dimethoate is contained in Section II.C.
16
-------
(2) Rebuttals Relating to the Presumption of
Reproductive and Fetotoxic Effects
The Agency received comments from five commentors
on the reproductive and fetotoxic risk criterion. The
Agency has reviewed the rebuttals and additional infor-
mation submitted (Memo 1978b). Based on this evaluation,
the Agency has concluded that these rebuttals do not
invalidate the three studies cited in the RPAR notice.
Budreau and Singh (1973) studied the effect of zero
and 60 ppm of dimethoate in the drinking water of five
generations of CD-I mice. The 1973 Budreau and Singh paper
is based on the more detailed thesis by Budreau (1972).
Dimethoate treatment significantly altered reproductive
performance, as indicated by reduced mating success and
longer reproduction time. In all generations, dimethoate-
treated females required significantly longer periods than
the controls to produce first litters, and second litter
mating success ranged from 33 to 61% (p<0.01) of the control
values. Although litter size and weight were not reduced at
birth, the survival rate of the total pups and litters was
significantly (p<0.01) reduced by dimethoate treatment in
generations I, III, IV, and V. The highest rate of mortality
occurred in the first postnatal week. The major flaw with the
Budreau and Singh (1973) study is the lack of multiple dose
levels on which to base dose-response relationships.
Scheufler (1975a) observed a significant increase in
the number of dead embryos (p<0.01) on the ninth day of
-17-
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pregnancy following administration of a single 40 mg/kg
dose of dimethoate intraperitoneally to female AB Jena-
Halle mice on the day of conception. The daily injection
of dimethoate at 40 mg/kg during the first 14 days of
pregnancy resulted in the death of four times as many
implanted embryos as the controls for this strain. The
administration of 25 mg/kg of dimethoate intraperitoneally
to female C57BL mice increased the number of non-pregnant
females to 7056 compared to the 20-3056 control value.
Likewise, for DBA mice, a dose of 20 mg/kg for 14 days
resulted in the absence of embryos in 50% of the treated
females. The usefulness of this study for risk extrapolation
is limited due to the route of administration. A lack of
reported data makes statistical interpretation difficult.
American Cyanamid Co. (1965) conducted a three
generation feeding study with CF1 strain albino mice, using
0, 5, 15, and 50 ppm of dimethoate in the diet. The report
concluded that "reproduction and lactation performance was
good for all groups." A review of the data by an EPA
scientist indicated that at 50 ppm, there was an effect,
albeit not statistically significant, on litter survival
(Courtney 1977) .
(a) Rebuttals Relating to More Than One Study
(i) Type of Effects Observed
American Cyanamid Co. (30000/16:#5A) defined
fetotoxicity as the failure of the fetus to survive through
the entire gestation process and pointed out that neither
18
-------
the five generation study of Budreau (1972)-/, nor Budreau
and Singh (1973), nor the three generation study of American
Cyanamid Co. (1965) demonstrated any such effect.
The Agency has rejected this rebuttal attempt.
Although the commentor's definition is very narrow,
Cyanamid is correct in stating that neither Budreau (1972),
Budreau and Singh (1973), nor American Cyananid Company
(1975) observed evidence of toxic damage to the fetus.
Budreau (1972) and Budreau and Singh (1973) did report an
increase in neonatal mortality. This is a postnatal toxicity
effect, as opposed to a fetotoxic effect. Since the RPAR
notice cited general reproductive (as well as fetotoxic)
effects, the Agency's original presumption of risk remains.
The Agency also points out that the Scheufler study did
display an increase in fetal mortality, or fetotoxicity.
T7 Budreau CT9T2T is a doctoral thesis upon which the
publication of Budreau and Singh (1973) is based. The
thesis was not cited in the RPAR notice.
19
-------
(b) Budreau and Singh (1973)
(i) Inconsistent Data
American Cyanamid Co. (30000/16:#5A) argued that the
Budreau and Singh data are suspect because the data from
Budreau (1972) is expressed not as survival percentages
[like the data in Budreau and Singh (1973)3 but as the
percent mortality of pups or litters. The registrant argued
that in every instance the percentage of survival given by
Budreau and Singh (1973) was nearly 20? lower than that
which could be calculated from Budreau (1972). The registrant
stated that this difference is large enough to change the
survival rate differences, from insignificant in the thesis
to significant in the publication.
The Agency has rejected this rebuttal attempt.
It appears that, in the thesis and report, the "n" value
20
-------
(number of pups surviving) was adjusted to consider only the
living pups; litters with 100J mortality were not considered.
There is no inconsistency between the data given in the
paper and in the thesis and no reason to view these data as
suspec t.
(ii) Drowning of Litters
American Cyanamid Co. (30000/16:#5A) stated that lost
litters, which were attributed to the effects of dimethoate,
were actually caused by drowning of entire litters by water
leaking into the plastic cages from the watering bottles.
The Agency has rejected this rebuttal attempt.
On page 103 of the thesis (Budreau 1972), last paragraph,
the author states, "Mortality among adult animals varied
from 4% for the fenthion group and 8J for the dimethoate and
control groups. A main factor in the mortality was swamping
of some cages by a bottle that inadvertently opened...no
mortality could be directly attributed to the diet."
The quoted statement was the only reference in the thesis to
death by drowning. The Agency notes that the author stated
that the deaths were of adult animals; no litters were
subject to drowning. Since an equivalent percentage of
deaths occurred in the dimethoate and control groups
from this accidental cause, these animals can be deleted
from consideration without impairing the study.
(iii) Dam Transfer Experiment
American Cyanamid Co. (30000/16:#5A) commented that
the dam transfer experiment, which indicated that the pups
-21-
-------
may have died because of pesticide residue in the milk, was
not performed with dimethoate but with fenthion.
The Agency has accepted this rebuttal attempt.
The Agency improperly interpreted this portion of the study.
(iv) Contaminated Drinking Water
American Cyanamid Co. (30000/16:#5A) also contended
that another possible cause of mortality would be from the
pups drinking the water containing dimethoate directly,
thus exposing themselves to very high dosages of dimethoate
on a body weight basis. The Agency has rejected this
rebuttal attempt. There is no evidence to support this
contention.
(v) Nutritional Difficulties
American Cyanamid Co. (30000/16:#5A) also argued
that litter mortality was attributable to factors other than
dimethoate treatment, such as nutritional difficulties. The
Agency has rejected this rebuttal attempt. There was
no evidence of nutritional difficulties in either the
adults or pups at birth. On the contrary, litter size
or weight at birth were not reduced, but pup mortality
did increase significantly with dimethoate treatment.
(vi) Lowered Mating Success
American Cyanamid Co. (30000/16:#5A) also stated that
Budreau and Singh (1973) could not identify why the mating
success of dimethoate-treated animals was lower than that of
the controls. The Agency has rejected this rebuttal attempt.
Budreau and Singh (1973) clearly attributed the lowered
22
-------
mating success to dimethoate treatment, but were unable to
pinpoint the exact mechanism of action, or target organ, for
the compound.
(vii) Condition of Test Animals
American Cyanamid Co. (30000/16:#5A) further questioned
the validity of the study because of the condition of the
animals used. The registrant cited a 25J decrease in weight
for dimethoate-treated animals in an experiment described by
the chart on page 73 in Budreau (1972). The registrant also
cited the "lethargic" condition of the test animals as
affecting mating success.
The Agency has rejected the first part of this
rebuttal attempt. The data on decreased weight refer to a
preliminary experiment in which the animals were housed
singly, and in which there was a great weight loss and a
concomitant lack of reproduction. In the 1973 paper,
however, the studies were performed on mice housed in groups
of M to 6 in plastic cages, a condition found to be'optimal
as a result of the preliminary studies detailed in the
thesis. The authors noted a minimal effect on weight gain
only in the first two weeks of treatment, and no increase
in mortality among the adults. The lethargic condition
of the males, which the registrant suggested as a reason
for the effect on mating success, could very well be the
result of the toxicological effects of dimethoate. The
difficulty in separating toxic effects from adverse reproduc-
tive effects is one of the flaws in the study.
23
-------
(viii) Selection of Test Animals
American Cyanamid Co. (30000/16:#5A) contended that
neither Budreau (1972) nor Budreau and Singh (1973) included
a description of the process for selecting test animals and
argued that anything less than a completely random selection
process could severely bias the results for all generations.
The Agency has rejected this rebuttal attempt. On
page 30 of Budreau and Singh (1973), the authors state that
the animals were randomly paired; on page 31» they state
that matings were performed at random for all generations.
There is no evidence that the selection procedure was
anything less than a completely random process.
(ix) Definition of "Reproduction Time"
American Cyanamid Co. (30000/16 :#5A) stated that the
term "reproduction time" was used inaccurately. The Agency
has rejected this rebuttal attempt. The term was used in
accordance with the definition, given on page 81 of Budreau
(1972), that reproduction time is "the number of elapsed
days from the first day when the female was presented
to the male to the day of delivery"; this would include time
for impregnation to occur. Although, as American Cyanamid
correctly pointed out, the reproduction time was significantly
different for dimethoate-treated animals only for the first
litter, the lowered mating success (33 to 61% of control
value) for second litter production may have masked a longer
9
reproduction time for the second litters.
24
-------
(x) Maternal Toxicity
Montedison USA, Inc. (30000/16:#25A) stated that no
teratogenic effects were observed in the Budreau and Singh
study, and that the effects observed, namely, lower mating
success, longer reproduction time, and reduced survival
and growth rates, were to be expected in severely intoxicated
females.
The Agency has rejected this rebuttal attempt.
Since the dosage of dimethoate used did not increase mortality
among the adults, and produced a small diminution of weight
gain only in the first two weeks of treatment, there is no
basis for attributing the adverse effects to maternal
toxicity.
(xi) Incorrect Dosage Data
Menzer (30000/16:#35) commented that the estimate of
water consumption made by Budreau and Singh (1973) was
unrealistic, since the stated daily dosage of 9.5 to 10.5 mg
dimethoate/kg would indicate that the mice drank only 4 ml.
of the dimethoate-treated water per day. The commentor
suggested that a more realistic estimate of water consumption
would be 12 to 15 ml. of water per day, resulting in a daily
dosage of dimethoate between 36 and 45 mg/kg rather than 10
mg/kg. American Cyanamid Co. (30000/16:#5A) also noted that
the actual dosage.given to the mice in the study was probably
closer to 36-45 mg/kg.
The Agency has rejected this rebuttal attempt. The
Agency has concluded that the Budreau estimate of 10 mg/kg/day
25
-------
is a reasonable estimate of the dose level, since pregnant
mice drink an average of 8.8 + 0.5 ml. of water per mouse
per day (Memo 1978b; Letter 1978); there was no difference
in water consumption at the beginning of gestation compared
to the end of gestation. At a dose level of 60 ppm in the
drinking water, 8.8 ml. of water in a 36 gram mouse would be
a dose of 13-6 mg/kg, which is quite close to the dose of 10
mg/kg calculated by Budreau.
(xii) Effect on Neuro and Endocrine Systems
The California Dept. of Food and Agriculture
(30000/16:#36) commented that the study by Budreau and Singh
(1973) indicated that dimethoate significantly reduced
mating success and increased reproduction time but argued
that since the studies dealt primarily with end effects, the
authors should have measured the effect of dimethoate on
functioning neuro and endocrine systems.
The Agency has rejected this rebuttal attempt. The
Agency agrees that studies of the mechanism of action of
dimethoate would be of interest but concludes that the lack
of such information does not affect the validity of the
adverse reproductive effects demonstrated by the Budreau and
Singh study.
(c) Scheufler (1975a)
(i) Lack of Detail
American Cyanamid Co. (30000/l6:#5A) argued that
Scheufler (1975a) was extremely abbreviated and lacked
-26-
-------
detail. The registrant cited the following specific examples:
1) although the number of corpora lutea, living and dead
fetuses, dead embryos, and weights of the fetuses are said
to have been recorded, these data are absent in the article;
2) it is not clear from the article whether the controls
were concurrent; and 3) the table in the article indicates
"total loss," but does not explain specifically what was
lost (fetuses, experimental animals, "nuclei," or something
else not mentioned). The registrant concluded that the
absence of other significant data prevents statistical
interpretation of the study.
The Agency has rejected most of these rebuttal attempts.
These rebuttal points apparently stem, in part, from difficul-
ties with the Agency's first translation of the German text
(Scheufler 1975a). Although a comparison of this translation
with the original article clarifies these rebuttals, the
Agency nevertheless had the article translated a second time
(Scheufler 1975b). On the first rebuttal point, the Agency
agrees that these data were not provided in the article; the
Agency points out, however, that these data were used to
determine the pre-implantation, post-implantation, and total
losses of embryos. The data on these losses were provided
in the first translation. On the second point, the Agency
agrees that the first translation is unclear on the concurrence
of controls. The second translation (Scheufler 1975b)
states, "Controls were also carried through with all experi-
ments in the same time period...." The German text is
-27-
-------
equally clear on this point: "Łu alien Versuchen wurden im
gleichen Zeitraum Kontrollen durchgefuhrt...." On the third
point, the second translation also makes clear that the
"total losses" are the pre- and post-implantation embryo/fetal
losses. Because the pre-implantation loss was an "unreliable
measurement value" (Scheufler 1975b), the author relied
primarily on the post-implantation loss to describe embryo-
toxic effects. The comparison of post-implantation embryo
loss with control values allows statistical interpretation
of the study.
(ii) Definition of "Nuclei"
American Cyanamid Co. (30000/16:#5A) stated that
the author [translator(?)] refers to "nuclei" a3 having been
lost but does not define nuclei. The Agency points out that
this term is often used by translators in referring to
embryos or fetuses (Memo 1978b).
(iii) Total Loss Data
American Cyanamid Co. (30000/16:#5A) quoted the
first translation that total loss was calculated "by assertion."
The registrant also noted that the author stated" he could
not use the pre-implantation data.
The Agency has rejected this rebuttal attempt.
The sentence referred to by the registrant, in the first
translation (Scheufler 1975a), reads: "The preimplantary
loss proved to be an unreliable measurement data after
several experiments, whereby concurrently the data for the
28
-------
total loss was reduced by assertion." The same sentence in
the second translation (Scheufler 1975b) reads: "The
pre-implantation loss proved in several experiments to be
an unreliable measurement value; this also limits the
definitive significance of the total loss." It is clear,
therefore, that the author did not calculate total loss "by
assertion." As already noted, the "total loss" refers to
pre-implantation and post-imp!antation loss of embryos [see
Section 11.A.(2)(c)(i)]. Since pre-implantation loss data
were unreliable, the value of the "total loss" (as a measure-
ment of embryotoxicity) was also reduced ["concurrently the
data for total loss was reduced by assertion"]. The author
relied on post-implantat1on loss to describe embryotoxic
effects.
(iv) Route of Exposure
American Cyanamid Co. (30000/16:#5A) also argued
that injecting dimethoate intraperitoneally was an entirely
inappropriate route of exposure. The Agency has rejected
this rebuttal attempt. Many investigators use this route of
administration in teratology or perinatal toxicity studies;
the Information gained cannot be dismissed as unscientific
or useless. The Agency would agree, however, that data
obtained from studies utilizing the oral route of admini-
stration would be preferable when analyzing potential
human risk.
29
-------
(d) Exposure Rebuttals
Several commentors (30000/16:#5A, #13, #35, #36)
indicated that the Agency incorrectly estimated oral
exposure to dimethoate (i.e., through food) in that all
food crops for which dimethoate is registered are not
actually treated with dimethoate.
The Agency accepts this rebuttal comment. The Agency
has revised its estimates of oral exposure to take into
consideration data submitted by commentors, including USDA,
concerning the percent of those crops actually treated with
dimethoate [see Section II.B(U)]. Because of a lack of
data concerning actual dimethoate residues on foods at
harvest, the Agency assumes residues to be present at
tolerance levels.
Several commentors (30000/16:#5A, #13, #25, #35,
#36) submitted information concerning anticipated dermal
exposure and indicated that the Agency overestimated
dermal exposure.
The Agency accepts these rebuttal comments. The
Agency has revised its estimates of dermal exposure to
take into consideration comments and other data submitted
[see Section II.B].
(c) Calculation of Margin of Safety
One commentor (30000:#16) criticized the manner
in which the Agency calculated the margin of safety (M0S)
for reproductive and fetotoxic effects. The M0S was
derived by dividing the dosage which produced no observable
effect in test animals by estimated total daily human
exposure. The Agency's human exposure analysis was calculated
-30-
-------
assuming that the applicator would become soaked with
dimethoate during application of the pesticide). The commentor
indicated that it is only marginally conceivable that a
young female applicator could be exposed (dermally) to
dimethoate in this manner but that it is impossible to
accept the premise that this event would take place daily
through puberty, pregnancy and lactation, as it was received
by the experimental animals.
The Agency has concluded that this rebuttal attempt
is partially successful. The Agency based its rebuttable
presumption for reproductive and fetotoxic effects upon
the study by Budreau and Singh (1973), a multigeneration
feeding study. The commentor1s point that a young woman
might be exposed to dimethoate only once or twice a year
and that this exposure is quite different from continual
daily exposure is well taken. However, new teratogenic
data unavailable when the RPAR was issued has been submitted
by Khera [unpublished, see section II.C(3)(a)].
Teratogenic studies such as those done by Khera
(unpublished) involve dosing a pregnant animal during
the critical periods of gestation, to determine if a terato-
genic or fetotoxic effect can be demonstrated. Because
the critical day of gestation, when any particular pesticide
may expect an effect is not known, multiple doses are given
for several days. The study by Khera (unpublished), therefore,
is actually a series of acute daily doses and can be used
as the basis for calculating the MOS for teratogenic effects.
31
-------
Duration of exposure may play an important role in
reproductive effects such as those observed by Budreau and
Singh (i.e., increased generation time, decreased litter
size, etc.). When teratogenic effects (Khera) are observed,
the potential exposure during the critical days of gestation
is the focus of concern.
(3) Rebuttals Relating to the Presumption of
Mutagenicity
The Agency received responses from five commentors
on the mutagenicity risk criterion. The Agency has re-
viewed the rebuttals and additional information submitted
(Memo 1978d). Based on this evaluation, the Agency has
concluded that these rebuttals do not invalidate the
presumption of mutagenicity risk. No evidence has been
presented to invalidate positive results in reverse mutation
assays with E. coli WP2 UvrA and WP67 (Hanna and Dyer 1975),
as well as with one forward mutation assay with E^. coli K-12
(Mohn 1973)* A dominant-lethal effect was reported, by Gersten
garbe (1975) in mice, but weaknesses were pointed out in the
protocol which make quantifying the mutagenic potential
difficult. Some of the rebuttals concerned the relative
potency of dimethoate; this issue will be considered in
assessing risk (see Section II.C). The Agency has accepted
a rebuttal against the use of plant tests cited in the RPAR
notice (because of the lack of control values for the
Agarwal et al. (1973) study and the uncertainty about the
heritability of effects reported in the Amer and Farah
(197*0 study. The Agency cited nine studies in the RPAR
notice, which are listed in Table 1.
-32-
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Table 1
Mutagenicity Studies Cited in Position Document 1
11 Rebuttal
11
1
11
11
11
^Reference
H Study Type
11 Species & Strain
11 Doses
11 Results
11
KFahrig
Ulnduction of mitoticllSaccharomyces
117 dose levels;
llpositive re-
11
111973
llgene conversions
llcerevisiae D4
1140 to 100 mM
llsponse; signif-
-11
1
11
11
11
llicant dose-
11
11
11
11
11
11 response
11
HHanna &
HBacterial systems
HEschericia coli,
115 to 10 ul
llpositive in E.
