S027? 101
REPORT DOCUMENTATION *ETOR1 NO-
PAGE
i EPA/SPRD-81/33	
4. Title end Subtitle
Dimethoate: Position Document 4
5. Report £>*!•
7- Authop(s)
9. Performing Organliation Name »nd Address
Special Pesticide Review Division
Environmental Protection Agency
Crysta1 Mai 1 #2
Arlington, V A
12. Sponsoring Organization Name and Address
Environmental Protection Agency
401 K St. S.W.
Washington, D.C. 20460
8, Performing Organisation Rept. No.
10.	Project/Task/Work Unit No.
11,	Contreet(C) or Grant(G) No
(C)
m
13. Type of Report & Period Covered
14.
IS. Supplementary Notes
16. Abstract 
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Dimethoate: Position Document
Acknowledgements
4
Carolyn K. Offut, Project Manager, SPRD, OPP
Patrick Miller, Project Manager, SPRD, OPP
Delores S. Henderson, Typing Support, SPRD, OPP
Rose Henderson, Typing Support, SPRD, OPP
Harvey Warnick, Section Head, SPRD, OPP
Frank Parsons, Branch Chief, SPRD, OPP (RETIRED)
Kevin Keaney, Branch Chief, SPRD, OPP
EPA Pro.ject Support Team
E. David Thomas, ASIB, BFSD, OPP
Harold Gaede, EAB, BFSD, OPP
Dave Severn, EFB, HED, OPP
William L. Burnam, TB, HED, OPP
Irving Mauer, TB, HED, OPP
William Schneider, TB, HED, OPP
David Coppage, EEB, HED, OPP
Julian Donoso, RCB, HED, OPP
Cara Jablon, OGC
EPA Pesticide Chemical Review Committee (PCRC)
Marcia Williams, Chairperson, SPRD, OPP
Charles N. Gregg, OWWM
Richard N. Hill, OPTS
Allen L. Jennings, SRD, OPM
Donna R. Kuroda, OHEE, ORD
John J. Neylan, PTSED, OE
Raymond Smith, OANR
Michael Winer, OGC

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Dimethoate PD 4
Table of Contents
Page No.
Final Notice of Determination Concluding Rebuttable
Presumption Against Registration and Continued Registra-
tion of Pesticide Products Containing Dimethoate				1
I.	Introduction		2
FIFRA Comments on Dimethoate PD 2/3		7
USDA Comments on Dimethoate PD 2/3		15
II.	Analysis of Comments		IB
A. Comments Relating to Risk		18
1.	Summary of the Agency's Risk Position
in PD 2/3			18
2.	Oncogenicity Risk		20
a.	Summary of Laboratory Animal Studies
Cited in PD 2/3		20
i. Gibel et al., 1973		20
ii. The National Cancer Institute		23
iii. Steiglitz et al., 197*1		28
b.	The Agency's Conclusions in PD 2/3
Regarding the Requirement of an Additional
Oncogenicity Study		28
c.	Comments on Requiring an Additional
Oncogenicity Study		29
d.	The Agency's PD 4 Response		30
3.	Teratogenic, Reproductive and Fetotoxic Effects..	31
a. Summary of Laboratory Animal Studies
Cited in PD 1		31
i. Budreau and Singh, 1973		31
ii. Scheufler, 1975		32
iii. The American Cyanamid Co., 1965		33

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Page No.
b.	Summary of Additional Laboratory Animal
Studies Cited in PD 2/3; Khera (undated).. 33
c.	The Agency's Conclusion in PD 2/3
Regarding General Reproductive and
Fetotoxic Effects and Teratogenic Effects.. 36
d.	Comments on No Observed Effect Level
(NOEL)		36
e.	The Agency's PD 1 Response		36
f.	Comments on the Need for Additional
Reproductive Studies		38
g.	The Agency's PD 4 Response		38
h.	Comments on the Khera (undated) Study		38 -
i.	The Agency's PD 4 Response		39
j. Comments on Wavy Ribs		40
k. The Agency's PD 4 Response		4C
4. Mutagenicity Risk				40
a.	Summary of Studies Cited in PD 1 on
Dimethoate-Induced Mutations in Sub-
Mammalian Test Systems		40
i. Fahrig, 1973		40
ii. Hanna and Dyer, 1975		41
iii. Mohn, 1973		41
iv. American Cyanaaid Co., 1977		41
v. Shirasu et al., 1976		41
vi. Agarwal et al., 1976		42
vii. Amer and Farah, 1974		42
b.	Dimethoate-Induced Mutations in Mammalian
Test Systems		43

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— i i i —
Page No.
i. Gerstengarbe, 1975	 ^3
ii. Bhunya and Behera, 1975	 43
c.	The Agency's Conclusion in PD 2/3 Regarding
Additional Mutagenicity Studies	 44
d.	Comment Contending That Dimethoate is Not
Mutagenic in the Ames System	 4 5
e.	The Agency's PD 4 Response	 45
f.	Comments on the Agency's Requirement of
a Dominant Lethal Test			 46
g.	The Agency's PD 4 Response	 47
5.	Delayed Neurotoxicity..	 47
a.	Summary of Laboratory Animal Studies Cited
in PD 1: American Cyanamid Co., 1965	 47
b.	The Agency's Conclusion in PD 2/3 Regarding
Delayed Neurotoxicity Testing	 48
c.	Comments on the Agency's Requirement for
Another Delayed Neurotoxicity Study	 48
d.	The Agency's PD 4 Response	 4Q
6.	Exposure Analysis-Dietary Exposure	 51
a.	The Agency's Exposure Calculation in
PD 2/3	 51
b.	Comment on the Agency's Calculation of
Dietary Exposure	 51
c.	The Agency's PD 4 Response	 51
7.	Exposure Analysis-Occupational Exposure	 54
a.	The Agency's Occupational Exposure
Calculations in PD 2/3	 54
b.	Comments on the Inadequacy of the Data
Used to Estimate the Potential Exposure
of Air Blast Applicators	 61

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Page No.
c.	The Agency's PD 4 Heapor.se	 61
d.	Comments on a University of California at
Riverside Field Monitoring Study of Appli-
cator Exposure to Organophosphate Pesticides
.Resulting from Use of Oscillating Boom
Sprayers and Air Blast Equipment	 62
e.	The Agency's PD 4 Response	 64
8. Risks of Alternatives to Dimethoate	 64
a.	Summary of the Agency's Toxicology Review
of Alternatives to Dimethoate	 64
b.	Comments on the Risks of Alternatives to
Dimethoate			 68
c.	The Agency's PD 4 Response	 70
B. Comments Relating to Benefits	 88
1.	Summary of the Agency's Benefit Analysis
in PD 2/3	 88
2.	Summary and Analysis of Comments Received
on PD 2/3	 91
a.	Air Blast Application of Dimethoate
for Citrus, Pome Fruit, and Pecans	 91
i. Comments on.the Need for and
Extent of Air Blast Application
for Citrus, Pome Fruit,
and Pecans	 91
ii. The Agenoy's PD 4 Response	 94
b.	Citrus	 95
i. Comments on Air Blast Application
of Dimethoate for Control of
Aphids and Citrus Thrips	 95
ii. The Agency's PD 4 Response	 95
c.	Pome Fruits	 96

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Page No.
i. Comments on the Use of Dimethoate
for Control of Rosy Apple Aphias... 96
ii. The Agency's PD « Response	 97
iii. Comments Regarding the Registra-
tion of Phosphamidon Having
Been Withdrawn	 9 8
iv. The Agency's PD 4 Response	 98
d. Pecans	.			 98
i. Comments on the Impact of a Minor
Increase in the Cost of Pecan
Production	 98
ii. The Agency's PD 4 Response	 98
C. Comments Relating to Regulatory Options	 99
1.	Summary of the Agency's Regulatory Options
in PD 2/3	 99
2.	Summary and Analysis of Comments Received
on PD 2/3	 102
a.	Cancel Dust Formulations	 102
i. Summary of the Agency's
Conclusions in PD 2/3	 102
ii. Comments on Cancellation of Dust
Formulations	 102
iii. The Agency's PD 1 Response	 103
b.	Require Protective Clothing and
Equipment	.	 103
i. Summary of the Agency's
Conclusion in PD 2/3	 103
ii. Comments on Requiring Protective
Clothing for Applicators of All
Dimethoate Products and All Uses... 103

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Page No.
iii. The Agency's PD 4 Response	 105
c.	Require Automatic Flagging	 110
i. Summary of the Agency's
Conclusion in PD 2/3			 HO
ii. Comments Opposing the Use of
Automatic Flagging Devices	 111
iii. The Agency's PD 4 Response	 11*1
d.	Prohibit Air Blast Application on Citrus,
Pone Fruits, and Pecans	 114
i. Summary of the Agency's
Conclusion in PD 2/3	 114
ii. Comments on Exposure with
Air Blast Application for
Citrus, Pome Fruit, and Pecans
Compared to Alternative
Application Techniques....	115
iii. The Agency's PD 4 Response....	 117
e. Warning Statement for Female Applicators	 118
i. Summary of the Agency's
Conclusion in PD 2/3	 118
ii. Comment on Requiring a More
Direct Warning	 119
iii. The Agency's PD 4 Response	119
iv. Comment Urging the Agency to
Withdraw Statement to Female
Applicators.....			 120
v. The Agency's PD 4 Response	120
D. Comments Relating to Testing Requirements	 120
1.	Summary of the Agency's PD 2/3 Position	120
2.	Summary and Analysis of Comments Received
on PD 2/3	 123