11
iDyer 1975
11
11WP2 uvrA and WP67 ;
11
Hcoli WP2 uvrA «
Ml
1
K
Kother E. coli &
11
11WP67 ; negative
11
11
1
USalmonella typhi-
11
11 in other
11
H
11
llmuriura strains
11
1|strains
11
1
H
11
11
11
11
HMohn 1973
HBacterial system
1IE. coli,
115 dose levels;
llpositive re-
11
11
11
IIK — 1 2/gal 1 Rs 18
11 ,
^sponse; signif-
-11
11
11
11
111 to 6X10 J M
llicant dose-
11
11
11
11
11
11 response
11
H American
UMetabolic-activationllS. typhimurium and
1120 to 100 ug/
1|no mutagenic
11
11 Cyanamid
1|with rat liver
1|E. coli strains
11 plate
1|response
H
11 Co. 1977
11 enzymes
11
11
11
11
UShirasu et1lBacterial systems
IIBacillus subtilis
Knot given
lino mutagenic
H
11 al. 1976
11
HH17 Rec+ and R45-
11
11 response
n
HAgarwal etIICytology Study
llbean (Phaseolus
HO.1 & 0.5*
Uchromosomal ab-
-n
lal. 1973
11
llvulgaris)
llspray at bud
Unormalities,
n
11
11
1
1|initiation
Hincluding frag-
-n
11
11
11
11
1|ments, sticki-
11
K
11
11
11
1|ness, & ana-
11
11
11
H
11
phase bridge
11
11
11
11
H
11 formation
11
1|Amer and
1ICy tology
llcotton (Gossypium
llboth pure and
llpositive muta-
11
UFarah 197411
Hbarbadense) and
^formulated di-
Hgenic response
11
H
11
llbean (P. vulgaris)
llmethoate at
11
11
1
11
11
llvarious dilu-
11
11
11
11
11
H tions
11
11
llGersten-
11 Dominant-lethal
llmale mice (Mus rous-
¦ Hsingle 80 mg/kg1lpositive muta-
11
^ garbe 197511
llculus) AB Jena-
Hor 6.66 mg/kg
Kgenic response
11
H
11
HHalle
lldaily for 30
H
11
1
11
11
11 days
11
n
1|Bhunya andHBone marrow cy tologyllmale and female, Hinjection of Kcentromeric II
fBehera H flmice (M. musculus) II1 cc/100 g bodyHfission and K
H1975 5 5 Hwelght Ustretching 1[
33
-------
(a) Rebuttals Relating to More Than One Study
(i) Purity of Test Compound
Montedison USA, Inc. (30000/16:#25A) indicated that
there were several contradictory findings among the submam-
malian mutagenicity tests and that this may be due to the
uncertain purity of the dimethoate used.
The Agency has rejected this rebuttal attempt. The
contradictory findings (i.e. there were positive as well as
negative results) can be explained by means other than
uncertainty about the purity of the test compound. The study
by American Cyanamid Co. (1977) [see Section II.A.(3)(J)(i)],
which was submitted as a study showing non-mutagenic effects,
was actually positive and supported Hanna and Dyer (1975),
which showed positive mutagenic activity in the same test
strain.
(ii) Diverse Test Results
Hutton (30000/16:#13) argued that the "highly diverse
lot of studies" presented in the mutagenicity section of
Position Document 1 could justify any conclusion one wished
to draw.
The Agency has rejected this rebuttal attempt.
Mutagenic agents rarely show positive responses in all
types of tests because the test results are subject to
differences in the sensitivity of the test system, differences
in absorption and metabolism, etc. The positive responses
observed dictate that the Agency's concern is prudent
in light of the potential human health risks.
3^
-------
(iii) Dosage Levels
Hutton (30000/16: #1 3) argued that test protocols
(none specified by commentor) used incredibly large dosages
that bear no relationship to the real world.
The Agency has rejected this rebuttal attempt.
In order to detect the relatively low probabilities of
mutations caused by the concentrations of chemicals found in
the real world, it would be necessary to use large numbers
of test subjects over a long period of time. This is
impractical. It is scientifically acceptable, and even
necessary, to use large dosages administered to a smaller
sample of test subjects over a shorter span of time to
magnify mutagenic effects to a statistically detectable
level.
(iv) Bacterial Assays; Variable Results
The California Department of Food and Agriculture
(30000/16:^36) argued that the introduction of a host of
variables into the bacterial tests cited in the RPAR notice
made interpretation of the results difficult. The commentor
cited the conflicting results of American Cyanamid Co.
(1977) and Mohn (1973) and suggested that the difference in
response could be due to the metabolism of dimethoate by the
microsomal liver fraction. The commentor also questioned
the source of dimethoate and its manner of incorporation
into the agar plate in Mohn (1973). The commentor argued
that the results suggest either that dimethoate was not
absorbed by the microorganisms, that it was no longer
present as dimethoate, or that the concentration was too
low.
35
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The Agency has rejected these comments. American
Cyanamid Co. (1977) has resolved the apparent difference
in results [see Section II. A . ( 3) ( j ) ( i) ]. E. coli' WP2 UvrA
responds to dimethoate, but only at relatively high concen-
trations (Hanna and Dyer 1975; American Cyanamid Co. 1977).
E. coli WP67, which differs from E. coli WP2 UvrA only in
lack of polymerase A, was also positive [tested only by
Hanna and Dyer (1975)1. Tests with S. typhimurium were
negative except for strain TA-100 (a very sensitive derivative
of TA-1535), which showed a dose-response suggestive of
mutagenic activity (American Cyanamid Co. 1977). Unfortu-
nately, the TA-100 had a very high background of mutational
frequency (230 to 522 colonies/plate), which reduced the
response. Normal rates should be about 160 colonies/plate
(De Serres and Shelby, 1979). In addition, another strain
of E- coli was positive in a forward mutation assay (Mohn
1973).- These results, therefore, are consistent with other
studies demonstrating a low potency mutagen, active by means
of base substitution.
(b) Hanna and Dyer (1975)
(i) Control Plates
American Cyanamid Co. (30000/16:#5A) indicated
that the authors did not use, or failed to report, the
results from negative and positive control plates.
The Agency has rejected this rebuttal attempt. The
study reported many negative responses among the chemicals
tested as well as positive responses for known mutagens,
-------
e.g., trimethyl phosphate. These responses are adequate
to demonstrate the proper operation of the system used
by Hanna and Dyer, especially since their results with
dimethoate were confirmed by American Cyanamid.
(ii) Dose Not Reported
American Cyanamid Co. (30000/16 :#5A) pointed out
that, since the authors did not state the dose used, a
dose-response relationship could not be calculated in a
statistical analysis.
The Agency has rejected this rebuttal attempt. The
Hanna and Dyer (1975) study is a spot test for mutageni-
city and is npt a quantitative test. In this context,
dose is not relevant to the determination of mutagenic
potential.
(iii) Incorrect Protocol
American Cyanamid Co. (30000/16:#5A) stated that
the protocol used was incorrect because the incubation
period was extended one additional day and because, when
the study was performed with the correct incubation period,
the results were negative rather than positive.
The Agency has rejected this rebuttal attempt.
The protocol was developed by Bridges et al. (1972) who
incubated their plates for two days. It is standard protocol
(De Serres and Shelby, 1979), however, to look for slow-growing
revertant colonies at 72 hours. Negative results with
37
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other compounds tested by Hanna and Dyer (1975) indicate
that no extraneous influences were introduced by this
extension.
(iv) Toxicity Estimate
American Cyanamid Co* (30000/16:#5) stated that
the determination of toxicity for this study was inadequate.
Toxicity "was estimated only by noting a reduction in the
number of revertants relative to negative controls."
The Agency has rejected this rebuttal attempt. The
toxic effect would only reduce the number of prototrophic
revertants. A positive test result is still valid in a spot
test because the growth of colonies due to endogenous
histidine being released from killed cells would be distributed
throughout the plate and would not be concentrated in the
center of the plate where the dimethoate was placed.
(v) Confirmation of Phenotypes
American Cyanamid Co. (30000/16:#5A) indicated that
colonies which appeared to be revertants were not purified
and retested on minimal plates to confirm their phenotypes.
The Agency has rejected this rebuttal attempt. The
procedure outlined by the registrant is very time consuming
and expensive; it is also superfluous in a screening examina-
tion such as this spot test.
38
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(c) Shirasu et al. (1976)
American Cyanamid Co. (30000/16:#5A) indicated that
this study supports the contention that dimethoate is not
mutagenic.
The Agency agrees that this study did not show
dimethoate to be mutagenic; this study, however, does not
rebut the presumption that dimethoate can act as a mutagen.
The test protocol used by Shirasu et al. (1976), which
resulted in a negative mutagenic response, is different from
those test protocols showing positive results (Hanna and
Dyer 1975). Shirasu et al. (1976) used a different inoculum
(0.02 ml of a 1 mg/ml solution on a paper disc) and incubated
test plates for two days. Hanna and Dyer (1975) used "a
crystal or 5-10 ul" of chemical placed directly onto the
plates, which were incubated for three days. These tests,
therefore, do not necessarily contradict one another. The
differences in method preclude direct comparison of the
positive and negative test results. The Agency notes that
positive results were observed in a spot test with the
same strain of E. coli [American Cyanamid Co. 1977] using
dimethoate at a concentration of 10,000 ug/disc [see Section
II.A.(3)(j)(i)].
(d) Mohn (1973)
(i) Invalid Test System
American Cyanamid Co. (30000/16:#5A) stated that the
testing system used in the Mohn (1973) study has not been
used widely enough to allow validation of its results.
-39-
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The Agency has rejected this rebuttal attempt. The
5-methyl tryptophan resistance mutation system used by Mohn
(1973) has been adequately studied, and the test was performed
with proper protocols to indicate valid mutations.
(ii) Low Potency of Compound
American Cyanamid Co. (30000/16:5A) indicated that
known mutagens, such as MNNG, were over 10,000 times^more
potent than dimethoate in this test system.
The Agency has rejected this rebuttal attempt.
The potency of' dimethoate is much less than MNNG in this
system; however, a proper dose-response curve at a non-toxic
level was demonstrated for dimethoate, indicating mutagenic
activity. ~"
(iii) Liquid Suspension Assay
American Cyanamid Co. (30000/16:#5A) indicated that
liquid suspension tests such as those used by Mohn (1973)
can give results which conflict with plate tests, depending
on the compound being tested (Ames et al. 1975)-
The Agency has rejected this rebuttal attempt. The
statement is misleading since Ames noted (Ames et al. 1975)
that liquid suspension tests were usually less sensitive
than plate tests. Ames also noted that the liquid suspension
test identified two mutagens that were not picked up with
the plate incubation system. Use of the liquid suspension
system does not make a test less valid.
-------
(e) Agarwal et al. (1973)
(i) Phytotoxicity of Dimethoate
Montedison USA, Inc. (30000/16 : #25A) argued that
mutagenicity tests on plants could'be questionable, owing to
the well-known phytotoxicity of dimethoate beyond a certain
level of concentration in the plant tissues.
The Agency has rejected this rebuttal attempt. One
of the criteria for dose selection in mutagenicity tests
is that toxicity be demonstrated at the high dose level.
Both plant studies reported a partial toxic effect at
the higher levels.
(ii) Lack of Controls
American Cyanamid Co. (30000/16:#5A) pointed out that
no controls were reported.
The Agency agrees that this is a valid criticism and
that this study is not acceptable as primary evidence
for the mutagenicity of dimethoate due to the absence of
reported controls. The increase in chromosomal fragmentation
and bridge formation, however, suggests that dimethoate may
produce cytogenetic effects for Phaseolus vulgaris.
(iii) Variation in Results
American Cyanamid Co. (30000/16:#5A) indicated that
the experiment was apparently repeated with variation
in results.
41
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The Agency has rejected this rebuttal attempt. There
is nothing in the paper which indicates that the experiment
was repeated. The chromosomal abnormalities, however, were
scored at both metaphase and anaphase, and thus a variation
in numbers could be expected.
(f) Amer and Farah (1974)
As previously noted [see Section II.A (3)(e)(i)],
the Agency has rejected a rebuttal against the use of
plant tests to demonstrate dimethoate's mutagenicity because
of dimethoate's phytotoxicity.
(i) Lack of Control Data and Analyses of Results
American Cyanamid Co- (30000/16:5A) pointed out that
neither control data nor descriptions or analyses of the
abnormalities were given.
The Agency has rejected this rebuttal response.
Although no control data were given, an unmistakable dose-
response curve was obtained for the root treatment data.
Photographs were furnished to describe the abnormalities.
Cii) Non-Heritable Abnormalities
American Cyanamid Co. (30000/16:#5A) cited a later
study by the authors (Amer and Farah 1976) which indicated
that the reduction in the mitotic index and the abnormal
mitoses (Amer and Farah 197-4) were not heritable or permanent
events and that the chromosome fragmentation was not neces-
sarily evidence of mutation.
HZ
-------
The Agency has accepted this rebuttal response. The
papers were concerned with cytological effects and the
majority of the effects reported were probably non-heritable
cytotoxic disturbances of the spindle apparatus. Evidently
no attempt was made to score mutagenic aberrations. Further-
more, the authors noted that most of the observed bridges
were sticky bridges. These sticky bridges may not be a
mutagenic response.
(iii) Differences Between Pure and
Formulated Dimethoate
American Cyanamid Co. (30000/16:#5A) argued that
wide differences were noted between pure and formulated
dimethoate. Pure dimethoate was cited as causing greater
abnormalities than the formulated product when applied as a
seed soak while the reverse was noted when applied to root tips.
The Agency has rejected this rebuttal attempt. Since
treatment with pure dimethoate (as compared to formulated
dimethoate) greatly decreased the number of dividing cells
and the mitotic index when applied to root tips but not
when applied as a seed soak, the differences probably
reflect a toxic effect and do not invalidate the results.
(iv) Procedural Errors
American Cyanamid Co. (30000/l6:#5A) indicated that
various procedural points should have been followed, as
recommended by Cohn and Hirschhorn (1971).
43
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The Agency has rejected this rebuttal attempt. Cohn
and Hirschhorn (1971), the reference presented by the
registrant, did not contain any information on protocol as
indicated by American Cyanamid's rebuttal submission.
Methods are not well, established for many of these studies,
and results must be interpreted on an individual basis.
(g) Fahrlg (1973)
(i) Lack of Survival Data
American Cyanamid Co. (30000/16:#5A) indicated that
no survival data were given in order to interpret the
results correctly.
The Agency has rejected this rebuttal attempt.
Detailed survival kinetics would be desirable, but the paper
does state that the inactivation ("inaktivierung") of
Saccharomycea shows a strong increase or is uniformly
strong as soon as a certain concentration threshold (85 mM)
is exceeded. Since the linear dose-response curve for
dimethoate was measured below this threshold, the results
are acceptable.
(ii) Lack of Detail
American Cyanamid Co. (30000/l6:#5A) indicated that
no record of background mutations, no negative controls, no
details on termination of the experiment, no information on
size of the test population, and no identification of the
solvents used were given.
44
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The Agency has rejected this rebuttal attempt. Many
experimental details were not reported in the paper as
published, but the positive control, methylmethan-
sulfonate, and the four organo-phosphorus insecticides
produced well-defined, linear, dose-response curves. There
is no evidence to suggest the lack of proper protocol.
(iii) Improper Handling of Test Colonies
American Cyanamid Co. (30000/16:#5A) indicated that
no precautions were taken to prevent colonies, which phenotyp-
ically resemble gene conversions, from arising through
sporulation and meiosis.
The Agency has rejected this rebuttal attempt. Five
hours of treatment should not have induced sufficient
sporulation to alter the results, particularily in view of
the•excellent dose-response curves obtained. Moreover, the
reference cited by the registrant (Zimmerman 1975), which
was the basis for the rebuttal, in fact states that storage
in buffers for more than six hours should be avoided.
Fahrig (1973) treated colonies for only five hours.
(h) Gerstengarbe (1975)
(i) Improper Controls
American Cyanamid Co. (30000/16:#5A) indicated that
identical negative controls were used in Experiments 1, 2,
and 4 despite their different experimental design and their
different time frames; no positive controls were used; and
only one dose was administered, precluding dose-response
analysis.
-------
The Agency agrees that this study should not be used
as the sole determination of mutagenicity, but the lack of
traditional controls does not justify excluding this study
from consideration because sufficient variation does
exi3t between the results of successive weeks of pairing
to indicate dominant-lethal damage to certain stages of the
germ cell maturation cycle. This is particularly true in
Experiment 1, which most closely follows standard protocols.
The post-implantation losses for the early stages of sperm
maturation were very similar to the control values, while
the spermatids and epididymal sperm were affected sufficiently
to produce losses as much as five-fold greater than controls.
(ii) Route of Administration
American Cyanamid Co. (30000/16:#5A), Montedison
USA, Inc. (30000/16:#25A), and Menzer (30000/16:#35) indicated
that the intraperitoneal route of administration is inappro-
priate for this type of study.
The Agency has rejected this rebuttal attempt.
Intraperitoneal injection of test material is an accepted
route of administration in the dominant lethal test. The
route of administration was chosen to reduce the variables
involved in transporting dimethoate to germ cells. It would
be preferable for regulatory purposes, however, to have
information derived from the oral route.
(iii) Source of Test Compound
American Cyanamid Co. (30000/16:#5A), Montedison
USA, Inc. (30000/l6:#25A), and Menzer (30000/16:#35) stated
46
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that the dimethoate used in the study was not analyzed by
the author and that a definitive source of the material was
not given.
The Agency has rejected this rebuttal attempt.
Gerstengarbe used the same source for dimethoate as did
Gibel et al. (1973) [Letter 1977; Letter 1975]. The
dimethoate was obtained from the Bitterfeld Co. and was
reported to be 98 to 99% pure. [See Section II.A. (1)(a)(i) . ]
(iv) Incorrect Dosage Data
American Cyanamid Co. (30000/16:#5A) indicated there
may have been a discrepancy in the reported dosages used.
The animals may have been given 1/4 the LD^q rather than
approximately 1/7 of the LD^q.
The Agency has rejected this rebuttal attempt.
It may be true that the dose was improperly reported,
but this would not negate the positive mutagenic effects
observed.
(v) Number of Animals Used
American Cyanamid Co. (30000/16:#5A) stated that
the numbers of animals reported in the tables in Ger-
stengarbe (1975) differ from the numbers as stated in
the methods section; the discrepancy casts doubt on the
statistical analysis.
47
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The Agency has rejected this rebuttal attempt.
The lower number of females listed in Gerstengarbe's dis-
cussion (see table on page 13 of that study) referred only
to those females with a plug. There is a discrepancy
in the numbers of males in Experiment 1 (40 males were
listed in the discussion, p.13, and 36 in the methods
section p.8). Gerstengarbe (Letter 1977) indicated that
the correct numbers are those listed in the methods section
on page 8 of the translation. The increase in both post-
and pre-implantation losses over the control group (5- and
3-fold increases, respectively) are large enough to suggest
a positive result, despite any uncertainty about the statisti-
cal analysis.
(vi) Dose/Sperm Relationship
The California Department.of Food and Agriculture
(30000/l6:#36) argued that the relationship between the
dose, sperm maturation, storage, and ejaculation is not
clear. An animal administered 80 mg/kg of dimethoate would
probably be unable to copulate for several hours afterward.
The Agency has rejected this rebuttal attempt.