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Fage No.
a.	Oncogenicity Testing	 123
i. The Agency's Position in PD 2/3.... 123
ii. Comments Objecting to Additional
Oncogenicity Testing	 123
iii. The Agency's PD 4 Response...	 123
b.	Reproduction Testing	 124
i. The Agency's Position in PD 2/3.... 124
ii. Comments Indicating the Need for
Additional Reproductive Studies.... 124
iii. The Agency's PD 4 Response	 125
c.	Mutagenicity Testing	 125
i. The Agency's Position in PD 2/3.... 125
ii. Comments Requesting that the
Spindle Effects Testing
Requirement Be Delected	 125
iii. The Agency's PD 4 Response	125
iv. Comments Urging the Use of
Mutagenicity Tests Presently
Proposed in the Pesticide
Registration Guidelines	 126
v. The Agency's PD 4 Response	 126
vi. Comments Recommending that
Muragenic Assays be Conducted
in Accordance with the SAP
Recommendations on the Guidelines.. 127
vii. The Agency's PD 4 Response..	 128
viii. Comments suggesting that the SAP
Recommendations on Spindle Effects
be Followed	 128
ix. The Agency's PD 4 Response	 128

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Page No.
x. Comments on Using 3one Marrow
Derived Cells in Spindle Effect
Assay	 129
xi. The Agency's PD 4 Response	129
d.	Delayed-Neurotoxicity Testing	 129
i. The Agency's Position in PD 2/3... . 129
ii. Comments Urging Re-evaluation of
the Requirement for Another
Delayed Neurotoxicity Study	 129
iii. The Agency's PD 4 Response	 129
e.	Applicator Exposure Studies	 130
i. The Agency's Position on PD 2/3. ... 130
ii. Comments on Additional
Applicator Exposure Studies	130
iii. The Agency's PD 4 Response	131
III. Conclusions	 132
Bibliography - Dimethoate PD 4	 138

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ENVIRONMENTAL
{OPP
PESTICIDE PRODUCTS
PROTECTION
}
CONTAINING
AGENCY
DIMETHOATE
FINAL NOTICE OF DETERMINATION CONCLUDING REBUTTABLE
PRESUMPTION AGAINST REGISTRATION AND CONTINUED REGISTRATION
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
SUMMARY: This Notice provides the Dimethoate Position
Document 4 supporting the Notice of Intent to Cancel Regis-
trations and Deny Applications for Registration for Pesticide
Products Containing Dimethoate, which is published elsewhere
in this issue of the FEDERAL REGISTER. Position Document 4
represents the final stage of the Agency's review of this
chemical under the Rebuttable Presumption Against Registration
Process. The Notice of Intent to Cancel Registrations and
Deny Applications for Registration of Pesticide Products
Containing Dimethoate describes the procedures for challenging
the regulatory actions taken by the Agency concerning
dimethoate.
FOR FURTHER INFORMATION CONTACT:
Harvey Warnick,
Environmental Protection Agency,
Special Pesticide Review Division (TS-791),
Office of Pesticide Programs,
Room 728D, Crystal Mall i2,
1921 Jefferson Davis Highway,
Arlington, Virginia 22202.

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SUPPLEMENTAHY INFORMATION:
I. INTRODUCTION
Under the Federal Insecticide, Fungicide, and Rodenticide
Act (FIFRA), as amended (7 U.S.C. 136 et seq.), the Environmental
Protection Agency (EPA or "the Agency") regulates all
pesticide products. Section 6(b) of FIFRA authorizes the
Administrator of EPA to issue a notice of intent (1) to
cancel the registration or (2) to change the classification
of a pesticide product, if in his judgment either the
pesticide or its labeling "does not comply with the provisions
of (FIFRA) or, when used in accordance with widespread and
commonly recognized practice, generally causes unreasonable
adverse effects on the environment...." FIFRA, section
3(c)(6), authorizes the Administrator to deny any application
for pesticide registration which does not meet the statutory
standards for registration.
To implement its authorized functions, the Agency has
designed the Rebuttable Presumption Against Registration
(RPAR) process (described in MO CFR 162.11), which involves
gathering data on the risks and benefits associated with the
use of suspect pesticides. By allowing all interested
parties to participate by submitting information, the
process enables EPA to make balanced decisions concerning
problem pesticides.

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The Agency published an RPAR notice in the FEDERAL
REGISTER of September 12, 1977 (42 FR 45086) for all pesticide
products containing dimethoate, an organophosphate insecticide
and acaricide, thereby initiating the Agency's public review
of the risks and benefits of dimethoate. The RPAR notice
cited three risk criteria which dimethoate had met or
exceeded. These three risk criteria were oncogenic effects
in test animals (40 CFR 162.11(a)(3)(ii)(A)), mutagenic
effects (multi-test evidence) (40 CFR 162.11(a)(3)(ii)(A)),
and reproductive and fetotoxic effects in test animals
(40 CFR 162.11(a)(3)(ii)(B)). A detailed Position Document 1
accompanied the September 12, 1977 notice.
The Agency issued a Preliminary Notice of Determination
concluding the Rebuttable Presumption Against Registration
of Pesticide Products containing Dimethoate and announced
the availability of Position Document 2/3 in the FEDERAL
REGISTER of November 19, 1979 (44 FR 66558). In Position
Document 2/3, the Agency analyzed the rebuttals it received
in response to the original RPAR notice, presented its
analysis of both risks and benefits associated with the
uses of dimethoate, and proposed a decision to aonclude the
RPAR process.
The Agency determined, in PD 2/3, that the information
submitted to rebut the risk criteria for oncogenicity,
mutagenicity, and reproductive and fetotoxic effects

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was insufficient to overcome the presumption against
dimethoate for these effects. In addition the Agency
received new teratogenic data, unavailable when PD 1
was issued, indicating that dimethoate posed a potential
teratogenic hazard. This new information was presented and
evaluated in PD 2/3 and the Agency concluded in PD 2/3 that
teratogenicity was an additional risk of concern for dimethoate.
In the Preliminary Notice of Determination, the
Agency determined that the risks arising from certain
uses of dimethoate are greater than the benefits of those
uses, unless risks are reduced by modifying certain terms
and conditions of registration. The Agency determined that
these modifications would significantly reduce risk without
significantly impacting on the benefits of the uses.
The modifications to the terms and conditions of
registration of dimethoate products proposed by the Agency
in the Preliminary Notice of Determination included:
(1)	Cancellation of dust formulations.
(2)	Label changes to require the use of protective
clothing and respirators.
(3)	Label changes to require automatic flagging for
aerial application.
(4)	Label changes to prohibit air blast application
on citrus, pome fruits, and pecans.

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(5) Label changes to include a warning to female
workers, using air blast equipment, of the potential
teratogenic effects of dimethoate.
In addition, the Agency determined that registrants
must submit data in the areas of oncogenicity, mutagenicity,
delayed neurotoxicity, and applicator exposure pursuant to
FIFRA sections 3(e)(2)(B).
FIFRA requires the Agency to submit notices issued
pursuant to section 6 to the Secretary of Agriculture for
comment and to provide the Secretary of Agriculture with an
analysis of the impact of the proposed action on the agricul-
tural economy under section 6(b). The statute also requires
the Administrator to submit notices issued pursuant to
section 6 to a Scientific Advisory Panel (SAP) for comment
on the impact of the proposed action on health and the
environment, at the same time and under the same procedures
as those described for review by the Secretary of Agriculture
under section 25(d).
Although not required to do so under the statute, the
Agency decided that it is consistent with the general
theme of the RPAB process and the Agency's overall policy of
open decision-making to afford registrants and other
interested persons an opportunity to comment on the bases
for the proposed action during the time that the proposed
action is under review by the Secretary of Agriculture and

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the SAP. AccoFdingiy, the Preliminary Notice and PD 2/3
were made available to registrants and ether interested
persons at the time the decision documents were transmitted
for formal external review. The Preliminary Notice was
published in the FEDERAL REGISTER; interested persons were
notified that PD 2/3 was available through publication of a
Notice of Availability in the FEDERAL REGISTER. Registrants
and other interested persons were allowed the same period of
time to comment, 30 days, that the statute provides for
receipt of comments from the Secretary of Agriculture and
the SAP.
The Agency received comments from thirteen (13) parties,
including the USDA and the SAP, in response to the notice of
November 19, 1979. The comments are addressed and analyzed
in Chapter II of this document. Chapter III summarizes the
Agency's final determination concerning pesticide products
containing dimethoate. SAP and USDA's responses are reproduced
in their entirety at the end of this chapter. All comments
are available for review in the public file located in the
Document Control Office, Rm. E-447, 401 M St., S.W., Washington,
D.C. 20460.