The animals were treated only once, one day before pairing
in Experiments 1 arid 2, which were the most important
tests. The rebuttal statement, therefore, applies only to
the long-term test (Experiment 4). The inability to copulate
would merely serve to reduce the percentage of females
9
observed with plugs; however, there were sufficient females
remaining to complete the study.
48
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(i) Bhunya and Behera (1975)
(i) Lack of Control Data
American Cyanamid Co. (30000/16:#5A) indicated that
no control data were given in th}.s study.
The Agency has rejected this rebuttal attempt. The
authors stated that control animals were used, but no data
were listed in the brief paper (which was in the form of a
letter to the editor). The authors indicated, however, that
there was a dose-effect relationship between the two doses,
which was most pronounced at 48 hours (17% of cells with
aberations at the centromere at a dose of 0.5% dimethoate
compared with 44% at 1.0% dimethoate). This is sufficient
in the absence of specific control data to indicate a
chromosome aberration effect at the centromere under the
conditions of this study.
„ (ii) Reversible Effects
American Cyanamid Co. (30000/16:#5A) stated that
the effects were reversible after 72 hours, and that it
is doubtful if they could be heritable.
The Agency has concluded that this rebuttal is
partially successful. There is a great reduction in
the number of aberrations with time, but at 72 hours
there is still a slight dose-response effect (11% aberra-
tions for 0.5% dimethoate and 15% for 1.0% dimethoate).
The reduction may be due to a cytotoxic effect. The ques-
tion of heritability is not resolved by this study.
49
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(j) New Studies Offered in Rebuttal
(i) American Cyanamid Co. (1977)
American Cyanamid Co. (30000/16:#5A) performed a
bacterial assay using jŁ. coli WP-2 UvrA~ and found that
"Dimethoate was not mutagenic" even at "extremely high
doses."
The Agency has rejected this rebuttal attempt. The
registrant repeated the spot test using the method and
strain used by Hanna and Dyer (1975); the test was again
positive (this result was not mentioned in the rebuttal).
Dimethoate exhibited an excellent dose-response curve from
100 ug/plate (11 revertants/plate) to 10,000 ug/plate (265
revertants/plate), which shows that dimethoate does indeed
induce mutagenic activity. Based on their study, the
registrant stated that dimethoate is a non-mutagen because
of its "potency" of less than 0.01 revertants/nanomole. The
statement that dimethoate is a non-mutagen is not correct by
this criterion because: 1) E_j_ coli WP2 was not the organism
used by the Ames group which originated this particular
definition of potency; and 2) the criterion for determining
a cut-off point for mutagenicity has not been firmly established
(Ashby and Styles 1978a; Ashby and Styles 1978b; Ames and
Hooper 1978; McGregor 1978).
(ii) Ashwood-Smith et al. (1972)
American Cyanamid Co. (30000/16:#5A) cited a study by
Ashwood-Smith et al. (1972) which found dimethoate to
be non-mutagenic in coli UvrA.
50
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The Agency has rejected this rebuttal attempt.
Ashwood-Smith et al. stated only that they used E. coli WP2
(try-), not the specific cryptic mutation UvrA (which
is unable to excise thymine dimers). Their results, there-
fore, are in agreement with Hanna and Dyer (1975) who also
found _E. coli WP2 to show negative results in a spot test.
Even if Ashwood-Smith et al. had used _E. coli WP2 UvrA, they
used only 1,000 ug/disc, which is less than the amount
American Cyanamid Co. (1977) found necessary for positive
results.
(4) Other Comments
In addition to the risk criteria discussed above,
the RPAR notice listed two other possible adverse effects
of dimethoate for which insufficient evidence existed
to initiate a rebuttable presumption. The Agency requested
registrants and other interested parties to submit data
on delayed neurotoxicity and synergism of dimethoate by
other pesticides. The Agency has received comments con-
cerning these effects and concludes that there is in-
sufficient evidence upon which to base a regulatory decision.
(a) Delayed Neurotoxicity
American Cyanamid Co. (1965b) performed demyelination
studies for dimethoate and its oxygen analog, dimethoxon,
in white leghorn hens. Because the data from this study
were inconclusive, the Agency requested comment on
dimethoate*s ability to induce delayed neurotoxicity.
51
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American Cyanamid Co. (30000/16:#5A) indicated
that the Bitterfeld study discussed in Section II.A.(b)
demonstrated that dimethoate does not produce delayed
neurologic pathologies.
The Agency rejects the Bitterfeld study as evidence
that dimethoate does not induce delayed neurotoxicity.
Since only macroscopic analyses were performed in this
study, there is no expectation that neurotoxicological
pathologies would have been detected.
The Agency concludes that insufficient evidence
exists to determine whether dimethoate can induce delayed
neurotoxicity and that the submission of new evidence
concerning dimethoate's ability to induce delayed neurotoxi-
city is warranted.
(b) Synergism of Dimethoate by Other Pesticides
Uchida et al. (1966) have reported on synergism
of dimethoate by EPN in mammals and insects. (Synergism
is defined as the greater toxicity of two compounds together
than would be anticipated from the sum of their individual
effects.)
American Cyanamid Co. (30000/16:#5A) pointed out
that dimethoate and EPN are generally not mixed and used
together. The Agency concludes that there is insufficient
evidence to indicate that dimethoate exceeds the risk
criteria enumerated in ^0 CFR 162.11 based on its possible
synergism by other compounds.
52
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B. Exposure Analysis
The Agency has revised and expanded the exposure
analysis discussed in Position Document 1. This revised
analysis considers rebuttal comments received in response
to the RPAR notice, data from USDA concerning use and use
practices, and published studies concerning worker exposure
to dimethoate and related pesticides.
In agriculture dimethoate is applied aerially or by
ground rig. Around the home, dimethoate is usually applied
by a hand-held sprayer. This exposure analysis will assess
applicator exposure under both the aerial and ground appli-
cation situations, as well as general population exposure
(i.e., through food residues).
(1) ExDosure Due to Aerial Application
There are no published data available showing the
amount of dimethoate an applicator will be exposed to
during aerial application. Exposure data is available,
however, for another organophosphate, parathion. Because
the Agency is concerned with teratogenic effects, exposure
values will be calculated based on a 60 kg female. Therefore,
the exposure values reported for parathion during aerial
application (Gordon et al. 1978) are used as a model for
estimating human exposure to dimethoate during aerial
application. This analysis will evaluate exposure to pilots
and associated ground crews supporting the aerial application
activity. The rationale for using parathion values to
estimate dimethoate exposure is as follows:
53
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-5
1) The vapor pressures of parathion (0.9*12 x 10 mm Hg
at 25°C) and dimethoate (2.5 x 10 ^ mm Hg at 25°C)
are comparable. It is generally recognized that
the residues of pesticides with relatively low volatility
in the air during or immediately after application
are predominantly present in the form of droplets
and particles;
2) The formulation most often used for both parathion
and dimethoate is an emulsifiable concentrate (E.C.);
and
3) The rates of aerial application of parathion (0.25
to 2.0 pounds a.i./2 gallons of water) and of dimethoate
(0.5 to 1.5 pounds a.i./2 gallons of water) are similar.
Exposure during aerial application can occur via the
respiratory or dermal route.
(a) Respiratory Exposure
In calculating inhalation exposure, the following
assumptions are made:
1) the ambient air concentrations observed for parathion
(Gordon et al. 1978) are the same as dimethoate at
each of the various sampling sites (e.g., airplane
cockpits);
3
2) the applicator's breathing rate will be 1.8 m. per hr;
3) 100% of all dimethoate inhaled will be absorbed;
54
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4) the applicator will weigh 60 kg (adult female); and
5) the applicator will wear no special protective
devices (e.g., respirator).
The following equation (memo 1979b) is used in calcula-
ting the respiratory exposure for dimethoate:
Respiratory ambient air concentration of 1.8 m^/hr
Exposure _
(ug/kg/day) = dimethoate (ug/m^) at the X (breathing X number of hours of
site in question rate) exposure/day
60 kg person
Data concerning the number of hours of exposure for
each activity (e.g., pilot spraying corn) was obtained by
the USDA/EPA Dimethoate Benefit Assessment Team (USDA/EPA
Assessment Team on Dimethoate, 1979).
(b) Dermal Exposure
In calculating dermal exposure the following assumptions
are made:
1) dermal exposures observed for parathion skin patch tests
(Gordon et al. 1978) are the same for dimethoate;
2) 15? of the applicator's total skin surface will be exposed;
3) 10? of the dimethoate coming into contact with the
uncovered skin will be absorbed; and
4) the applicator will weigh 60 kg (adult female).
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The following equation (memo 1979b) is used in
calculating the dermal exposure to dimethoate.
60 kg person
(2) Exposure Due to Ground Application:
Respiratory and Dermal Exposure
(i) Boom and Compressed Air Application
Situations
Dimethoate is often applied using boom type equipment
in large agricultural situations and by compressed air equip-
ment (hand pump sprayers) in home garden application situa-
tions. Specific data concerning applicator exposure to
dimethoate under these conditions in the U.S. is not available.
However, similar information concerning applicator exposure to
dimethoate in the Sudan is available.
exposure of spraymen applying dimethoate. The final spray
concentration was 1.27 g/liter (Copplestone et al. 1976).
All of the spraymen used a knapsack mist blower which
was powered by a two-stroke engine and had a liquid capacity
of 10 liters. A 2-mm diameter nozzle was used. One liter
of solution was delivered each minute at a constant pressure
of 152KPa (22 pai). Therefore, the tank was refilled about
Dermal concentration of
Exposure = dimethoate on the
(mg/kg/day) skin (ug/cm)
X 3000 cm2 X 10 % absorbed X number of hours
exposed per day
In the Sudan, a survey was carried out on the
-56-
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every 10 minutes. The dermal and respiratory exposure of
spraymen to dimethoate, which was reported in that study, is
used as the basis for all the exposure analysis calculations
of dimethoate during boom and compressed air equipment
application in this analysis.
It should be noted, however, that using the exposure
figures developed by Copplestone et al. (1976) will probably
result in an overestimation of boom rig type applicator
exposure in the U.S. In the Sudan the applicators carried
the sprayer on their backs which dispensed the spray
solution under pressure in a wide mist pattern. The applicators,
therefore, walked forward into their own spray. In the U.S.
dimethoate is applied by mechanical sprayers which are
equipped with wheels and are pulled behind by tractors. The
applicator drives the tractor and is well forward of the
spray. Because the applicator (tractor driver) is generally
forward of the spray, actual exposure would be less than
that experienced by applicators in the Sudan. However,
because the Agency is not aware of studies showing applicator
exposure during application of dimethoate in the U.S.,
the data obtained in the Sudan (Copplestone et al. 1976)
will be used for this analysis. Applicator exposure resulting
from the use of compressed air type equipment (e.g. hand
held sprayers used around the home) would be expected to
closely approximate the Sudan exposure data.
-------
The following equations (memo 1979b) are used to calculate
the respiratory and dermal exposure resulting from the ground
application of dimethoate.
Respiratory respiratory exposure
Exposure = observed in Sudan
(mg/hr)
X used in the U.S.
concentration of dimethoate
used in the Sudan
concentration of dimethoate
number of hour
X spraying (USDA
State/EPA Asse
ment Team on
Dimethoate).
60 kg person
Dermal dermal exposure
Exposure » observed in the2
Sudan (mg/cm/hr )
concentration of dimethoate
X used in the U.S.
X 10% absorption
concentration of dimethoate
used in the Sudan
60 kg person
Dimethoate is registered for use on a wide variety of
agricultural commodities. Time, however, precluded an
in-depth exposure analysis of every use. The USDA/EPA
Benefit Assessment Team on Dimethoate (1979) identified
those uses which account for the majority of the dimethoate
used, as well as uses which do not represent high annual
use but are important minor uses. These uses and the
estimated combined dermal and inhalation exposure are found
in Table II.
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(ii) Air Blast Application Situations
High volume air blast application equipment (greater
than 300 gal./A) is commonly used in citrus, pecans and pome
fruit (apples and pears) orchards. Specific data concerning
applicator exposure to dimethoate under these conditions is
not available. Wolfe et al. (1967), however, reported the
dermal and respiratory exposure of workers to several
selected pesticides using airblast equipment. In the
absence of specific dimethoate data the Agency will assume
the exposure values of workers applying 0.05% parathion E.C.
to be the same as dimethoate. The Agency feels this assumption
is reasonable because both dimethoate and parathion are
organophosphates and both are emulsifiable concentrates
applied at similar concentrations.
Air blast equipment is also used when treating grapes.
In the case of grapes, however, dimethoate is applied in a low
volume air carrier/semi-concentrate form (approximately 40-50 gal/
A.). Because the spray concentration for grapes is higher than
that of citrus, pecans and pome fruits the Agency will use the
Copplestone model (Copplestone et al., 1976) when calculating
worker exposure during application of dimethoate to grapes.
(3) Exposure to Farm Workers
Exposure to dimethoate can also occur when farm
workers enter treated fields to cultivate or otherwise
manage the treated field. Exposure to this subgroup,
however, is expected to be very low. It has been shown
59
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(Nelson, et al. 1966, Menzer and Thomas 1970) that dimeth-
oate residues degrade rapidly after spraying. It is unlikely,
in the light of modern cultural practices and the established
preharvest interval of up to 28 days after treatment, that
workers would enter fields immediately after treatment.
Workers entering treated fields several days after treatment
are not expected to encounter high exposure due to resi-
dues on treated crops. In addition, diraethoate is
somewhat systemic in nature in that it passes through the
surface of the plant and is translocated within the plant,
thereby further reducing the possibility of worker exposure.
(4) General Population Exposure
The general population exposure to dimethoate and
concurrent risk resulting from eating treated foods is
discussed in Section II.C.(3)(b)(i) and presented in Table II.
Little information is available on dimethoate residues
on crops at harvest; therefore, the Agency assumes these
residues to be present at tolerance level (memo 1979c).
Not all crops for which dimethoate is registered are actually
treated with dimethoate. The percent of each crop treated,
therefore, was included in the calculation of oral exposure
(memo 1979c).
C. Risk Analysis
Three risk criteria were identified for dimethoate
in Position Document 1: oncogenicity, mutagenicity, and
reproductive and fetotoxic effects. The Agency has reviewed
comments submitted in response to these risk criteria and has
utilized these comments in formulating risk assessments for
each of these risk criteria.
60
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Table II
Calculated Combined Dermal, Inhalation, and Oral Exposure Values
During Aerial and Ground Applications of Dimethoate to Various Crops
Combined Dermal and ORAL TOTAL
CROP
TYPE OF
SPRAYING
SUBGROUP
Inhalation DAILY
EXPOSURE (mg/kg/day)
EXPOSURE
(mg/kg/day)
EXPOSURE
(mg/kg/day)
corn
air
pilots
0.0083
0.0032
0.012
corn
air
flaggers
0.008
0.0032
0.011
corn
air
mixer/loader
0.0063
0.0032
0.010
ornamental
ground
commerical
high concentration
compressed air
0.00012
0.032
0.0033
ornamental
ground
home garden high
concentration
0.000152
0.0032
0.00335
grape
ground
Boom highest conc.
0.0012
0.0032
0.0041
grape
ground
Air carrier
(custom)
Goppelstone et al.
0.0207
0.0032
0.0239
grape
ground
dust
0.130
0.0032
0.1332
cotton
air
pilot
0.0017
0.0032
0.005
cotton
air
mixer/loader
0.00095
0.0032
0.00042
cotton
ground
applicators
0.0078
0.0032
0.0011
cotton
ground
mixer/loader
0.00033
0.0032
0.004
citrus
air
pilot, ground
crew mixer/loader
same as corn
61
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Table II (continued)
CROP
TYPE OF
SPRAYING
SUBGROUP
Combined Dermal and
Inhalation DAILY
EXPOSURE (mg/kg/day)
ORAL
EXPOSURE
(mg/kg/day)
TOTAL
EXPOSURE
(mg/kg/day)
citrus
sorghum
veg.
field
(tomato,
broccoli)
veg. (Fla)
vector
control
(house fly)
forest
pine
(seed
orchard)
pecan
safflcwer
pome
ground
(airblast)
air
air
ground
ground
ground
ground
(airblast)
air
ground
(airblast)
applicators
mixer/loader
same as corn
pilot
flaggers
mixer/loader
applicator
applicator
applicator
applicator
mixer/loader
same as corn
0.39
0.013
0.013
0.0062
0.00005
0.0019
0.0008
0.119
commercial applicator 0.242
including mixer/
loader
0.0032
0.0032
0.0032
0.0032
0.0032
0.0032
0.0032
0.0032
0.0032
0.3932
0.0162
0.0162
0.0094
0.0033
0.0051
0.0040
0.12
0.245
pome
ground
hose sprayer
0.00017
0.0032
0.0034
62
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Table II (Continued)
Combined Dermal and ORAL TOTAL
CROP
TYPE OF
SPRAYING
SUBGROUP
Inhalation DAILY
EXPOSURE (mg/kg/day)
EXPOSURE
(mg/kg/day)
EXPOSURE
(mg/kg/day)
soybean
air
same as corn
wheat
air
same as corn
tobacco
High conc.
ground
applicator
including mixer/
loader
0.00012
0.0032
0.0036
alfalfa
High conc.
ground
applicator
including mixer/
loader
0.00052
0.0032
0.0084
veg. fields ground
(lettuce)
applicator
mixer/loader
0.0002
0.00026
0.0032
0.0032
0.0034
0.0035
¦¦
63
ft
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(1) Oncogenicity Risk Analysis
The Agency has reviewed rebuttal comments submitted
in response to the oncogenicity risk criteria discussed
in the RPAR notice and accompanying position document. In
Section II A.(1), the Agency responded to rebuttal comments
and concluded that the individual rebuttal comments do not
invalidate the oncogenic risk criterion. However, based
on a re-analysis of the studies involved and the rebuttal
comments as a whole, the EPA Carcinogen Assessment Group has
concluded that the weight of evidence for carcinogenicity of
dimethoate is only suggestive, warranting further studies,
but not adequate to justify a quantitative assessment of
cancer .risk.
There were two studies involved: Gibel et al.
(1973) and NCI (1977). The Gibel study, showing positive
results in rats, was poorly documented and very weakly
positive. There was an excess cancer occurrence only when
the total yield of tumors of all types and of both sexes
were combined. The NCI study in rats and mice was negative,
but this study was one of the early NCI bioassays which used
only 10 matched control animals. Furthermore, the NCI study
cannot be directly compared with the Gibel study. Gibel used
a different strain of rat and although there was severe
toxicity of the blood-forming tissues in the Gibel study,
no such effect was observed in the NCI study.
In more detail the results of the two Studies were as
follows:
64
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Gibel et al. (1973) reported the effect of dimethoate
on 10-week old Wistar rats of both sexes. The compound was
given by gavage twice weekly at 5, 15, and 30 mg/kg dose level
One group of animals was also given 15 mg/kg intramuscularly.
Treated animals showed strong hyperplasia of blood-forming
parenchyma of the bone marrow involving erythropoesis,
granulopoesis and megakaryopoesis. Non-bony myeloid meta-
plasia, primarily in the liver and spleen, was seen in 59%
of treated animals. In addition granulyocytosis was found
in 22%of the animals. There was a significant increase in
malignant tumors when all sites were combined among treated
animals at the highest dose levels for both oral and intra-
muscular routes of administration. No significant difference
was found in benign tumors, but when benign and malignant
tumors were combined, the incidence was statistically
significant in the high dose group. The Agency considers
a chemical to be a presumptive cancer risk when it causes
a statistically significant excess incidence of benign
or malignant tumors in humans or animals (Albert et al.,
1977).
The authors also studied the effect of dimethoate
applied percutaneously twice a week for six weeks to mice of
AB strain. The concentration of dimethoate was not stated.
The spleen showed considerable metaplasia, frequently
with complete atrophy of white pulp. The red pulp showed a
partially localized and diffuse myeloid proliferation
with numerous immature cell forms, which made it difficult
to recognize the basic structure. The authors felt that the
mice also developed a myeloproliferation syndrome similar to
that observed in Wistar rats.
-------
In 1977, the National Cancer Institute bioassay
program completed a feeding study in Osborne-Mendel rats and
B6C3F1 hybrid mice of both sexes. The time-weighted average
doses were 310 and 155 ppm for male rats, 38^ and 192
ppm for female rat3 and 500 and 250 ppm for mice of both
sexes. Pathologic evaluation revealed no statistically
significant increase in tumors associated with dlmethoate
treatment in either species of animal, and it was concluded
that there was no carcinogenic effect under the conditions
of the experiment. No significant changes were noticed in
the hematopoietic system in rats or mice in the NCI study.
In summary, the evidence for carcinogenicity is
only suggestive. Therefore, the Agency concludes that
a dimethoate oncogenicity study with the same strains of
mice (AB mice) and rats (Wistar) used by Gibel is warranted.
(2) Mutagenicity Risk Analysis
One of the risk criteria for which the Agency
issued an RPAR against dimethoate was mutagenicity. After
reviewing the comments and rebuttals on this presumption
of risk, the Agency concluded that the risk had not been
rebutted. This section presents an analysis of mutagenicity
studies on dimethoate and attempts to draw conclusions
relative to human risk from dimethoate's ability to induce
mutagenic effects and concludes that risk is very low.
66
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(a) Relevant Positive Tests
(i) Reverse Mutation Bacterial Assays
Di&athoate has been shown to be mutagenic in a
reverse mutation spot assay using two strains of Escher-
ichia coli, jS. coli WP 67 (Hanna and Dyer 1975) and _E. coli
WP 2 uvrA (Hanna and Dyer 1975; and American Cyanamid 1977).
Mutagenicity was also demonstrated in a quantitative reverse
mutation plate assay using jS. coli WP2 uvrA and Salmonella
typhimurium TA100 (American Cyanamid 1977). Many other
strains of bacteria were tested with negative results. The
relative mutagenic potency of a chemical cannot be determined
with a spot test; however, a low potency for dimethoate was
suggested in the spot tests by the necessity to incubate the
plates 72 hours rather than 48 hour3 to see any positive
results with J2.. coli.
A low mutagenic potency for dimethoate was confirmed
with coli WP2uvrA in quantitative plate assays. The
positive control, N-methyl N'nitro-nitrosoguanidine (MNNG),
at 20 ug/plate produced greater than 1,000 revertants/
plate while 10,000 ug/plate of dimethoate produced an
average of 310 revertants/plate (American Cyanamid 1977).
Thus dimethoate is at least 1,600 times less potent than MNNG
under the conditions of this assay. The results with
S>. typhimurium TA100 displayed a similar relationship but
were difficult to quantify since a decrease in the dose
response curve was seen at 1,000 ug dimethoate/plate and the
cells were killed at 10,000 ug/plate. In the TA-100 S9
67
-------
activated system the highest number of revertant colonies
observed was 594 at 1,000 ug/plate (^imethoate (although this
figure was undoubtedly reduced by the toxicity); MNNG,
at 20 ug/plate, produced > 3,000 revertants/plate. The
unactivated TA100 assay suggested mutagenicity but it is not
reliable since the negative controls had an extremely high
background count (522 revertants/plate).
(ii) Forward Mutation Bacterial Assay
Dimethoate was shown to induce forward mutations in
E. coli K-12 as detected by resistance to 5-methyltryptophan
(Mohn 1973)• The potency, however, is relatively low
compared to the positive controls, MNNG and methyl raethane-
sulfonate (MMS) [Mohn 19731- 1 x 10~^M dimethoate was
required to produce a nutation frequency similar to that.
_7
produced by only 1.7 x 10 M MNNG; thus dimethoate is
about 2,000 times less potent than MNNG under the conditions
of this assay.
.(iii) Dominant-Lethal Assay (Mouse)
Dimethoate was shown to significantly increase
resorptions after treatment of the male AB Jena-Halle mice
during the first through the fifth week of sampling.
The usefulness of this data for a is limited since a
non-standard protocol (which included the intraperitoneal
injection of test material and the omission of positive
controls) was employed in the study.
-------
(iv) Yeast Gene Conversion Assay
Mitotic gene conversion was induced by dimethoate
in Saccharomyces cereviaiae D4 (Fahrig 1973). The potency
of dimethoate is low; 50 mM dimethoate induced about the
same number of conversions as 0.5 mM of the MMS control.
(v) Unscheduled DNA Synthesis in
Mammalian Cells
Ahmed et al. (1977) reported an increase in unscheduled
DNA synthesis in SV-40 transformed human cells (VA-4)
after administration of 100 uM and 1000 uM dimethoate
with metabolic activation. Results were negative
(p < 0.5) at 100 uM and 1000 uM without metabolic activation.
No significant (p < 0.05) increase was reported after
administration of 10 uM with or without metabolic activation.
This study is of limited value for purposes of
risk assessment due to a lack of quantification. The
authors, for example, used only 3 dose levels and reported
results as positive or negative. This precluded determining
if there was a dose response relationship. In addition no
positive controls were used so the activity of the pesticides
studied cannot be related to a known mutagen.
This study does indicate, however, that dimethoate has
a potency at least 100 X less than other pesticides that
were found to increase unscheduled DNA synthesis in this
particular assay. Chlordane, aldrin, dieldrin, carbaryl,
diquat, 2,^-D and captan were all reported as positive
at the lowest level tested (1 uM) while dimethoate was
reported as negative at 10 uM and positive at 100 uM.
69
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(b) Studies Suggestive of Mutagenesis
(1) Plant Cytological Analysis
Amer and Farah (197-4) studied the cytology of
Vlcia faba and Gossypium barbadense after exposure to
dimethoate. A dose-response effect was seen in the per-
centage of abnormal mitoses, but the effects were probably
due to spindle disturbances. Some fragmentation and bridge
formation were seen but were not dose-related. The study
provides limited information on mutagenic effects and,
at best, is suggestive of mutagenesis in V- faba.
Amer and Farah (1976) conducted further studies
on the effect of dimethoate on the cytology of V. faba. In
meiosis, spindle "disturbances" were the primary effect.
Stickiness and sticky bridges were also reported, but these
effects can be caused by other chemicals considered not to
be mutagenic (Kihlman 1971). A low percentage of frag-
mentation was reported. It was not possible to determine
the background levels for. this effect since the distribution
of effects in. negative controls was not described. The
authors also found that the transmission of these effects to
following generations was very low.
Agarwal et al. (1973) studied the effect of dimethoate
on the bean, Phaseolus vulgaris. The study was inadequately
reported. No negative or positive controls were used
for the chromosome scoring experiment~ Fragmentation was
not dose-related. Stickiness was also reported as a major
effect but may not be an indication of mutagenicity. This
study is at best only suggestive of mutagenesis and, as
mentioned above, of little value in determining mammalian
risk.
70
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(ii) Mammalian Cytogenetic Analysis
Bhunya and Behera (1975) studied the effect of
dimethoate on bone marrow cell chromosomes of adult mice,
Mus musculus. Although the paper reported that a substantial
number of chromosome breakage effects at the centromere
are caused by dimethoate the experiment is inadequately
reported and i3 in abstract form. The authors for example,
stated that controls were performed but none were presented
in the abstract. Since no supporting data is available,
this abstract should not be used as a primary determinant
for risk analysis and regulation.
(c) Negative Test3
Ashwood-Smith et al. (1972) reported that dimethoate
was negative for mutagenic effects in a reverse mutation spot
test assay using E. coli WP2 try ~. This result is in
agreement with Hanna and Dyer (1975) and Shirasu et al. (1976).
Shirasu et al. (1976) reported that dimethoate was
negative for mutagenic effects in a recombination deficient
assay using Bacillus subtilis H 17 Rec+ and B. 3ubtilis
M45 Rec~. They also reported negative results in a reverse
mutation assay using E. coli WP2 B/r try". E. coli WP2
try~hcr is the same strain used by Hanna and Dyer (1975)
and American Cyanamid (1977) (they used the notation WP2
uvrA~) in studies which showed positive results after
incubation of the plates for 3 days. Shirasu et al., however,
incubated their plates for two days; the negative results
were clearly due to their insufficient incubation time.
71
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Table III
Summary of Dimethoate Mutagenicity Studies
Paper
Study
Results
Comments
Hanna & Dyer
(1975)
American
Cyanamid Co.
(2/2/77)
Salmonella typhimurium
his C117
his GH6
his D3053
TA 1530
TA 1531
TA 1532
TA 153^
TA 1535
Escherichia coli
WP2
WP2 uvrA
CM561
CM571
CM611
WP67
WP12
Salmonella typhimurium
TA 1530
TA 1535
TA 100
TA 1538
TA 98
TA 1537
E. coli WP2 uvrA
Haplold Microorganisms
These test were spot tests
using "a crystal or 5-10 ul
of each chemical" directly
onto the bacterial lawn
Revertants were not seen
until after 72 hr incubation
(try-, uvrA-)
Required 72 hr. incubation,
(try-, urvA", polA")
plate tests, with and
without S 9
200 ug/plate
1,000 ug/ plate
1,000 ug/plate
200 ug/plate
1,000 ug/plate
1,000 ug/plate
1,000 ug/plate, 48 hour
incubation
72
-------
table III (continued)
American
Cyananld
S.
Tfl
iS
hlrnurlin
TA 98
TA 100
TA 1537
disc tests, 1,000 ug/plate,
72 hrs Incubation (11/16/77)
10,000 ug/plate
10,000 ug/plate
10,000 ug/plate
American
Cynanid
(11/16/77)
Mohn
(1973)
E. coll
WP-2 uvrA"
S. typhlmurlum
TA T—
TA 1537
TA 98
TA 100
TA 1538
E. coll
JfP-2 uvrA"
E. coll K12
Torward mutation
to 5-HT resistance
disc tests at
10,000 ug/plate dlmethoate
plate tests, 10,000; 1,000; 100; and 0,48 hours incubation
high spontaneous mutation rate, toxic response at 10,000 ug/plate
10,000, 5,000, 1000, 100, 0 ug/plate, good dose response
curve, no difference with or without S-9, MNG (no dose given) produced
71,000 revertsnts/plate while dlmethoate produced 254 to 456
revertants/plate at 10,000 ug/plate
-7
much less potent than controls, 1.7 * 10 M
concentration q>prox. equivalent to 1.0 x 1
dlmethoate concentration
MNNG
73
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Table III (continued)
Shirasu
et al. (1976)
Ashwood-Smith
et al. (1972)
Bacillus subtilis
H17 Rec assay
B. subtilis
MU5 Rec assay
E. coli WP2 B/r try"
reversion assay
E. coli WP2 try "her" uvrA)
reversion assay
S. typhimurium
reversion assay
•I
ii
EC. coli WP2 try"
reversion assay
TA 1535
TA 1536
TA 1537
TA 1538
Gerstengarbe
1975
Mouse-dominant-lethal
Fahrig
(1973)
Agarwal et al.
(1973)
Saccharomyces cerevisiae
DM gene conversion
Cytology of
Phaseolus vulgaris
(+)
Amer and Farah
(1971)
Cytology of
Vicia faba
(+)
Amer and Farah
Cytology of
Vicia faba and
Gossypium barbadense
(-)
Bhunya, et 1.
(1975)
Cytogenetic mouse
study
Ahmed, et al.
Unscheduled DNA
synthesis in transformed
mammalian cells
spot test: inoculum of dimethoate onto disc was 0.2
ml of 1 mg/ml solution
II
fl
11
11
If
ft
spot test) 1 ug/disc.
i.p. route of inoculation, no positive controls,
non-standard protocols used.
0.5 mM MMS control induced approx. same nimber
of convertants as 50 riM Dimethoate
no controls, no dose-response at metaphase
no controls reported, "non-transmissable"
spindle effects were the primary aberration reported
no controls reported, primarily spindle
effects were reported
poorly reported, questionable validity
no positive controls were reported, effects
were not nunerically quantified
71
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(d) Summary
Dimethoate has been 3hown to be mutagenic in
bacteria, in transformed mammalian cells, and with less
certainty in a strain of mouse (dominant lethal assay).
There are three studies which strongly suggest mitotic
disturbances in plants and one study, poorly documented,
which suggests chromosome abnormalities in mice. These
studies are summarized in Table III.
The data available to the Agency indicates that
dimethoate: 1) causes gene mutations in bacteria but not
in eukaryotic systems, 2) is suspected of producing spindle
effects which predispose to numerical chromosome aberrations
(data in higher plants only), 3) causes dominant lethal
effects in mammals (study used nonconventional protocol), 4)
causes chromosome breakage in mammalian bone marrow. Thus
there is some evidence that dimethoate can produce chromosome
aberrations in mammalina systems. In addition, the dominant
lethal stuuy indicates the potential for the chemical to
reach the target gonad cells. The chromosomal effects
produced by dimethoate in higher systems plus the ancillary
information in eukaryotic microorganisms showing gene
conversion, coupled with the evidence suggesting that
the chemical reaches the mammalian gonad, leads the Agency
to conclude that humans may be a risk from exposure to
dimethoate. Additional studies are required to substantiate
this mutagenic risk, and to estimate the magnitude of the
risk.
There appears to be some qualitative evidence
bearing on the mutgenic potential of dimethoate. The only
-------
studies which can be used for a quantitation of potency are
the bacterial assays and the yeast gene conversion assay.
These, however, show a very low order of potency, near lower
detection limits, and were noted in only a few of the many
strains used. The mammalian cell unscheduled DNA synthesis
assay, although not suitable for numerical quantification,
also indicates a low potency compared to other pesticides
studied.
It is generally agreed by the scientific community
that a risk assessment for human hazard connot be made from
microbial data alone since these studies are performed in
repair deficient cells and are unassociated with normal
mammalian metabolic processes. The dominant-lethal assay
does show that mutagenic events may occur in mice at
relatively high i.p. doses of dimethoate. The metabolism
studies, however, show a rapid elimination of dimethoate
and its metabolites from the body with minimal amounts
remaining in germinal tissues.
The Agency concludes that dimethoate has a relatively
low mutagenic potency which is shown by submammalian
assays and by the metabolic studies. This low potency,
together with low exposure as discussed in Section B,
indicates that human risk is low. Additional test data is
necessary to evaluate the quantitative risk of this com-
pound. The Agency's Mutagenicity Guidelines will indicate
suitable assays. '
-76-
-------
In light of the available evidence which indicates
that Dimethoate may pose a potential mutagenic risk to
humans, the Agency believes it is prudent to take appropriate
measures to reduce the potential mutagenic hazard as discussed
in Section IV C.
(3) Reproductive and Fetotoxic Effects
Risk Analysis
(a) New Data
New data (Khera unpublished) showing a dimethoate
formulation to be a mild teratogenic agent has been received
by the Agency. There data were unavailable at the time the
RPAR was issued.
Khera (unpublished) administered Cygon 4E containing
47.3$ dimethoate to pregnant cats (in gelatin capsules) on
days 14 to 22 of gestation. The doses were 0, 3> 6, or 12
mg/kg per day of Cygon 4E which corresponds to 0, 1.4, 2.8,
or 5.7 mg/kg per day of dimethoate. On day 43 of gestation,
the fetuses were removed, weighed, and examined.
There were no signs of maternal toxicity in any cats
treated. Dimethoate, at all doses tested, caused no effect
on the number of live fetuses, resorption, dead fetuses, or
mean fetal weight. Both the total number of anomalous
fetuses and the number of litters having anomalous fetuses
were increased at the high dose when, compared to controls,
but this increase was not statistically significant (p=0.05,
Student + Test). When the incidence of one abnormality
(Polydactyly, or increase in the number of digits on the
paws) at the high dose was compared to the controls, the
results were statistically significant.
77
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There was no dose-response noted at 3 or 6 mg/kg with
regard to any anomaly, including Polydactyly. Although a
no-adverse effect level for all parameters can be set at 6
mg/kg per day of Cygon 4E, the author (Khera) indicated that
this teratogenic effect should be verified through additional
testing. This additional testing would determine if the
effect were due to dimethoate itself, the pesticidally inert
ingredients, or the combination of these (Cygon 4e).
The same dimethoate formulation, Cygon 4E, was tested
at doses of 0, 3i 6, 12, or 24 mg/kg per day (corresponding
to 0, 1.4, 2.8, 5.7, or 11.3 rcg/kg per day dimethoate) in
pregnant Wistar rats by oral intubation. There were 20
female rats started in each group, and the number of pregnant
dams was 17, 17, 15, 16, and 16, respectively. One dam at
the highest dose died from Cygon-induced cholinergic signs
of toxicity, and another seven showed similar signs of
toxicity but recovered. Decreased maternal weight gain was
seen at the high dose, but no adverse maternal effects were
noted at the lower doses.
There were no effects cf treatment on the number of
live fetuses per dam, number of dead or resorbed fetuses, or
fetal weight. At doses of 12 and 24 mg/kg per day Cygon 4E,
there were significant increases in number of anomalous
fetuses/number of fetuses examined and the number of
litters having at least one anomalous fetus/number of
litters examined, when compared to controls.
78
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When individual variations were examined, the two
high doses had a significant (p=0.05) increase in fetuses
with wavy ribs. The author (Khera) characterized these
anomalies as being "of minor types and of unknown signifi-
cance." It should be noted that these effects (wavy ribs),
which are often considered indicators that the ernbryotoxic
or fetotoxic dose is approached, occurred at either the
maternal toxic dose or one-half of that dose. If the only
significant effect observed when animals are dosed up to
maternal toxic levels is an increase in wavy ribs, then
this increase in wavy ribs is considered of marginal impor-
tance (Burnam 1979). Again, as in the cat teratology study,
the presence of unknown inert ingredients makes interpretation
difficult. The no-observed-effect level for any parameters
was 6 mg/kg per day of Cygcn 4E.
In both studies by Khera, the no-observed effect
level was 6 mg/kg per day for Cygon 4E (2.8 mg/kg per day
dimethoate). The occurance of minor teratogenic effects
at higher doses indicates that Cygon 4E has the potential
to interfere with fetal development. Additional studies are
required to fully determine the significance of these
findings.
(b) Teratogenic Risk
Reproductive risk is generally expressed in terms
of margins of safety. The margin of safety (MOS) is the
ratio of estimated exposure of a group of people tc the
dosage level (exposure) causing no-observable adverse
effect (NOEL) in an appropriate animal study. The Agency
-------
will use the NOEL of 2.8 mg/kg per day as observed by
Khera for calculating margins of safety for dimethoate.
(i) General Population Risk
Teratogenic risk can be calculated for two population
groups: 1} The General Population and 2) Applicators.
The general population would be at risk due to dimethoate
residues in food.
The most conservative (worst case) estimate of general
population exposure is to assume dimethoate to be present
on foods at tolerance levels. Summation of tolerances for
all foods treated with dimethoate multiplied by the food
factor {percent contribution of each food to total diet)
provides a worst case estimate of 0.0085 mg/kg per day for a
60 kg female on an average diet. Not all crops for which
dimethoate is registered are actually treated each year.