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F IF RA SCIENTIFIC ADVISORY PAN'EL
REVIEW OF PRELIMINARY NOTICE OF DETERMINA-
TION CONCLUDING THE REBUTTABLE PRESUMPTION
AGAINST REGISTRATION (RPAR) OF PRODUCTS
CONTAINING DIMETHOATE
The Federal Insecticide, Fungicide, and
Rodenticide Act (FIFRA) Scientific
Advisory Panel has completed review of
plans by the Environmental Protection
Agency (EPA) for initiation of regulatory
action on dimethoate pesticide products
pursuant to section 6(b)(1) of FIFRA, as
amended. The review was conducted during
open meetings held in Arlington, Virginia,
during the periods November 29, 1979,
and January 17-18, 1980.
Maximum public participation was encouraged
for the review. FEDERAL REGISTER notices
of Panel meetings concerned with the
review of dimethoate were published on
November 14, 1979 and November 27, 1979.
In addition, telephonic calls and
special mailings were sent to members of
the general public who had previously
expressed an interest in activities
of the Panel. Written and oral statements
(page 7a follow)

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ucre received from EPA technical staff
and from representatives of the American
Cyanacid Company. In addition, oral
comments were received from Mr. Harold
Alfred of the Pesticide Impact Assessment
Program, University of California.
Informal comments were also received
from Mr. Harold H. Collins of the
National Agricultural Aviation Association.
The Panel wishes to recognize the
excellent support provided by the Agency
during review of dimethoate. The
superb presentation of the Agency
position on dimethoate by Ms. Marcia
Williams, Mr. William Waugh, and other
EPA technical staff enabled the Panel to
concentrate on central issues and avoid
lost time from problems of communication.
Additionally, the Panel wishes to
commend the Agency for exhibiting an
excellent spirit of cooperation in
making available relevant references and
background data on dimethoate in advance
of the meeting.
In consideration of all matters brought
out during the meeting and careful

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reviev of all documents submitted by
the Agency and other parties, the Panel
unanimously submits the following
report.
Panel Position on Dimethoate
Question 1« What is the significance of
W8vy ribs in teratology studies such as
those conducted by Khera (unpublished)?
It has been noted that these effects
(wavy ribs) are often observed when the
embryotoxic or fetotoxic dose is approached.
Are wavy ribs a true teratogenic effect?
Answer. The Panel is unable to confirm
that wavy ribs are a true teratogenic
effect. Additionally, the Panel is
unable to assess the significance of
wavy ribs in studies conducted by Khera.
Appropriate scientific data was not
presented to the Panel for proper
assessment of the topics outlined in
number 1.
Question 2. What is the significance of
Polydactyly observed by Khera (unpublished)?
Ansver. The significance of Polydactyly
cannot be properly assessed. The Panel
is unaware of data which clearly relates
(page 8a follow?)

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-8a-
thc phenor.onon of Polydactyly as a
dose-related toxicological manifestation
which Is well documented in the literature¦
In Khera's study It Is Impossible to
deternine whether Polydactyly was an
effect attributable to the agent
or whether it was a background effect.
Question 3. In calculating the dietary
exposure for the general population, the
Agency assumed dimethoate residues to be
present at tolerance levels. Tolerance
levels were used because actual residue
data were not available. The Agency
then added this dietary exposure to
anticipated occupational exposure to
arrive at total applicator exposure.
The Agency noted, however, that the oral
exposure component, based on residues at
tolerance levels, was in many cases
greater than the occupational component
and that the exposure figures for
occupational exposure (without the
dietary component) most closely approximated
actual exposure. Vas the Agency correct
in its conclusion that applicator
exposure, without oral exposure, most

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closely approximates actual applicator
exposure? Given the available data, can
the SAP propose another method of
estimating applicator exposure for
dimethoate?
Answer. The Panel could not adequately
respond to all the facet6 of this
question because of time constraints
during the meeting. However, several
possible approaches for better definition
of huaan exposure were suggested. In
general, the Panel agrees with the
approach utilized by the Agency, but
wishes to point out that in view of the
blodegradabillty of dimethoate it is
unlikely that the dietary level for this
compound will approach tolerance levels.
Additionally, the Panel recommends that
appropriate field human monitoring
studies be conducted to determine
applicator exposure levels. Such
studies are technically feasible and
should be considered as the best means
to characterize potential hazards in
humans•
(page 9a follows)

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Question A. Docs the SAP agree with the
Agency's conclusion concerning the
mutagenic risk froo dimethoate?
Answer. Yes! The Panel concurs with
the Agency that the mutagenic risk is
low and that strong regulatory action
is not warranted.
Ques tion 5. Does the SAP agree that an
additional oncogenicity study is required
to answer the question concerning the
oncogenic potential of dimethoate?
Answer¦ Ho! The Agency's proposal to
require an additional oncogenicity study
because of a study done abroad which is
not interpretable does not seem co
be a valid undertaking. The Panel is of
the opinion that the NCI bioassay study
was a valid test for the oncogenic
potential of dimethoate. This is
reinforced by the fact that dimethoate
is an organophosphorus compound and that
this class of pesticides are not known
to be carcinogenic. Although the NCI
study had flavs, the problem is that
there is no such thing as a completely
satisfactory test. Every test is