When the percentage of crops actually treated with dimethoate
is factored into this worst case estimate, the probable case
value becomes 0.0032 mg/kg per day (memo 1979c). The
corresponding margins of safety are as follows for the
general population exposed to dimethoate through food
residues.
2.8 mg/kg/day
Worst Case: = M0S of 329
0.0085 mg/kg/day
2.8 mg/kg/day
Probable Case: = MOS of 875
0.0032 mg/kg/day
80
-------
The MOS of 329 is unrealistic in that this figure
assumes all crops to be treated with dimethoate and residues
to be present at tolerance levels. Moreover, it is likely
that the probable case MOS of 875 is in itself a grosr
overestimate of risk as this MOS was derived assuming
dimethoate residues to be present at tolerance levels. It
is generally recognized that organophosphate pesticides such
as dimethoate degrade rather rapidly and that several weeks
may elapse between application and consumption of the
treated crop. It is likely, therefore, that the MOS for
general population risk is several orders of magnitude
higher than 875. A lack of data concerning dimethoate
residues at harvest, however, precludes estimates of the
actual MOS.
(ii) Applicator Risk
Smaller subpopulations engaged in the application of
dimethoate would experience greater exposure and concurrent
risk than that identified for the general population.
-------
Table IV
MARGINS OF SAFETY FOR VARIOUS USERS OF DIMETHOATE
CROP
TYPE OF
SPRAYING
HQS for
SUBGROUP
Combined Dermal and
Inhalation DAILY
EXPOSURE (Tor fe-
male mg/kg/day)
ORAL
EXPOSURE
TOTAL
EXPOSURE
MOS For
Terato-
genic
Effects (1)
corn
corn
corn
ornamental
ornamental
grape
grape
grape
cotton
cotton
cotton
cotton
citrus
air
air
air
ground
ground
ground
ground
ground
air
air
ground
ground
air
pilots
fl aggers
mixer/loader
conmercial
high concentration
compressed air
home garden high
concentration
Boom highest conc.
highest
conc. (custom)
Copperstone model
dust
pilot
mixer/loader
applicators
mixer/loader
pilot ground
crew mixer/loader
O.OO83
0.008
0.0063
0.00012
0.000152
0.0012
0.0207
0.130
0.0017
0.00095
0.0078
0.00033
same as corn
0.0032
0.0032
0.0032
0.0032
0.0032
0.0032
0.0032
0.0032
0.0032
0.0032
0.0032
0.0032
0.012
0.011
0.010
0.0033
0.00335
0.00W
0.0239
0.1332
0.005
0.001J2
0.0011
0.004
233
255
280
843
836
636
117
21
560
667
255
700
(1) Based or) 2.8 NOEL (Khera unpublished)
80.1
-------
Table IV (continued)
MARGINS OF SAFETY FOR VARIOUS USERS OF DIMETHOATE
CROP
TYPE OF
SPRAYING
SUBGROUP
Combined Dermal and
Inhalation DAILY
EXPOSURE (for fe-
male mg/kg/day)
ORAL
EXPOSURE
TOTAL
EXPOSURE
MQS for
Terato-
genic
Effects
citrus
sorghum
veg. fields
(Tomato,
Broccoli)
veg. (Fla)
vector con-
trol (house
fly)
forest pine
(seed or-
chard)
pecan
High conc.
pecan
safflower
pome
pome
ground
(air blast)
air
air
ground
ground
' ground
ground
ground
(air blast)
model
air
ground
(air blast)
ground
applicators
mixer/loader
same as corn
pilot
flaggers
mixer/loader
applicator
applicator
applicator
applicator
mixer/loader
applicator
mixer/loader
same as corn
commercial applicator
including mixer/loader
hose sprayer
0.39
0.013
0.013
0.0062
0.00005
0.0019
0.0008
0.00044
0.00022
0.li9
0.242
0.00017
0.0032
0.0032
0.0032
0.0032
0.0032
0.0032
0.0032
0.0032
0.0032
0.0032
0.0032
0.0032
0.3932
0.0162
0.0162
0.0094
0.0033
0.0051
0.0040
0.0036
0.00342
0.122
0.245
0.0034
170
170
298
848
549
700
778
819
23
12
823
80.2
-------
Table IV (continued)
MARGINS OF SAFETY FOR VARIOUS USERS OF DIMETHOATE
CROP
TYPE OF
SPRAYING
SUBGROUP
Combined Dermal and
Inhalation DAILY
EXPOSURE (for fe-
male mg/kg/day)
ORAL
EXPOSURE
TOTAL
EXPOSURE
HOS for
Terato-
genic
Effecta
soybean
wheat
tobacco
High conc.
alfalfa
High conc.
veg. field*
(lettuce)
air
air
ground
ground
ground
same as corn
aame as corn
applicator
including mixer/
loader
applicator including
mixer/loader
applicator
mixer/loader
0.00042
0.0052
0.0002
0.00026
0.0032
0.0032
0.0032
0.0032
0.0036
0.0084
0.0034
0.0035
778
333
823
800
80.3
-------
Estimates of exposure to these subpopulations are identified
in Section II.B, and the MOS for each subgroup is presented
in table IV. MOS figures for applications also include
dietary exposure.
(4) Fish and Wildlife Risk Analysis
The Agency did not presume against dimethoate based
on acute toxicity to aquatic, avian, or mammalian species.
The Agency has, however, identified those uses of dimethoate
which would result in the greatest potential environmental
impact. This section presents an analysis of risk to aquatic
and terrestrial wildlife from dimethoate use on cotton
(aphids, thrips, fleahoppers, and plant bugs), on alfalfa
seed crop (lygus bugs), and on citrus (aphids).
Rates and numbers of applications of dimethoate for use on
cotton, alfalfa seed crop and citrus are shown below:
Use Application Rate Number of
(lbs a.i./A)* Applications (per season)
Cotton 0.1 - 0.2 1-3
Alfalfa Seed Crop .5 1
Citrus 1.25 - 2.0 multiple
* Pounds active ingredient/acre.
-81-
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Environmental fate data indicate dimethoate can be
retained in the environment for a period of time sufficient
to allow potential exposure to aquatic and terrestrial
wildlife species (memo 1978c). The EPA Pesticide Incident
Monitoring System (PIMS) shows one suspected runoff-caused
fish kill in a stream adjacent to a dimethoate treated field
(EPA 1978b).
Acute toxicity values for aquatic species tested
ranged from 6.0 ppm to 155 ppm for fish and 0.043 ppm to 0.4
ppm for invertebrates. The lowest acute toxicity values
reported were 96-hour LCgg concentrations of 6.0 ppm for the
bluegill sunfish, Lepomis macrochirus (USDI 19 64)-and
0.043 ppm for the stonefly, Pteronarcys californica (Sanders
and Cope 1968). Five-day concentrations reported for
terrestrial wildlife ranged from 332 ppm for pheasants
(Phasianus colchicus) to 1011 ppm for mallards (Anas platy-
rhynchos) [Hill et al . 1975]. A field study conducted to
determine the effects of dimethoate applied at 0.25 and 0.50
pounds/acre (clover) on small mammals failed to show direct
impacts (Barrett and Darrell 1967). Researchers speculated
that a decline in a house mouse (Mus musculus) population
was due to a decreased food supply.
At recommended use rates for cotton and alfalfa seed
crop, initial residues of dimethoate on terrestrial wildlife
food sources in and around treated fields would range from 2.3
to 50 ppm and 6 to 120 ppm, respectively. These concentrations
are below 5-day dietary LC^g concentrations for avian
species tested, indicating a low acute hazard. LC5q va1ues
for sensitive aquatic species tested indicate dimethoate
-82-
-------
use would pose a low acute hazard for fish and a moderate
hazard for invertebrates.
Use of dimethoate on citrus at recommended use rates
would result in initial, residues of 10 to 480 ppm on terrestrial
wildlife food sources. These concentrations overlap the
toxic range for some of the sensitive avian species tested,
indicating some hazard. The hazard of acute toxicity to
fish appears low, but that for sensitive aquatic invertebrates
would be relatively high. In general, of the three uses
considered, dimethoate use on citrus appears to present the
greatest potential for acute hazard due largely to high
application rates and the potential for multiple applications.
An analysis of the comparative toxicity of dimethoate
and alternative compounds for use on cotton, alfalfa seed
crop, and citrus was made early in the RPAR process. These
data were not presented in this document since cancellation
is not being considered as a necessary regulatory option.
In general, however, it appears that the alternatives would
pose an acute hazard to aquatic and terrestrial species
tested that is greater than or equal to dimethoate.
III. BENEFIT ANALYSIS OF DIMETHOATE
As part of its regulatory review of dimethoate,
the Agency, together with the USDA, has conducted an
analysis to determine the economic impact of the possible
cancellation of dimethoate. This analysis takes into
consideration the availability and cost of alternative
83
-------
chemicals. This analysis will address only those uses
identified as important (high exposure/heavy usage) by the
USDA/EPA Assessment Team on Dimethoate (1979). Use situ-
ations not addressed in this portion of the Position Docu-
ment will be discussed in Section V. C.
A. Introduction
Annual dimethoate use was estimated at about 2.8
million pounds AI (active ingredient) applied to about 4.7
million agricultural acres. This analysis provides estimates
of annual use and economic impacts of a potential cancel-
lation action for the following classes of use sites:
grains, field crops, fruits and nuts, vegetables, and other
use sites. The economic impacts of the cancellation of
dimethoate are summarized in Table V'. Major alternative
chemicals for each use site are identified in Table VI.
This analysis demonstrates that, in certain
instances, the cost of producing a product (crop) will
decrease if dimethoate is not available. This apparent
decrease in cost to the farmer may be due to several
factors:
1) Comparative performance data between dimethoate
and alternatives, indicating the quantity and quality of the pro-
duct, may not have been available for the site under study.
In this case the use of an alternative, which may be less
-84-
-------
expensive to apply on a per acre basis may result in infer-
ior produce, which in turn would result in lower gross
profits for the grower. Because comparative performance
data were unavailable, the positive changes in income
may reflect a false economy.
2) Alternatives may in fact be more economical than
dimethoate; however, growers may be turning to other
pesticides slowly.
3) Dimethoate may be used by some growers for
other than financial considerations (e.g., acute toxicity,
IPM considerations, large inventories of dimethoate, etc.).
B. Grains
0
Dimethoate use on grains (corn, sorghum, and wheat)
accounted for about 792,500 pounds AI applied to about 1.74
million acres (Table V). Less than one percent of the U.S.
wheat and corn acres are treated, compared to 7.8 percent
for grain sorghum.
For all of the grain use sites, several effective
alternatives are available. If dimethoate were cancelled
total production costs were estimated to increase $1.03
million for corn and to decrease $0.9 million for sorghum.
For wheat,, the total production cost changes were qualitative-
ly assessed as minor; alternative controls are less expensive
on a per-acre basis ($0.67 and $1.42 less per acre treatment
with malathion and parathion respectively).
-84.1-
-------
The lost values of production for corn and sorghum were
estimated as $7_.8 million and $328,500, respectively.
Revenue losses were not estimated for wheat; however, yield
losses may result with the use of alternatives, since they
are less effective for greenbug control at low temperatures.
The total loss in farm income (changes in costs of
production and value of production) for corn producers was
estimated as $8.03 million, or $12.52 per impacted acre.
For sorghum, the overall impact was a $608,000 increase in
farm income or $0.55 per impacted acre; impacts between
states, however, were highly variable and ranged from a loss
of $3.87 per acre in South Dakota to a gain of $1.63 per
acre in Texas. A qualitative evaluation of total farm
income effects for wheat indicated a minor impact.
Even though significant economic impacts would be
experienced by some grain producers (e.g., $8,000,000 for
corn growers), only a small proportion of the total U.S.grain
production would be affected. Production impacts due to the cancel-
85
-------
lation of dimethoate are not expected to affect the economic
supply or the final consumers of U.S. grain.
C. Field Crops
Dimethoate use on field crops (safflower, soybeans,
cotton, tobacco, and alfalfa) accounted for about 501,000
pounds AI applied to about 1.95 million acres (Table
V). Less than one percent of U.S. acreage in soybeans,
tobacco, and alfalfa are treated with dimethoate. For U.S.
cotton and California and Arizona safflower acreages,
14.6 and 26.0 percent are treated with dimethoate.
85.1
-------
For most of the field crops several alternative controls
are available. Although no alternative insecticides are
available for spider mite control on soybeans, this pest is
only a minor and sporadic problem.
If dimethoate were cancelled, total costs of production
would increase for safflower ($3^,000), cotton ($1.73
million), and tobacco ($5,600). Production costs would
decrease by $21,600 for soybeans. A qualitative assessment
of cost changes for alfalfa hay (less than a $0.70 to $2.16
per acre increase) or seed (less than a $0.70 to $3.51 per
acre increase) indicated negligible effects.
Since there were no losses in production for these
field crops, the changes in farm income would be identical
to the changes in the costs of production. Estimated farm
income effects per impacted acre are -$1.0*1 for safflower,
+$1.27 for soybeans, -$0.71 for cotton, and -$3.^8 for
tobacco. Farm income effects for alfalfa could not be
estimated because of data limitations on use and comparative
performance.
Even though significant economic impacts would be
experienced by some field crop producers (e.g., $1,726,000
for alfalfa growers, $34,000 for safflower growers, etc.),
86
-------
only a small proportion of the total U.S. grain production
would be affected. Production impacts due to cancellation
of dimethoate are not expected to affect the economic
supply or the final consumers of U.S. grains.
D. Fruits and Nut3
¦Dimethoate use on fruit and nut crops (apples, pears,
citrus, grapes, and pecans) accounted for about 839,000
pounds AI applied to about 533,000 acres (Table V) . The
percent of total U.S. acreages treated with dimethoate
were 2.6 percent for apples, <1.0 percent for pears, 12.0
percent for citrus, and 17.0 percent for pecans. About 50.5
percent of the California grape acreage was treated with
dimethoate.
86.1
-------
For apples, pears, and pecans several effective
alternatives for dimethoate are available; the efficacy
and performance of alternatives for grapes and citrus are
limited. If dimethoate were cancelled total estimated
production cost increases for these crops are $89,700 for
apples, $551,000 for citrus, $9.99 million for grapes, and
$745,800 for pecans. The minor levels of dimethoate used on
pears would have negligible effects upon total production
costs.
Changes in the values of production would either be
negligible or not expected for apples, pears, and pecans.
Annual grape production losses in California, valued at
$40,700 are expected from vine losses due to insects
commonly referred to as sharp shooters. Significant adverse
effects on the quantity and quality of citrus production are
possible; however-, data were not available to evaluate the
economic magnitude of such effects.
Estimated decreased farm incomes for apples and pecans
are, respectively, about $90,000 and $745,800 (or $7.00 and
$14.34 per impacted acre). For citrus the farm loss could
exceed $551,000, or at least $3.58 per impacted acre
(significant quality losses due to thrips damage could not
be assessed with available data). The decreased farm income
for impacted grape producers would be $9.99 million, or
$3.83 per acre; total insecticide use would increase. Farm
income effects for all pear producers would be negligible;
income effects on an impacted acre basis could not be
estimated.
87
-------
Even though significant economic impacts would be
experienced by some U.S. fruit and nut producers (e.g.,
$9,990,000 for grape growers, $7^5,000 for pecan growers,
etc.), consumer impacts are not expected for pears and
apples due to the small proportion of the total U.S. produc-
tion affected. Price increases may occur for pecan, citrus
and grape products; but these increases are qualitatively
not expected to be of major significance. Consumer impacts
could not be quantitatively estimated due to the lack
of necessary data.
E. Vegetables
Dimethoate use on vegetable crops (tomatoes, broccoli,
beans, peppers, and lettuce) was estimated at about 612,800
pounds AI applied to about 49^,700 acres (Table V). The
percent of total U.S. acres treated with dimethoate ranged
from 7.1 percent for lettuce to 66.2 percent for fresh
tomatoes.
Effective alternatives are generally available
except for broccoli, fresh snap beans, and fresh tomatoes.
If dimethoate were cancelled, increases in total production
costs were estimated at about $2.1 million for all of the
88
-------
crops and ranged from a $2.7 million increase for fresh
tomatoes to a $371,000 decrease for processing tomatoes.
Total production cost changes could not be estimated for
lettuce and other vegetables due to biological and usage
data limitations. However, the overall change in production
costs would be expected to be minor.
For broccoli, the reduction in farm income was esti-
mated at $1.27 million, or $74.15 per acre. Farm income
losses for dry, fresh snap beans, and processing snap beans
were, respectively, $1.8 million, $3.6 million, and $130,800
88. 1
-------
(or $6.81, $76.70, and $3.60 per acre). For fresh tomatoes,
the total farm income loss was estimated at $3.9 million, or
$43.50 per acre.
Since no production losses were estimated for process-
ing tomatoes, the increase in farm income due to less expensive
alternative controls would be $371,000, or $12.37 per acre.
The overall farm income changes for lettuce and other vegetable
crops could not be estimated with available data.
Consumer impacts for fresh snap beans are expected to
be minor in the long term because of such factors as: (1) con-
sumers substituting other fresh or processed vegetables in
their diets, (2) expanded fresh bean production in other areas,
and (3) snap beans designated for the processing market divert-
ing to the fresh market. For broccoli, dry beans, processing
snap beans, tomatoes, and lettuce, consumer impacts would
qualitatively be either negligible or not expected. Con-
sumer impacts for other vegetable crops could not be esti-
mated due to the lack of necessary data.
89
-------
F. Other Use Sites
Dimethoate use was investigated on several other use
sites which included APHIS quarantine programs (citrus blackfly
and hog cholera vector control), livestock premises, forest
seed ochards and nurseries, and ornamentals. Total known
dimethoate use on these sites may exceed 150,000 pounds AI
(Table V).
Dimethoate was not used in 1978 for APHIS quarantine
programs, since hog cholera was declared eradicated on
January 1, 1978, and since effective control of the citrus
blackfly is being achieved with a parasite program. With the
hog cholera control program, tetrachlorvinphos + DDVP is a
89.1
-------
comparably effective alternative for dimethoate. For the
citrus blackfly control program, malathion can be substituted
for dimethoate at an increased dooryard tree treatment cost of
$2.15; if infestations return to the 1974 levels, the total cost
increase would be about $234,500.
For adult fly and maggot control in livestock facili-
ties, dimethoate use accounted for 50,600 pounds AI. Several
effective alternatives are available at near comparable cost;
the production cost increase of alternatives may be as large
as $30,900, or $0.44 per 1,000 square feet treated. No adverse
agricultural income or consumer price effects are expected.
Known dimethoate use for forest seed orchards and
nurseries is limited to 150 acres in the South. Several effec-
tive alternatives are available; use of azinphos-methyl would
reduce treatment costs by $2.25 to $4.50 per acre. No adverse
effects upon producer incomes or consumer prices are expected.
Dimethoate use on ornamentals may approach 50,000
pounds AI with about 90 percent applied commercially and 10
percent used by homeowners. A few site/pest combinations
(e.g., camellia/tea scale, boxwood/Comstock mealybug, and
juniper/juniper midge) may have pest control problems due
to a lack of cost-effective alternatives. However, since
most producers grow more than one type of ornamental, any
economic impact would probably be of a short term nature
until damaged stock was replaced with different varieties.
Impacts on consumers are expected to be minor since many
substitute ornamental varieties are available in the market.
90
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Table V. Use and Economic Impacts of a Diraethoate Cancellation on Grains
Dimethoatc Use
Pounds AI
Grain Crop Applied
Acres
Treated
Percent
of U.S.
Avail lability
of Alternatives
Econonic Impacts
Producer Impacts
Change in Change in Change Change in
Production Value in Farm Farm Income
Costs Production Income Per Acre
Consuner
Impacts
Corn 320,000 611,200 <1.0 several
Sorghum 171,895 1,103,110 7-8 several
Wheat minor; minor; <1.0 several
NA NA
thousand dollars dollars-
+1,037.0 -6,993-7 -8,030.7 -12.52
- 936.1 - 328.5 + 607.9 + .55
minor; minor; NA minor; NA NA
decrease
-thousand dollars—
none
none
none
NA - not available
91
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¦fable V (continued). Use and Economic Impacts of a Dimethoate Cancellation on Field Crop3
Diraethoate Use
Field Crop
Pounds AI
Applied
Acres
Treated
Percent
of U.S.
Availability
of Alternatives
Economic Impacts
Producer Impacts
Change In Change in Change Change in
Production Value in Farm Farm Income
Costs Production Income Per Acre
Consumer
Impacts
Alfalfa 112,500 <300,000 <1.0 several
Cotton 362,800 1,600,000 T4.6 several
Safflower 16,282 32,565 26.0; several
Cal. &
Ariz.
Soybeans 8,500 17,000 <1.0 limited
Tobacco 528 1,600 <1.0 several
thousand dollars
minor; NA minor; NA minor; NA
+1,726.5 none -1,726.5
+ 31>0 none - 3*l»0
21.6 none
+ 5k6 none
+ a.6
5.6
-dollars—
NA
- .71
-1.0U
+1.27
-3.H8
-thousand dollars-
none
none
none
none
none
NA - not available
92
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Table V (continued). Use and Economic Impacts of a Dimethoate Cancellation c'r, Fruits and Nuts
Dimethoate Use Economic Impacts
Producer Impacts
Change In Change in Change Change in
Fruit or Pounds AI Acres Percent Availability Production Value in Farm Farm Income
Nut Crop Applied Treated of U.S. of Alternatives Costs Production Income Per Acre
Ccnsuncr
Impacts
Apples
25,000 13,600 2.6
Citrus 319,100 153,700 12.0
Grapes 1)57,048
313,909 50.5;
Cal.
Pears negligible; negligible; <1.0
NA
Pecans 37,630
NA
52,000
17.0
several
limited
limited
several
several
thousand dollars
~ 90.0 none - 90.0
potentially V
+ 551.0 significant; >- 551.0
NA
+ 9,950
- tO.7
NA
+71)5.8
NA
none
-9,990
negligible; negligible; negligible;
NA
-715.8
-dollars-
- 7.00
>-3.58
-31.83
NA
-It.31
-thousand doll;
nons
rinor overall
MA
NA
none
mi nor;MA
NA- not available
1/ Potentially significant on affected acres but not immediately Indicated.
2/ Minor overall but potentially important for some citrus varltl03 sold for fresh consumption.
93
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Table V (continued). Use and Economic Impacts of a Dimethoate Cancellation on Vegetables
Dimethoate Use
Vegetable
CroŁ
Pounds AI
Applied
Acres
Treated
Percent
of U.S.
Availability
of Alternatives
Economic Impacts
Producer Impacts
Change in Change in Change Change in
Production Value in Farm form Income
Costs Production Income Per Acre
Ccnstner
Imoacts
Broccoli 8,600 17,100 26.6 limited
Beans-dry 193,800 258,300 17:2 several
-fresh 35,500 H7.100 51.6 limited
snap
-process- 27,100 36,300 13.0 several
ing snap
thousand dollars dollars-
+ 68.0 -1,200.0 -1,268.0 -71.15
-117.3 -1,877.0 -1,759.7 - 6.81
-101.6 -3,711.0 -3,612.1 -76.70
-100.2
- 231.0
- 130.8
- 3.60
-thousand dollars-
negligible
negligible
minor in the long
run; NA
negligible
94
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Table V (continued) Use and Economic Impact3 of a Diraethoate Cancellation on Vegetables
Dlmethoate Use
Bconcxnic Impacts
Producer Impacts
Change in
Change in
Change
Change in Consuner
Vegetable
Pounds AI
Acres
Percent
Availability
Production
Value
In Farm
Farm In cane Impacts
Crop
Applied
Treated
of U.S.
of Alternatives
Costs
Production
Income
Per Acre
thousand dollars —
—dollars thousand dollars-
Lettuce
12,900
16,000
7.1
several
variable;
NA
> -.1 to
>+.02 none
0
4->
•=7
1
+121.8
to -7.57
+121.8
Tomatoes
237,200
89,100
66.2
limited
+2,689.0
-1,200.0
-3,889.0
-13.50 negligible
-fresh
-processing
97,500
30,000
9.0
several
-371.0
none
+371.0
+12.37 none
Other vegetables
-cabbage
NA
NA
NA
several
NA
NA
NA
>-3.87 to +2.77 NA
-peppers
_>150
>100
NA
several
variable;
NA
>-2.7 to +1
.7 ^-6.70 to +1.11 HA
>-2.7 to +1.7
-Swiss chard NA
NA
NA
several
NA
NA
NA
>-1.05 to +1.37 NA
-turnips
NA
NA
NA
several
NA
NA
NA
>-1.05 to +1.37 NA
NA - not available
95
-------
Table V (continued). Use and Economic Impacts of a Dimethoate Cancellation on Other Use Sites
Dimethoate Use
Economic Impacts
Producer Impacts
Change in
Change
in
Change
Change in
Consumer
Other Use
Pounds AI
Units
Percent
Availability
Production
Value
in
Income
Impacts
Sites
Applied
Treated
of U.S.
of Alternatives
Costs
Production
Income
Per Unit
-thousand dollars
dollars
—thousand
dollars—
Citrus
<1,631
<108,9*11
NA
limited
<*23'l. 5
none
<-234.5
-2.15 per tree
none
blackfly
tree
treatment
treatments
Forest
100
100
2.1;
limited
-.1
none
+.H
+4.50
none
-nurseries
acres
South
-seed
50
100
6.1;
limited
-.2
none
+.2
+2.25
none
orchards
acres
South
Hog
none
none
none
limited
none
none
none
none
none
cholera
Livestock
50,600
69-7 million
<1.0
several
. +30.9
none ¦
-30.9
per 1000
none
facilities
sq. ft.
sq. ft.
Ornamentals >50,000
NA
NA
several
NA .
NA
na
NA
minimal;
NA
NA - not available
96
i
-------
Table VI. Site/Pest Uses of Dimethoate and Alternatives Used
In The Economic Analysis
Alfalfa (hay crop)
aphids
leafhoppers
Alfalfa (seed crop)
aphids
Lygus bug
Apples (commercial)
aphids, apple maggot,
and codling moth
(Midwest and eastern
states only)
mites (except rust
mite)
Beans (dry)
aphids
leafminers
Lygus bug
diazinon
malathion
methyl parathion
parathion
azinphosmethyl (not
registered for use in CA)
carbaryl
malathion
methoxychlor
demeton
disulfoton
methyl parathion
carbofuran
methidathion (Pacific
and intermountain states)
oxydemeton-methyl (CA only)
trichlorfon
azinphosmethyl
phosalone
phosmet
cyhexatin
demeton
propargite
disulfoton
malathion
parathion
parathion
malathion (CA and NW only)
parathion
mites
propargite
-97-
-------
Beans (fresh snap)
aphids
leafminers
Lygus bug
Beans (snap processing)
aphids
leafminers
Lygus bug
Broccoli
aphids
Cabbage
aphids
diazinon
disulfoton
malathion
methyl parathion
mevinphos
parathion
diazinon
methyl parathion
parathion
carbaryl (CA only)
malathion
methomyl (CA only)
methyl parathion
oxydemeton-methyl (CA only)
parathion
diazinon
disulfoton
malathion
methyl parathion
parathion
diazinon
methyl parathion
parathion
Carbaryl (CA only)
malathion
methyl parathion
oxydemeton-methyl (CA only)
parathion
mevinphos
oxydemeton-methyl
diazinon
malathion
mevinphos
oxydemeton-methyl
parathion
-98-
-------
Citrus (grapefruit, lemons, oranges
aphids
and tangerines)
demeton (grapefruit, lemons,
oranges)
malathion
mevinphos (grapefruit, lemons
oranges)
phosphomidon (tangerines -
AZ and CA only)
rotenone
thrips
azinphosmethyl
diazinon
dioxathion
formetanate (AZ and CA only)
methomyl (AZ and CA only)
parathion
phosphamidon (tangerines -
AZ and CA, only)
sulfur
Citrus (Quarantine Programs)
citrus blackfly
malathion
Corn
Banks grass mite
disulfoton
oxydemeton-methyl
propargite
parathion
Cotton
cotton aphids
azinphosmethyl
dicrotophos
malathion
methyl parathion
cotton leafhoppers
dicrotophos
malathion
methyl parathion
trichlorfon
Lygus bug
dicrotophos
malathion
methyl parathion
monocrotophos
spider mites
dicrotophos
methyl parathion
monocrotophos
thripa
azinphosmethyl
carbaryl
dicrotophos
malathion
methyl parathion
-99-
-------
Forestry
Nantucket pine tip moth
Grapes (CA only)
leafhoppers
mites
thrips
Lettuce
aphids
Livestock premises
house fly
Pears
aphids
azinphosmethyl
carbaryl + ethion
carbaryl + naled
carbophenothion
endosulfan
ethion
malathion
methomyl
naled
phosalone
•carbaryl + ethion
carbaryl + naled
carbophenothion
endosulfan
ethion
malathion
methomyl
naled
phosalone
propargite
malathion
naled
demeton
diazinon
disulfoton
endosulfan
malathion
mevinphos
parathio n
fenthion
malathion
ronnel
tetrachlorvinphos
tetrachlorvinphos + DDVP
azinphosmethyl
carbaryl
endosulfan
phosmet
-100-
-------
Pears (continued)
leafhoppers
pear psylla
mites (except rust mite)
azinphosmethyl
carbaryl
amitraz
azinphosmethyl
endosulfan
oil
phosmet
cyhexatin
phosalcne
Pecarta
aphids
Pepper3
aphids
leafminers and pepper maggot
dlalifor
disulfoton
phosalone
malathion
methomyl
oxydemeton-methyl
parathion
malathion
parathion
trichlorfon
Sctfflower
Lygus bug
Sorghum
aphids (incl. greenbugs)
Banks grass mite
(excl. Trans-Pecos area of
Texas)
naled
demeton
diazinon
disulfoton
malathion
oxydemeton-methyl
parathion
phorate
systox
diazinon
disulfoton
oxydemeton-methyl (SW only)
parathion
phorate
-101-
-------
Soybeans
Mexican bean
beetle
carbaryl
Swiss Chard
aphids
leafminers
Tobacco
green peach aphid
Turnips
aphids, leafhoppers
and leafminers
Tomatoes (fresh)
aphids
leafoiners
thrips
Tomatoes (processing)
aphids
leafminers and thrips
Wheat
greenbuga
diazlnon
malathion
parathion
malathion
parathion
acephate
diazinon
malathion
diazinon
malathion
mevinphos
parathion
methomyl
monocrotophos
oxamyl (CA and NJ only)
parathion
monocrotophos
parathion
oxamyl (FL, SC, AL
and CA only)
parathion
methomyl
parathion
parathion
malathion
parathion
102
-------
IV. Development and Selection of Regulatory Options
A. Introduction
In Sections II and III above, the Agency identified
the human and environmental risks associated with the use of
dimethoate and identified the benefits associated with each
of its uses. 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 accomplish that
goal, the Agency has identified 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 describes the
process which the Agency used to develop potential courses of
action for evaluation and identifies the options which were
ultimately selected for in-depth evaluation. Section V iden-
tifies options which the Agency will implement.
B.. Basis for the Development of Options
FIFRA provides that the Administrator may cancel
the registration of a pesticide whenever he determines
that it no longer satisfies the statutory standard for
registration which requires (among other things) that the
pesticide performs its intended function without "unreason-
able adverse effects on the environment" [FIFRA Section
3(c)(5); 7 USC Section 136a(e)(5)2- "Unreasonable adverse
effects on the environment" means "any unreasonable risk to
man or the environment, taking into account the economic,
-103-
-------
social and environmental costs and benefits of the use of
any pesticide" [FIFRA Section 2(bb); 7 USC Section 136(bb)].
In taking any final action under Section 6(b), the Adminis-
trator is required by statute to "consider restricting a
pesticide's use or uses as an alternative to cancellation
and shall include among those factors to be taken into
account the impact of such final action on production and
prices of agricultural commodities, retail food prices, and
otherwise on the agricultural economy..." [Section 6(b)].
In effect, FIFRA requires the Administrator to
weigh the risks and benefits associated with each use of
a pesticide. If he determines for any particular use
that the risks exceed the benefits, he shall cancel the
registration of the pesticide for that use unless he finds
that those risks can be sufficiently reduced (so that
they are outweighed by the benefits) by the imposition
of restrictions upon use through modifications to the
terms and conditions of registration (reflected by changes
in the labeling) and/or by the classification of the use
for restricted use.
The development of regulatory options involves
the formulation (and/or modification) of the term3 and
conditions of registration which are intended to reduce the
risks attendant to the use(s) of the pesticide. Each option
is then evaluated on a use-by-use basis to determine whether
it achieves an adequate reduction in risk without causing
unacceptable economic consequences, so that the remaining
benefits of the use exceed the remaining risks of that
use.
-1 04-
-------
C. Risk Reduction Methods
The development of the regulatory options
designed to reduce the risks accompanying the use of
dimethoate focused on means to reduce the level of human
exposure to dimethoate. In addition to dietary exposure,
individuals may be exposed to dimethoate before or during
application. Before application, mixers and loaders may be
exposed both dermally and via inhalation as the result of
splashing, vaporization, or accidental spills; during
application, pilots and flaggers involved in aerial applica-
tion, as well as ground applicators, may all be exposed both
dermally and via inhalation.
The Agency has considered each of these exposure
situations, and has identified several categories of regula-
tory options which include various methods of risk reduction.
These proposed regulatory options are as follows:
1) Continue registration of all uses
without restriction;
2) Continue registration of all uses without
restriction but require additional oncogenicity,
mutagenicity and delayed neurotoxicity studies;
3) Continue registration of all uses but
a) require additional oncogenicity, mutagenicity
and delayed neurotoxicity studies, and
b) amend the terms and conditions of certain
registrations;
-105-
-------
M) Continue registration of all uses but
a) require additional oncogenicity, mutagenicity
and delayed neurotoxicity studies,
b) amend the terms, and conditions of
certain registrations,
e) require comprehensive studies to
determine the amount of exposure incurred
during all air blast application situations;
5) Continue the registration of most uses but:
a) require additional oncogenicity, mutagenicity
and delayed neurotoxicity studies,
b) amend the terms and conditions of certain
registrations,
c) require comprehensive studies to
determine the amount of exposure incurred
during all air blast situations,
d) cancel the use of all dust formulations;
6) Continue registration of most uses but
a) require additional oncogenicity, mutagenicity
and delayed neurotoxicity studies,
b) amend the terms and conditions of certain
registrations,
c) specifically prohibit the use of air blast
equipment when treating citrus, pecans, and
pome fruits,
-106-
-------
d) require comprehensive studies to determine
the amount of exposure incurred during all
air blast situations not covered in (c) above,
e) specificially warn female workers
involved in air blast application
practices of the potential teratogenic
effects of dimethoate,
f) cancel the use of all dust formulations;
7) Cancel all uses.
The risks and benefits of each of the above options
are described below.
(1) Option #1
Continue registration of all uses without
restrictions
Adopting Option 1 would indicate that the Agency
concludes that the benefits associated with each use
outweigh the respective risks and that therefore none of
the uses of dimethoate cause unreasonable adverse effects.
This option would return pesticide products which contain
dimethoate to the registration process, would not reduce the
mutagenic or reproductive/teratogenic risks associated with
the use of dimethoate, would not result in any adverse economic
impact and would retain the U3e of dimethoate. The choice of
this option would indicate that the Agency is willing to
tolerate a level of risk greater than the levels of risk
estimated for other options in order to retain the highest
possible benefits.
-107-
-------
(2) Option #2
Continue registration of all uses without
restriction but require additional oncogeni-
city, mutagenicity and delayed neurotoxicity
studies
Adopting Option 2 would indicate that the Agency
concludes that the benefits associated with the use of
dimethoate outweigh potential risks based on available
studies. This option, however, indicates that the Agency
requires additional testing and indicates a desire on the
part of the Agency to reevaluate the oncogenicity and
mutagenicity risk picture when these new data are available.
This option would not reduce mutagenic or reproductive/
teratogenic risk in the short run as discussed in Section
III. This option would not result in any adverse economic
impacts and would retain the use of dimethoate as currently
registered.
(3) Option #3
Continue registration of all uses but
a) require additional oncogenicity, mutagenicity
and delayed neurotoxicity studies, and
b) amend the terms and conditions of certain
registrations.
Adopting Option 3 would indicate that the Agency
concludes that potential risks are too high relative to the
benefits associated with the use of dimethoate. This
option, however, would indicate that benefits of dimethoate
-108-
-------
use would outweigh risks if specific changes in application
practices were implemented. In addition, this option would
indicate the Agency's conclusion that additional data
concerning the oncogenic and mutagenic potential of dimethoate
are required. Implementation of this option would reduce
risks to acceptable levels (Table VII and VIII) without
substantial adverse economic impacts. Modifications that
would be implemented under this option fall into three
major categories, discussed in detail below:
1) Require protective clothing for all formulations
and all uses,
2) Require respirators for pilots and mixer/loaders,
and
3) Require automatic flagging for all aerial
application situations.
(a) Require Protective Clothing For All Products
and All Uses
This modification is intended to reduce risk by
reducing dermal exposure. The protective clothing would
consist of wide brimmed hats, impermeable gloves, rubber or
synthetic rubber boots or boot covers, long-sleeved shirt
and long pants made of a closely woven fabric. This protec-
tive clothing would be worn by all applicators, including
homeowners, and by all personnel involved with mixing,
loading, transferring, or otherwise handling this pesticide.
-109-
-------
In calculating dermal exposure to dimethoate the
•Agency assumed that 10$ of the dimethoate coming into
contact with skin will be absorbed and that 15? of the total
2
body surface (approximately 1.8 m ) will be exposed, or
2
about 2000 cm . For purposes of calculating dermal
exposure, the Agency assumes that the amount of dimethoate
absorbed will be reduced five-fold (Severn unpublished)
when protective clothing is used.
Applicators are exposed to dimethoate orally (i.e.,
through food) in addition to the dermal and inhalation
routes of exposure. As discussed in Section II.C.(3)(b)(i)
the MOS resulting from oral exposure alone was 875 (probable
case). This MOS is likely to be an overestimate of the true
oral exposure picture in that this figure was derived assuming
dimethoate residues to be present at tolerance levels. The
Agency used tolerance levels in calculating exposure due to a
lack of data concerning actual residues at harvest. It is
generally recognized, however, that organophosphorous pesticides
such as dimethoate degrade rather rapidly and that actual
residues at harvest are many orders of magnitude lower than
tolerance levels. In calculating applicator exposure this
artifically high oral exposure value was added to anticipated
occupational exposure in calculating margins of safety for
teratogenic effects. This addition of artifically high oral
exposure values has the effect of artifically increasing total
applicator exposure. Table III, for example, indicates that
the oral exposure is over 65? of the total exposure for
110
-------
pilots spraying cotton, 92% of total exposure for mixer/loaders
involved in the application (ground) of dimethoate to
lettuce, etc.