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flawcd. It is a question of degree.
The Panel docs not believe that the ."."CI
study was flaved to the point where it
is of no value in regulatory action.
This position was also taken by the
Carcinogen Assessment Group (CAC) of the
Age ncy.
Proposed Regulatory Action
The Panel concurs with the Agency'6
proposed regulatory action on dimethoate
except as specifically noted below.
Exception 1. Prohibiition of Che
conventional use of human flaggers to
mark swaths in aerial spraying and
associated requirement for uae of
automatic flagging devices*
Panel comment. The Panel rejects this
proposal on the basis that insufficient
research has been accomplished to
illustrate that the technique would be
an effective regulatory procedure to
reduce risks to man and the environ"
nent. To institute such a requirement
aerosB the board without determining the
limitations of the procedure in various
agricultural situations would appear to
(page 10a follows)

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-10a-
be inadvisable. The Panel recognizes Che
potential usefulness of such devices,
but recommends chat the Agency not make
their use an absolute requirement until
appropriate research has been completed
to ensure that sucli devices are practical
tools for reducing risks in spray
applications. Additionally, the Panel
encourages the Agency to promote research
on flagging devices to expedite their
development and availability to farmers.
Except ion 2. Agency proposal to preclude
use of air-blast equipment on citrus,
pecans, and pome fruits.
Panel comment. The Panel does not
support this proposal on Che basis that
appropriate data is lacking to adequately
compare applicator exposure from use of
air-blast equipment vith exposure
resulting from use of oscillating boos
type sprayers. Additionally, the Panel
is avare that a high number of farmers
prefer the use of air-blast equipment
and If dlmethoate is not available then
It is likely that substitute pesticides
which may be more hazardous may be

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selectcd for use in air-blast equipment.
Testimony was given by a representative
from the State of California relative to
planned research with disethoate in the
near future to assess applicator exposure
from air-blast equipment in comparison
with oscillating boom type sprayers.
The Panel requested that his research
plans to be expanded to ensure examination
of urine samples to gain insight on
possible absorption of pesticides by
applicators. This will provide data not
only on the agent, but also the mechanism
of application.
It is Important to emphasize that
dime thoate is a valuable pesticide
component of integrated pest management
(IPM) programs for citrus insect pests
and that such programs are almost
totally based around the use of air-blast .
equipment to apply reduced dosages and
selective coverage.
Additional Testing Requirements
The Panel concurs with the Agency's
position relative to p.daitional testing
requirements with the following specific
exceptions and comments.

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Excgption 1. Oncogenicity testir.£--Thc
panel considers the National Cancer
Institute study on dimethoate to be
a valid assessment of the oncogenic
potential of dinethoate. Additional
studies are not considered essential.
Exception 2. Mutagenicity testing—The
Panel concurs that additional mutagenicity
testing is needed to properly assess the
mutagenic potential of dinethoate*
However, to ensure appropriate assessment
the Panel recommends that mutagenic
assays be conducted in accordance with
recommendations previously submitted by
the Panel to the Agency (May 31, 1978;
Review of Proposed Rulemaking on
Subpart F, Guidelines for Registering
Pesticides in the United States).
Additionally, the Panel suggests that
the Agency follow the recommendation
previously submitted by the Panel on
tests to assess the potential for
spindle effects (November 30, 1979 -
Review of FIFRA section 6(b)(1) action
on Benomyl and Thiophonate-methy1). The
Panel also recommends consideration of

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the use of bone marrow derived cells in
assays for spindle effects.
Exception 3. Delayed Neurotoxicity
Studies--The Panel requests the Agency
reevaluate the need for additional
delayed neurotoxicity studies in view of
research reported by T.B. Gaines 1969,
entitled "Acute Toxicity of Pesticides"
(Toxicology and Applied Pharmacology
Vol. 14, 515-534). No paralysis was
observed by Dr. Gaines in tests conducted
with diaethoate.
Exception 4. Reproductive Tests--The
Panel recommends that the Agency require
additional reproductive tests on diaethoate.
The Panel notes positive effects in two
studies on reproduction iaplying the
possibility of effects on nales. Therefore,
ve suggest that the Agency require a
reproductive test to determine dose-response
effects on females (e.g., prevalence of
pregnancy, pre and post implantation
loss, survival and growth of young,