This additive contribution of the oral component
also has the effect of masking the risk-reducing effect of
regulatory options on risk. If 92$ of the exposure theoreti-
cally results from.the oral route (mixer/loader for lettuce)
it is obvious that, even though regulatory options such as
protective clothing eliminate a large portion of the 8?
non-oral exposure (worker exposure), this reduction in worker
exposure does not significantly affect the MOS for teratogenic
effects (because the majority of the exposure results from
the additive effect of an artifically high oral exposure
value).
Therefore, in order to evaluate the risk-reducing
effect of the various options, the Agency calculated margins
of safety for teratogenic effects resulting from worker
exposure separately from that of worker exposure combined
with oral exposure. In this way the risk-reducing effects
of the various regulatory options can be observed without the
masking influence of artifically high oral exposure.
Table VII shows MOS values for various activities and the
effect of each regulatory option without the oral exposure
values. For example, unprotected workers involved in the
ground application of dimethoate (custom applicators) to
grapes have a MOS of 135. The MOS for these workers when
protective clothing is required increases to 467. If the
111
-------
Table VII
APPLICATOR EXPOSURE AND MARGINS OF SAFETY FOR VARIOUS USERS OF DIMETHOATE
Excluding Dietary (oral) Exposure
COMBINED DERMAL HQS UNDER
EXPOSURE
(DERMAL AND
INHALATION)
WHEN PROTEC-
MOS WHEN
PROTECTIVE
TOTAL EXPOSURE
WHEN PROTECTIVE
CLOTHING AND
CROP
TYPE OF
SPRAYING
SUBGROUP
AND INHALATION
EXPOSURE
CURRENT
PRACTICES (1)
TIVE CLOTHING
IS REQUIRED
CLOTHING IS
REQUIRED
RESPIRATORS
REQUIRED
corn
air
pilots
0.0083
337
0.00806
317
0.00086
corn
air
flaggers
0.008
350
corn
air
mixer/loader
0.0063
1141
0.0013
651
0.00088
ornamental
ground
commercial
high concentration
compressed air
0.00012
23,333
0.000037
75,676
0.00002
ornamental
ground
hone garden high
concentration
0.000152
18,121
0.000015
62,222
0.00003
grape
ground
boon highest
oonc.
0.0012
2,333
0.0001
7,000
0.00023
grape
ground
highest
cono. (custom)
copplesto.ie model
0.0207
135
2/
22
0.006
167
0.0038
grape
ground
dust
0.130
0.130
22
0.013
cotton
air
pilot
0.0017
1,617
0.0016
1,750
0.00017
MQS WHEN
PROTECTIVE
CLOTHING AND
RESPIRATORS
ARE REQUIRED
3,256
3,182
WO,000
93,330
12,171
737
215
16,171
(1) Based on a 2.8 mg/kg NOEL (Khera unpublished)
(2) Exposure is via Inhalation
112
-------
Table VII (continued)
APPLICATOR EXPOSURE AND HARGINS OF SAFETY FOR VARIOUS USERS OF DIHETHOATE
Excluding Dietary (oral) Exposure
COMBINED DERMAL M3S UNDER
EXPOSURE
(DERMAL AND
INHALATION)
WHEN PROTEC-
TS WHEN
PROTECTIVE
CROP
TYPE OF
SPRAYING
SUBGROUP
AND INHALATION
EXPOSURE
CURRENT
PRACTICES (1)
TIVE CLOTHING
IS REQUIRED
CLOTHING
REQUIRED
cotton
air
mixer/loader
0.0095
295
0.00065
1,308
cotton
ground
applicators
0.0078
359
0.0021
1,167
cotton
ground
mixer/loader
0.00033
8,185-
0.00011
25,151
citrus
citrus
air
ground
(air blast
model)
pilot ground
crew mixer/loader
applicators (2)
mixer/loader
same as corn
0.39
7
0.078
36
sorghum
air
same as com
veg. fields
(tomato,
broccoli
air
pilot
flaggers
mixer/loader
0.013
0.013
0.0062
215
215
152
0.0128
0.0013
219
651
veg. (Fla.)
ground
applicator
0.00005
56,000
0.00001
280,000
vector con-
trol (house
fly)
ground
applicator
0.0019
1,171
0.0009
3,111
TOTAL EXPOSURE
WHEN PROTECTIVE
CLOTHING AND
RESPIRATORS ARE
REQUIRED
HQS WHEN
PROTECTIVE
CLOTHING AND
RESPIRATORS
ARE REQUIRED
0.00011
0.00115
0.00007
0.071
0.011
0.00088
0.000007
0.00032
20,000
1,931
1*0,000
39
2,000
3,182
100,000
8,750
(2) Applicator Is alao mixer/loader
113
-------
Table VII (continued)
APPLICATOR EXPOSURE AND MARGINS OP SAFETY FOR VARIOUS USERS OP DIMETHOATE
Excluding Dietary (oral) Exposure"
CROP
TYPE OP
SPRAYING
SUBGROUP
COMBINED DERMAL MQS UNDER
AND INHALATION CURRENT
EXPOSURE PRACTICES (1)
EXPOSURE
(DERMAL AND
INHALATION)
WHEN PROTEC-
TIVE CLOTHING
IS REQUIRED
HQS WHEN
PROTECTIVE
CLOTHING 13
REQUIRED
TOTAL EXPOSURE
WHEN PROTECTIVE
CLOTHING AND
RESPIRATORS ARE
REQUIRED
MQS WHEN
PROTECTIVE
CLOTHING AND
RESPIRATORS
ARE REQUIRED
forest pine
(seed orchard)
pecan
high cono.
aafflow
pane
pome
soybean
wheat
tobacco
high cono.
alfalfa
high conc.
ground
ground
(air blast
model)
air
ground
(air blast
model)
ground
air
air
ground
ground
applicator
applicator (2)
mixer/loader
sane as corn
hose sprayer
same as corn
same as corn
applicator
including
mixer/loader
applicator
Including
mixer/loader
0.0008
0.119
ccnmercial applicator 0.242
including mixer/
loader
0.00017
0.00012
0.0052
3,500
24
12
16,471
6,667
538
0.00025
0.0252
0.0527
0.00005
0.00013
0.00163
11,200
111
53
56,000
21,538
1,718
0.00014
0.0232
0.0485
0.000032
0.00008
0.00097
20,000
121
58
87,500
35,000
2,887
(2) Applicator is also mixer/loader
114
-------
Table VII (continued)
CROP
TYPE OF
SPRAYING
APPLICATOR EXPOSURE AMD MARGINS OP SAFETY FOR VARIOUS USERS OP DIHETHOATE
Excluding Dietary (oral) Expos-ire
SUBGROUP
COMBINED DERMAL MOS UNDER
AND INHALATION CURRENT
EXPOSURE PRACTICES (1)
EXPOSURE
(DERMAL AND
INHALATION)
WHEN PROTEC-
TIVE CLOTHING
IS REQUIRED
HQS WHEN
PROTECTIVE
CLOTHING IS
REQUIRED
TOTAL EXPOSURE
WHEN PROTECTIVE
CLOTHING AND
RESPIRATORS ARE
REQUIRED
HQS WHEN
PROTECTIVE
CLOTHING AND
RESPIRATORS
ARE REQUIRED
veg. fields
(lettuce
ground
applicator
mixer/loader
0.0002
0.00026
11,000
10,769
0.00007
0.00009
1(0,000
31,111
0.000013
0.000054
65,116
51,852
115
-------
Table VIII
APPLICATOR EXPOSURE AMD MARGINS OP SAFETY FOR VARIOUS USERS OF DIMETHOATE
Including Dietary (oral) Exposure
COMBINED DERMAL
AND INHALATION TOTAL EXPOSURE HQS WHEN
EXPOSURE WHEN HQS WHEN WHEN PROTECTIVE PROTECTIVE
PROTECTIVE PROTECTIVE CLOTHING AND CLOTHING AND
CROP
TYPE OF
SPRAYING
SUBGROUP
CLOTHING IS
REQUIRED
ORAL
EXPOSURE
TOTAL
EXPOSURE
OjOTHING IS
REQUIRED
RESPIRATORS ARE
REQUIRED
RESPIRATORS
ARE REQUIRED
corn
corn
corn
air
air
air
pilots
flaggers
mixer/loader
0.00806
0.0013
0.0032
0.0032
0.0113
0.0075
248
373
0.00406
0.00408
690
686
ornamental
ground
commercial high
concentration
oompressed air
0.000037
0.0032
0.0033
865
0.00322
870
ornamental
ground
home garden high
concentration
0.000015
0.0032
0.00325
862
0.00323
867
grape
ground
boas highest
concentration
0.0004
0.0032
0.0036
778
0.00343
816
grape
ground
highest
concentration
(custom)
Copplestone model
0.006
0.0032
0,0092
286
0.007
400
i
grape
ground
dust
0.130
0.0032
0.1332
21
0.0162
173
cotton
air
pilot
,0.0016
0.0032
0.0048
583
0.00337
831
cotton
air
mixer/loader
0.00065
0.0032
0.0039
718
cotton
ground
applicators
0.0024
0.0032
0.0056
500
0.00334
838
116
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CROP
TYPE OF
SPRAYING
Table VIII (continued)
APPLICATOR EXPOSURE AND MARGINS OF SAFETY FOR VARIOUS USERS OF DIMETHOATE
Including Dietary (oral) Exposure
COMBINED DERMAL
AND INHALATION
EXPOSURE WHEN
PROTECTIVE
CLOTHING IS ORAL TOTAL
SUBGROUP REQUIRED EXPOSURE EXPOSURE
MOS WHEN
PROTECTIVE
CLOTHING IS
REQUIRED
TOTAL EXPOSURE
WHEN PROTECTIVE
CLOTHING AND
RESPIRATORS ARE
REQUIRED
MOS WHEN
PROTECTIVE
CLOTHING AND
RESPIRATORS
ARE REQUIRED
cotton
cltpjs
citrus
sorghum
veg. fields
(tomato,
broccoli)
veg. (Fla.)
vector con-
trol (house
fly)
forest pine
(seed orchard)
pecan
high concen-
tration
ground
air
ground
(air blast)
air
air
ground
ground
ground
ground
(air blast)
mixer/loader
pilot groung
crew mixer/loader
applicators (1)
mixer/loader
sane as corn
pilot
flaggers
mixer/loader
applicator
applicator
applicator
applicator (1)
mixer/loader
0.00011
same as corn
0.078
0.0128
0.0013
0.00001
0.0009
0.00025
0.0252
0.0032
0.0032
0.0032
0.0032
0.0032
0.0032
0.0032
0.0032
0.0033
0,081
0.16
0.0075
0.0032
0.0011
0.0035
0.0281
818
35
175
373
875
683
800
99
0.00327
0.0712
0.0016
0.00321
0.00108
0.00352
0.00331
0.0261
856
38
609
872
686
795
838
106
(1) Applicator also does mixing/loading
117
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Table VIII (continued)
CROP
TYPE OF
SPRAYING
APPLICATOR EXPOSURE AND MARGINS OF SAFETY FOR VARIOUS USERS OF DIMETHOATE
Including Dietary (oral) Exposure"
SUBGROUP
COMBINED DERMAL
AND INHALATION
EXPOSURE WHEN
PROTECTIVE
CLOTHING IS
REQUIRED
ORAL
EXPOSURE
TOTAL
EXPOSURE
HQS WHEN
PROTECTIVE
CLOTHING IS
REQUIRED
TOTAL EXPOSURB
WHEN PROTECTIVE
CLOTHING AND
RESPIRATORS ARE
REQUIRED
HQS WHEN
PROTECTIVE
CLOTHING AND
RESPIRATORS
ARE REQUIRED
saf flower
air
same as com
pome
ground
(air blast
model)
ooonerolal applica-
tor Including
mixer/loader
0.0527
0.0032
0.055?
50
0.0517
51
pane
ground
hone sprayer
0.00005
0.0032
0.0033
861
0.00323
867
soybean
air
sane as corn
wheat
air
same as corn
tobacco
high cono.
ground
applicator
Including
mlxer/loader
0.00013
0.0032
0.0033
818
0.00328
851
alfalfa
high conc.
ground
applicator
including
mixer/loader
0.00163
0.0032
0.0018
583
0.00117
671
veg. fields
(lettuoe)
ground
applicator
mlxer/loader
0.00007
0.00009
0.0032
0.0032
0.0033
0.0033
818
848
0.00321
0.00325
861
862
118
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oral exposure complement for this same worker wearing
protective clothing is added the MOS drops to 286 (Table
VIII). This MOS of 286, therefore, is artifically low and
does not accurately reflect risk nor does it reflect the
risk-reducing effects of regulatory options. The effect of
regulatory options on the MOS for each use situation,
therefore, is calculated twice, first without the oral
exposure complement (Table VII) and secondly with the oral
exposure complement (Table VIII).
Even though there is some risk from dietary exposure,
it is likely that MOS figures in Table VII most accurately
reflect total risk (MOS) for application and that figures in
Table VIII are overestimated.
In the case of protective clothing, increased produc-
tion costs of dimethoate-treated commodities or other
economic impacts would not be expected (memo 1979e)
because applicators commonly own or wear the required
protective clothing.
(b) Require Respirator For Pilots
and Mixer/Loaders
In calculating respiratory exposure the Agency
assumed 100% of the dimethoate entering the lungs would be
absorbed. For purposes of calculating the decrease in
exposure and concurrent risk reduction afforded by respirators,
the Agency assumes that proper respiratory protective
devices will reduce the inhalation exposure by 90% (Severn
119
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unpublished). Application situations requiring respirators
will be those of pilots and mixer/1oaders for whom margins of
safety are shown in tables VII and VIII. As was the case
with protective clothing, MOS figures are calculated twice;
once including oral exposure (Table VIII) and once without the
oral complement (Table VII). Pilots would not be required
to wear respirators when their planes are equipped with
positive ventilation equipment.
The economic impact of requiring applicators to wear
respirators capable of removing particulate matter (e.g.
canister type) would be negligible. Custom applicators would
be expected to have such equipment at present; hence no addi-
tional investment costs would be required on the part of custom
applicators (memo 1979e).
(c) Require Automatic Flagging For All Aerial
Application Situations
Flaggers are individuals stationed at predetermined
points in a field who indicate to pilots applying dimethoate
where to begin (or stop) applying the pesticide. As a result
these individuals can come into direct contact with the
pesticide and are at risk as indicated in Table II. This
modification is intended to eliminate risk by requiring the
use of automatic flagging equipment. Automatic flaggers
are small mechanical devices mounted on the aircraft which
dispense a marker which the pilot can use to mark the
beginning and/or end of the swaths. These devices eliminate
120
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the need for flaggers and therefore eliminate the risk to
this segment of the population. The economic impact of
requiring automatic flagging equipment would be minor. The
relative cost of using automatic flagging versus conventional
flagging (human flaggers) would be dependent upon several
factors such as: 1) topography, 2) level of application
accuracy desired, 3) field acreage, and 4) field dimension.
Several types of automatic flagging devices that use
biodegradable paper, smoke, or other marking methods are
available. Flagging devices using bio-degradable paper
flags retail for $395.00; a case of 400 flags retails for
$42.00 or $0.11 per flag. One to five flags are used per
swath, depending on the terrain and desired accuracy
of application (memo 1979a).
Given the low investment and operating costs
associated with automatic flagging equipment, the custom
applicator may be able to reduce costs by adopting flagging
rather than the more conventional methods. Current labor
costs per worker for conventional flagging may range
from $4 to $5 per hour and workers may not be available when
needed.
In conclusion, negligible economic impacts are
associated with implementing automatic flagging for
dimethoate both at the production and consumption levels.
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(4) Option #4
Continue registration of all uses but
a) require additional oncogenicity,
mutagenicity and delayed neurotoxicity
studies;
b) amend the terms, and conditions of
certain registrations, and
c) require comprehensive studies to
determine the amount of exposure incurred
during all air blast application situations.
Adopting Option 4 would indicate that the Agency con-
cludes that benefits associated with the use of dimethoate
outweigh potential risks when specific application practices
are implemented as discussed in Option 3. This option indi-
cates that the Agency desires to evaluate its position when
additional data are available on air blast application techni-
ques. This option indicates that there is insufficient expo-
sure data concerning air blast application situations to
determine whether margins of safety for reproductive/terato-
genic effects do in fact fall in the range of 39-121 as
discussed in section III (Table VII). This option would not
reduce risk beyond that resulting from the implemention of
specific application practices as discussed in Option 3. This
option would not result in any adverse economic impacts and
would retain the use of dimethoate as currently registered.
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(5) Option #5
Continue registration of most uses but
a) require additional oncogenicity,
mutagenicity and delayed neurotoxicity
stud i es,
b) amend the terms and conditions of
certain registrations, and
c) require comprehensive studies to
determine the amount of exposure
incurred during all air blast situations;
d) cancel the use of all dust formulations.
Adopting Option 5 would indicate that the Agency
concludes that benefits associated with most uses of
dimethoate outweigh potential risks when specific changes in
application practices are implemented. This option would
encompass all the changes in application practices discussed
in Option 3 (protective clothing, respirators, and automatic
flagging), and would provide for the gathering of compre-
hensive information concerning applicator exposure during
air blast application as discussed in Option 4. This
option would permit dimethoate to be applied using air blast
equipment while exposure information is being gathered.
Option 5 goes on to indicate that the Agency concludes
that risk resulting from the use of dust formulations ofi
dimethoate outweigh benefits derived from the use of dust
formulati ons.
123
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Cancellation of dimethoate dust on grapes would
have no economic impacts at the producer or consumer levels
because the dimethoate wettable powder formulation is more
widely used on grapes and would be expected to replace the dust
formulation for this crop use. No adverse effects on the quant-
ity or the quality of grape production are expected (memo
1979e).
Dimethoate dust formulations are also registered
for use on potatoes; however, very little of the dust
formulation is used (Waugh, memo). Other formulations of
dimethoate are available for this use and no adverse economic
effects are expected from its cancellation (Memo 1979e).
(6) Option 1/6
Continue the registration of most uses but,
a) Require additional oncogenicity,
mutagenicity and delayed neurotoxicity
3tudies,
b) Amend the terms and conditions of
certain registrations, and
c) Specifically prohibit the use of
air blast equipment when treating
citrus, pecans, and pome fruits,
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d) Require comprehensive studies to
determine the amount of exposure
incurred during all air blast
situations not covered in (c) above,
e) Specifically warn female worker
involved in air blast application
practices of the potential teratogenic
effects of dimethoate,
f) Cancel the use of all dust formulations
•' Adopting Option 6 would indicate that the Agency
concludes that benefits associated with most uses of
dimethoate outweigh potential risks when specific changes
in application practices are implemented (protective clothing,
respirators, automatic flagging). This option would encompass
all the changes in application practices, discussed in Option
3, but would go on to specifically prohibit the use of air
blast application equipment when treating citrus, pecans,
and pome fruits (apples and pears). This option indicates
that in the case of citrus, pecans, and pome fruits, available
protective equipment will not reduce the risk experienced by
applicators using air blast equipment to an acceptable level
(Table VII). This option goes on to indicate that the
Agency concludes that the risk resulting from the use of
dust formulations of dimethoate outweigh benefits derived
from the use of dust formulations. In addition, this
option specifies the Agency's requirement for additional
125
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applicator exposure data concerning air blast application
practices other than citrus, pecan and pome fruits. Option
6 would permit the use of air blast equipment {for crops
other than citrus, pome fruits and pecans) while air blast
exposure information is being gathered.