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etc.) and or. nalcs (c . p. • » spcriatoscncsis,
seainal vesicle size, etc.).
DATE: February 7, 1980
FOR THE CHAIRMAN:
H. Wade Fowler, Jr., Ph.D.
Executive Secretary,
FIFRA Scientific Advisory Panel

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-14-
U.S. DEPARTMENT OF AGRICULTURE COMMENTS
U.S. Department of Agriculture
Office of Environmental Quality
Washington, D.C. 20250
December 12, 1979
Mr. Edwin L. Johnson,
Deputy Assitant Adminstrator
for Pesticide Programs
U.S. Environmental Protection Agency
Washington, D.C. 20460.
Dear Mr. Johnson:
This is in response to your letter of
November 8, forwarding the U.S. Environmen-
tal Protection Agency's (EPA) preliminary
notice of determination concluding
the rebuttable presumption against
registration (RPAR) and the proposed
notice of intent to cancel and/cr modify
the terms and conditions of registration
of pesticide products containing dimethoate.
After interacting with EPA in the
development of the biological, economic,
and exposure Information on dlmethoate,
ve are pleased to review and comment on
the preliminary notice of determination
and the accompanying position document*
We concur with the decision to continue
registration of dlmethoate on field

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-15-
crops, grains, grapes, curtain minor
and/or specialty crops, livestock
premises, forest seed orchards, nurseries,
ornamentals, vegetables, and for fly
control. We also agree with the decision
to cancel registrations for use in dust
f o rmulat i o as.
The USDA supports the proposed modification
of labeling to include statements
requiring protective clothing and
equipment for application. This action
is in concert with the USDA/EPA joint
publication, "Apply Pesticides Correctly,
a Guide for Commercial Applicators."
With regards to the proposed requirement
for automatic flagging when dimethoate
is aerially applied, we encourage
EPA to maintain the full range of
options to minimize exposure. This could
continue the registrations and might
involve label statements requiring
protective clothing and equipment to
minimize exposure flaggers may experience.
We feel that studies should be done to
indicate actual exposure to dimethoate

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by all workers in the aerial application
process.
We also have reservations regarding the
cancellation of dimethoate use on
citrus, pone fruits and pecans when
It is applied by air blast equipment.
Growers have Indicated that equipment of
this nature is essential for adequate
application to these commodities.
Otherwise, more frequent, less effective
applications would be required. The
general term, "air blast equipment",
needs a more precise definition in fully
interpreting this regulatory option. Ve
are prepared to cooperate with EPA to
develop directions to provide for
minimal exposure In these situations.
Regarding the warning to female workers,
we believe that all persons including,
and perhaps especially, those who are
pregnant should always endeavor to avoid
or reduce exposure to all pesticides.
If EPA wishes to alert female workers
using air blast equipment of possible
hazards resulting from exposure to

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diraethoate durinn pregnancy, we suggest
that a more direct warning such as
"Pregnant women should avoid exposure"
would be more effective.
We are dedicated to the mutual resolution
of issues concerning the health of farm
workers and the general public as well
as issues affecting crop production
and the environment*
Sincerely,
Barry R. Flamxa,
Director.

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II. ANALYSIS OF COMMENTS
In response to the issuance of the Preliminary Notice
of Determination and Position Document 2/3 on November 10,
1979, and the publication in the FEDERAL REGISTER of November
19, 1979 (44 FR 66558) of a Notice of Availability for
Position Document 2/3, the Agency received comments from the
Secretary of Agriculture, the SAP, and 11 other concerned
individuals and organizations. These comments are organized
by topic and discussed in this section. Except as discussed,
the Agency has not changed any other aspect of its analysis
presented in Position Document 2/3.
A. Comments Relating to Risk
1. Summary of the Agency's Risk Position in PD 2/3.
The Agency's qualitative and quantit£tive risk assessment is
based on its evaluation of the hazard of dimethoate in
conjunction with a best estimate of the potential for human
and environmental exposure.
The potential for human and environmental exposure to
dimethoate was derived from available data and assump-
tions about work place practices, current agricultural
practices, dietary habits, body weight, breathing rates,
dermal exposure, similarity of application techniques, etc.
The exposure figures obtained represent the Agency's best
estimate of the exposure potential of dimethoate. Although
there are uncertainties in these estimates, they permit a