Option 6, however, would go on to state the Agency's
concern for women applicators applying dimethoate via air
blast equipment during pregnancy. Under Option 6 the Agency
would require all products containing dimethoate which can
be or are intended to be used with air blast equipment to
bear the following warning:
"Warning to Female Workers" (16 pt. Red lettering)
The United States Environmental Protection Agency
has determined that dimethoate, an active chemical
ingredient in this product, causes birth defects in
laboratory animals. Exposure to this product during
pregnancy should be avoided.
For products which are not intended for use with air
blast equipment the following statement shall appear on all
1abeli ng:
"Warning (16 pt. Red lettering)
Do not use this product with Air Blast
Equi pment."
126
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Adopting Option 6 would indicate, as does Option 5,
that the Agency concludes that risks resulting from the
use of dust formulations of dimethoate outweigh benefits
derived from the use of dust formulations. Option 6 would
decrease applicator risk as discussed in Option 3 and would
eliminate risk resulting from the use of dust formulations
and of air blast application on citrus, pecans and pome
fruits. This option would not result major economic impacts
and would retain most dimethoate use patterns.
In determining whether to prohibit the use of air
blast equipment or cancel dust formulations, the Agency must
evaluate the potential human risk posed by alternative chemicals,
or alternative formulations of dimethoate. As discussed below,
air blast applicators may switch to alternative chemicals rather
than apply dimethoate by other application methods (e.g. boom,
hydraulic equipment or by air).
The potential risk posed by alternative pesticides will
be discussed separately for each crop as well as for dust
formulat i ons.
Citrus
The use of dimethoate on citrus is limited, for the
most part, to Arizona and California. Approximately 46% of
the citrus acres in Arizona and California are treated with
dimethoate. In both states thrips is the primary pest
although aphids are also a problem. The major alternatives
127
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to dimethoate use on citrus are formetanate, malathion,
phosphamidon, demeton and mevinphos (USDA/EPA 1979). None
of these pesticides have identifiable adverse chronic or
delayed toxic effects, although a complete data base is
lacking for many of these compounds. Available data
(memo 1979h) indicate that these major alternatives do not
appear more hazardous than dimethoate.
Pome Fruits (Apples and Pears)
In the case of apples dimethoate is primarily used to
control aphids and mites. Only 2.6% of the total U.S.
apple acres are treated with dimethoate (USDA/EPA 1979). If
growers were to switch to alternative pesticides, azinphosmethyl,
cyhexatin, propargite and demeton would be the compounds of
choice. Available data (memo 1979h) indicates that,
with the exception of azinphosmethyl which is under review,
these major alternatives do not appear more hazardous than
dimethoate.
Azinphosmethyl Is more acutely toxic than dimethoate
and, based on a recent National Cancer Institute study, may
pose a carcinogenic risk (memo 1979h). However, because
only 2.6% of apple acres are treated with dimethoate, any
incremental risk due to the use of azinphosmethyl as a
substitute is assumed to be insignificant. Moreover,
azinphosmethyl is a restricted use pesticide and can only be
used by trained pesticide applicators.
128
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Available pesticide usage surveys indicate no use of
dimethoate on pears in recent years (USDA/EPA 1979).
Because dimethoate is not used on pears, prohibiting the
use of airblast application practices would not result in
increased risk due to alternatives.
Pecans
Dimethoate is most often applied to pecans to control
aphids. The primary alternatives to dimethoate for use on
pecans are phosalone and dialifor. Phosalone is slightly more
acutely toxic than dimethoate. Agency records indicate that phosa-
lone has been tested for oncogenicity, delayed neurotoxicity,
reproductive and teratogenic effects with negative results.
Dialifor is more acutely toxic, than dimethoate and has under
gone the same tests as phosalone with negative results. The
vast majority of toxicity data supporting dialifor, however,
was carried out at Industrial Bio-Test and these data have
not been validated. Therefore, conclusions concerning the
reliability of these data cannot be made at this time.
Dimethoate is not of great importance for pecans
in that phosalone is the most popular compound for aphid
control (USDA/EPA 1979). Although the validity of the
data concerning dialifor is in question, phosalone and
129
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dialifor do not appear to be more hazardous than dimethoate.
Dust Formulations
Dimethoate dust formulations are used on grapes and
to a very minor degree on potatoes. Dimethoate in the form
of a wettable powder is the alternative compound/formulation
of choice for grapes and pototoes. Because the wettable
powder formulation results in lower applicator exposure,
the total risk for the wettable powder formulation would be
less than that of the dust formulation.
129.1
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The economic impact of precluding airblast
application practices differ for each crop and will be
discussed separately.
(a) Citrus
Of the 245,000 dimethoate acre-treatments applied to
citrus annually, about 69,900 (29%) and 175,300 (71%) are
applied by air and ground equipment, respectively. This
restriction would impact upon those users applying dimethoate
by ground equipment, most of which are believed to be
air-blast treatments.
Restrictions of air-blast application would leave
users with' three application method alternatives: 1) aerial
2) oscillating booms, or 3) manually operated hydraulic
guns. Crew size, exposure time, and man-hour requirements
for these methods and for air-blast are as follows:
man-hours/acre required
crew 3ize exposure time/acre for application
air-blast
2
15
minutes
0.5
aerial
3
1
minute
0.05
oscillating boom
3
15
minutes
0.75
manual spraying
4
1.5
hours
6.0
130
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The use of oscillating boom sprayers or manually
operated hydraulic pressue guns for citrus thrips control is
both inappropriate and prohibitively expensive. These
application methods are used for pest control requiring
"thorough coverage" high gallonage (more than 1,000 gallons
spray per acre) treatments in which all interior and exterior
parts of the tree are wetted by the spray material. The
cost of. thorough coverage treatment runs from $40 to $50 per
acre depending upon citrus type, tree size, and specific
application method used. Aphid and thrip control generally
involve a mist spray application of pesticide since only the
outside or peripheral parts of the tree require treatment.
The cost of mist spray application using air blast sprayers
(100 - 500 gallons spray/acre) averages about $20 per acre.
Thus, oscillating booms and manual spraying are generally
ruled out for dimethoate use on citrus because of expense
and the lack of fit of these methods for aphid and thrip
control.
Aerial application, an alternative to air-blast
ground equipment, is in widespread practice. Aerial applica-
tion i3 less expensive than air-blast application, averaging
about $5—$10 per acre compared to $20 per acre for air-blast.
Based on cost alone it would seem logical to assume that all
citrus applications of dimethoate could be performed by air.
However, aerial applications are limited by two factors:
131
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1) effect i venes s - air-blast treatments are more
effective than aerial when moderate to heavy pest infestations
are present.
2) capacity - it is doubtful whether available aircraft
could handle all the acreage requiring treatment, at least
in the short run.
It is safe to conclude that aerial application
could replace ground sprayers in some or many instances.
However, it would be inappropriate to assume that all ground
applications of dimethoate on citrus could be replaced by
aircraft due to the treatment effectiveness and equipment
availability factors outlined above. Some dimethoate users
would use aerial application, a few might switch to ground
application techniques other than air-blast sprayers, and
some would use alternate insecticides. Because of a lack of
data at present it is not possible to predetermine the
relative adoption ratios of these three strategies and their
associated economic impacts. Thus, impact of restricting
air-blast application could range from zero impact to the
same impact as cancellation ($551 ,000/year) [USDA/EPA 1979
memo 1979f].
(b) Pome Fruit
Unlike citrus, only small acreages of apples and
pears receive aerial pesticide applications. Although
dimethoate is registered for aerial application on apples
132
-------
and pears, growers rely almost exclusively on ground equipment,
particularly air-blast equipment, for pest control. As in
citrus, apple and pear growers prefer not to use large
quantities of water when spraying in order to minimize
sprayer travel and refill time, to avoid soil compaction,
etc.
Due to the high cost of ground application methods
other than air blast, if ground application of dimethoate
were prohibited on apples and pears, current dimethoate
users would probably utilize alternative pesticides. The
economic effect would likely be equivalent to the cancellation
impacts (about $90,000 per year) [memo 1979f3 -
(c) Pecans
Approximately 1,430 farms currently produce pecans
on 52,000 acres with two dimethoate applications per year.
Approximately 90% of these acres were treated with ground
equipment. If air blast application were not permitted
growers would either purchase hydraulic sprayers with which
to apply dimethoate, at a cost of approximately $3000 or use
some alternative pesticide.
If hydraulic equipment was purchased and assuming
a seven year economic life, annual investment costs would
not be expected to exceed $650 per year for each farmer
(memo 1979d). The operating costs per acre would also
increase with hydraulic sprayer because 1) fewer acres
can be treated per hour with hydraulic equipment (2 acres/
hour) than with air blast equipment (4-5 acres/hour),
and 2) larger work crews are required (one worker for air
blast equipment compared to three workers for hydraulic
-133-
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systems). Under these conditions the anticipated increase
in investment and operating costs per grower would be
approximately $1082.00 and up to $1.4 million for all
growers.
Based on existing information on the performance
and costs of available alternatives, as well as the problem
of farm labor shortage, few producers of pecans would be
expected to invest in hydraulic spray equipment. Therefore,
this regulatory option would have the same result as a
dimethoate cancellation ($745,999) for many of the impacted
producers.
(7) Option #7
Cancel All Uses
Adopting Option 7 would indicate that the Agency
concludes that the risks associated with all of the uses
outweigh the respective benefits and thereby result in
unreasonable adverse effects. This option would eliminate
all of the uses of dimethoate. Cancellation would eliminate
all of the reproductive/teratogenic and mutagenic risks
associated with the use of dimethoate (Table III) , but at a
cost to growers of $8 million per year for corn, $10
million dollars per year for grapes, and 3.9 million dollars
for fresh tomatoes. Additional losses for other commodities
are also expected (Table IV). The choice of this option
would indicate that the Agency is unwilling tolerate the
level of risk associated with any use of dimethoate.
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V. RECOMMENDED OPTIONS
A. Comparison of Options
In selecting a regulatory option, the Agency must
decide which of the proposed options achieves the most appro-
priate balance between risks and benefits. This decision turns
in part on the key factual elements summarized above, and in
part on the relative merits of each proposed option.
Option 1 (which would continue the registration for
all uses) and Option 7 (which would cancel the registration for
all uses) represent all or nothing approaches to regulating. By
adopting Option 1, the Agency would not reduce the potential
risks, nor would it otherwise recognize that the RPAR
review confirmed the presumption of mutagenicity and reproductive/
teratogenic effects. Option 1 would be reasonable only if
the benefits clearly outweigh the risks, and if reductions
in risk cannot be achieved without unacceptable impact on
the benefits. Option 7 would be reasonable only if the
risks clearly outweigh the benefits, and if significant
reductions in risks cannot be achieved by measures short of
cancellation without unacceptable impacts on the benefits.
A review of the data indicates that neither situation
prevails and that alternative options are available which are
environmentally and economically sound. Therefore, Options 1
and 7 are not reasonable regulatory measures in this case.
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Option 2 provides a mechanism for the development
of additional information concerning oncogenicity and
teratogenicity. This option, like Option 1, fails
to reduce potential risk from mutagenic and reproductive/
teratogenic effects. Because other options are available
which will reduce risk without adverse economic impacts,
Option 2 is not acceptable.
Option 3 goes beyond the information-gathering
process discussed in Option 2 and focuses on methods of
reducing exposure to applicators- Option 3 is preferable to
Option 2 in that it delineates specific requirements intended
to reduce applicator risk. These risk-reducing requirements
(e.g., protective clothing, respirators, automatic flagging)
are particularly appealing in that the requirements have so
little economic impact. This option does not, however,
address the high risk air blast application situations nor
the risk resulting from the use of dust formulations.
Because other options are available which will either reduce
risk in these areas without significant economic impact or
will produce additional data with which to evaluate risk,
Option 3 is not acceptable.
Option 4 encompasses all the risk-reducing characteris-
tics contained in Option 3 but goes on to indicate that the
air blast method of application results in comparatively
high exposure and risk. This option indicates that additional
studies are needed to accurately determine the amount of
exposure incurred during air blast application. This option
-136-
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concludes that the benefits derived from the use of air
blast equipment outweigh risks and that air blast equipment
may be used while exposure related information is being
gathered. This option fails, as does Option 3, to reduce
risk due to air blast application techniques, due to dust
formulations nor does Option 4 warn female applicators of
potential teratogenic danger resulting from air blast
application practices. Because other options are available
which will reduce risk and which will warn applicators of or
eliminate risk from air blast application without signifi-
cant economic impact, Option 4 is not acceptable.
Option 5 differs from Option 4 in that the selection
of Option 5 would result from the conclusion that risks
resulting from the use of dust formulations outweigh
potential benefits. Option 5, however, fails to make
provisions for reducing risk associated with selected high
risk air blast application situations. Because another
option is available which provides additional reduction in
risk, without significant economic impact, Option 5 is not
acceptable.
Option 6 differs from Option 5 in that Option 6
eliminates three specific use situations (citrus, pome
fruits, and pecans) where applicator risk is unacceptably
137
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high in light of the benefits derived from this use and
provides for precautionary labeling to inform female applica-
tors of potential teratogenic hazard resulting from other
air blast application practices rather than eliminating this
method of application altogether. Option 6 maintains the
majority of the economic benefits derived from the use of
dimethoate. Under Option 6 the decision to permit some air
blast application methods is an interim decision, and will
be reevaluated when additional air blast exposure data
becomes available.
B. Recommended Options
The Agency recommends adoption and implementation
of regulatory option number 6. Option 6 is selected because
it represents the best available course of action for
reducing or eliminating applicator exposure and concurrent
risk, while maintaining a generally high level of benefits
and for gathering additional toxicological data needed to
better evaluate risk. In adopting Option 6, the Agency is
proposing to take regulatory action in three general areas:
1) generation of additional data; 2) modifying the terms and
conditions of registration for the uses of dimethoate; and
3) cancellation of selected high risk application practices
and high risk formulations.
1) Generation of additional data
Option 6 identifies data gaps in the areas of chronic
health studies and worker exposure. The option provides a
mechanism for the generation of additional oncogenicity,
mutagenicity, neurotoxicity and exposure data, as discussed
-1 38-
-------
in Section VI, in a timely manner for a reassessment of
human risk if this additional data indicates such a
reassessment to be necessary.
2) Altering selected application practices
Option 6 identifies selected application practices
which result in comparatively high risk, and proposes
specific changes in the terms and conditions of registration
to modify the practices and product labeling which have
the effect of reducing risk to acceptable levels without
significant impact upon benefits.
3) Cancellation of selected high risk application
practices and formulations
Option 6 identifies specific air blast application
situations (citrus, pome fruits and pecans) and formulations
(dusts) which result in unacceptably high exposure and
consequent ri sks.
C. Use Situations not Addressed In This Analysis
Dimethoate is used in a variety of situations not
analyzed in this position document, such as minor and
specialty crop uses, general fly control, etc. The USDA/EPA
Assessment Team on Dimethoate did not identify these as
major/high volume uses nor as uses resulting in high worker
exposure. Because these are minor/low volume uses of
dimethoate the Agency assumes that comparatively few indivi-
duals will be exposed and those who are exposed will be
exposed to relatively low levels of dimethoate and, therefore,
will experience low risk.
139
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The Agency makes this assumption based on the
exposure and risk figures derived for the high volume/high
exposure uses discussed in sections II.B and II.C. (3)-
Even in the case of high volume uses, with the exception of
certain air blast application situations, exposure and risk
are relatively low. Therefore, in the case of low volume/minor
use situations exposure and risk is expected to be even
lower than that of the high volume/high exposure uses.
Because the Agency ha3 determined that risk is acceptable
(when protective clothing, etc., is used) in the high
volume/high exposure uses it follows that risk would
also be acceptable in the low volume/low exposure use
patterns not analyzed in this Position Document if the same
protective measures are required. Therefore, the Agency
proposes to continue the registration of all uses not
analyzed. The Agency points out, however, that all changes
in use pattern practices identified in Section IV (e.g.
protective clothing, respirators, etc.) shall apply to all
minor uses not analyzed in this Position Document.
VI. Additional Testing Requirements
The Agency has identified several areas requiring
additional testing. Registrants are hereby directed
to submit such data as discussed below (FIFRA, 3(c)(2)(b)).
140
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A. Oncogenicity
As discussed in sections II.A (1) and II.C (1) the
evidence for oncogenicity is suggestive and warrants further
study. Therefore, the Agency hereby directs registrants to
conduct an oncogenicity bioassay using dimethoate in the
same strains of mice and rats as that of the Gibel study.
This study shall be completed and submitted within three
years of the Agency's final determination (Position Document
4) concerning this chemical. Protocols for this study shall
be submitted to the Agency within 3 months of the publication
of the final Notice of Determination for dimethoate.
B. Mutagenicity
As discussed in section II. C (2) insufficient data
exists upon which to base a mutagenicity risk assessment.
The Agency concludes, therefore, that additional testing is
required. The Agency hereby directs registrants to provide
adequate test data concerning dimethoate's ability to cause
gene mutations in animal cells. Registrants shall also
conduct a dominant lethal study in mice as well as studies
designed to detect spindle effects which may result in
numerical chromosomal aberrations. Protocals for these
studies shall be submitted to the Agency within 3 months of
the publication of the final Notice of Determination
for dimethoate. Tests shall be completed and submitted
-141-
-------
within eighteen months of the publication of the final
Notice of Determination for dimethoate. In addition,
further testing may be required based on the results of the
studies discussed above in order to properly evaluate
mutagenic potential and or risk.
C- Delayed Neurotoxicity
As discussed in Dimethoate Position Document 1 (EPA
1977) and in section II.A (4)(a) of this document, insuffi-
cient data is available to determine whether dimethoate can
induce delayed neurotoxic effects. Therefore, the Agency
hereby directs registrants to conduct appropriate neurotoxi-
city testing in accordance with the final registration
guidelines. Protocols for these studies shall be submitted
to the Agency within 3 months of the publication of the
final Notice of Determination for dimethoate. These tests
shall be completed and submitted within eighteen months of
the promulgation of the final registration guidelines.
D. Applicator Exposure Data
As discussed in section IV.C (4) there is insufficient
applicator exposure data concerning air blast application
situations to determine whether there are sufficient margins
of safety for reproductive/teratogenic effects. The Agency
hereby directs registrants to conduct appropriate field
142
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studies to determine worker exposure (dermal and inhalation)
during application of dimethoate using air blast type
application equipment. Registrants shall gather such data for
each crop where air blast equipment is used or on crops deemed
representative of such applicator exposure situations.
Registrants shall submit to EPA proposed test protocols for
gathering applicator exposure data within three months of the
Agency's ftnal determination and shall complete all such
tests and submit all exposure data within eighteen months of
the Agency's final Notice of Determination concerning this
chemi cal.
14 3
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Dimethoate: Position Document 2/3
References*
Agarwal, K.B., H.N. Mehrotra, and B.K. Paul. 1973.
Effect of organic insecticides on cytology of bean
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•Copies of non-copyrighted references will be provided
on request. There will be a charge to cover duplication
costs for such requests. A copy of the Position Document
and all references are available for inspection in the
Special Pesticide Review Division (TS-791)» Office of
Pesticide Programs, Environmental Protection Agency,
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149
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to William Waugh, Project Manager, SPRD.
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9
150
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Memo. 1978d. Mutagenicity of dimethoate [undated draft
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)
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t 1979- From Julian Donoso, Chemist, HED to William Waugh,
> Project Manager, SPRD.
I
Memo. 1979d. Economic impact analysis of cancelling air
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151
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1979- From H.W. Gaede, Supervisory Economist, BFSD to
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