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19
rough calculation of risk to the population at large and
population subgroups, such as applicators or flaggers, with
specific exposure potential. They also permit comparison of
risk from dimethoate with that posed by other pesticides
which are used as alternatives to dimethoate.
The dimethoate RPAR was based on information indicating
that dimethoate posed the following risks to humans:
(1) oncogenicity, (2) mutagenicity, and (3) reproductive
and fetotoxic effects.
In Position Document 2/3 the Agency determined that
the information submitted to rebut the risk criteria for
oncogenicity was insufficient to overcome the presumption
against dimethoate for this effect. However, the Agency
concluded, based on a re-analysis of the studies involved
and the rebuttal comments, that the weight of evidence
for dimethoate's carcinogenicity is only suggestive, and
that the evidence warrants further studies.
The Agency also determined that the rebuttal submissions
were insufficient to remove the Agency's concern that
dimethoate poses the risks of reproductive and fetotoxic
effects to humans. In addition, new teratogenic data (Khera,
undated), unavailable when the RPAR was issued, were
submitted. These data indicate the potential of dimethoate
to produce teratogenic effects.
The Agency further determined that the rebuttals
and additional information submitted did not invalidate the

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-20-
mutagenicity risk presumption. However, the Agency concluded
that the risk appears to be low and that additional test
data are necessary to evaluate the quantitative mutagenic
risk of this compound.
The Agency received comments concerning delayed
neurotoxicity and the synergism of dimethoate with other
pesticides, and concluded that there is insufficient
evidence to indicate that dimethoate meets or exceeds
the risk criteria enumerated in 40 CFR 162.11 for these
effects, but that additional information concerning
dimethoate's ability to induce delayed neurotoxicity must
be generated.
The Agency determined that the principal risks of
oncogenicity, mutagenicity, and reproductive and fetotoxic,
and teratogenic effects are posed to applicators, who may be
exposed to dimethoate before or during application through
both inhalation of and dermal contact with the pesticide.
The greatest risk to applicators is incurred by (1) the
ground application of dust formulations on grapes, and
(2) air blast spraying of citrus, pecans, and pome fruits.
2. Oncogenicity Risk—a. Summary of Laboratory Animal
Studies Cited in PD 1 — i. Gibel et al., 1973. Gibel et al.
(1973) studied the effects of dimethoate on 10-week-old
Wistar rats of both sexes. FoFty animals per group were
employed in the study. Fresh solutions of dimethoate

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were made at the time of administration to limit hydrolysis.
The compound was given twice weekly by gavage at 5, 15, and
30 mg/kg dose levels. One other group of animals was given
15 mg/kg intra-muscularly.
Animals were weighed at regular intervals. Only
the animals that lived 3 months in the study and showed no
post mortem changes were examined histologically. Blood and
bone marrow were also examined.
Treated animals showed strong hyperplasis of the
blood forming parenchyma of the bone marrow involving
erythropoesis, granulopesis, and megakaryopoesis. Nonbony
myeloid metaplasia was seen primarily in the liver and
spleen in 59 percent of the treated animals. In addition,
granulocytosis was found in 22 percent of the animals.
There was a significant increase in the incidence
of benign and malignant tumors among treated animals at the
30 mg/kg dose level for oral administration and at the 15
mg/kg dose level for intra-muscular administration. In
addition, there was a significant linear trend (p<0.01) for
the oral route. (See Table 1).

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TABLE 1 - Incidence of tumors In rats treated with dlmethpate
bose milligrams
per kilogram
houte
Average
surv ival
(days)
Benign
Tumors
Malignant
Tumors
p values
0
oral
*17 3
3/3b
0/36
-
5
oral
518
7/26
2/26
-
15
oral
511
5/25
3/25
-
30
oral
627
2/25
1/25®'
0.0132
\
0
Intra-
muscular
711
1/35
0/35
-
15
Intra-
muscular
570
5/30
6/30^
0.0072
a/ 1 liver sarcoma, Imallgnant reticulosis, and 2 sarcomas of the spleen.
b/ 1 sarcoma of the spleen, 1 soft tissue sarcoma, 1 ovarian sarooma, 1 reticulum
cell sarcoma, 1 spleen sarcoma, and 1 liver sarcoma.

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-23-
Gibel et al. (1973) also studied the effects of aimethoate
on mice. Percutaneous application of fresh solutions of
dimetnoate was given twice a week for six weeks on shaved
back skin of AB mice of both sexes; the animals survived for
only 270 days. Five animals out of 19 showed malignant
tumors, of which there were four leukoses and one breast
carcinoma. The spleen showed considerable metaplasia
with often complete atrophy of white pulp. The follicles of
the white pulp showed a loose narrow lymphocytic mantle
around the central arteries. The trabecular framework of
the spleen was generally narrowed and reduced. 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 mice
also developed the myeloproliferative syndrome similar to
that observed in rats.
The benign tumors observed in the control animals
were exclusively fibroadenoma of the breast. The authors
did not mention the incidence of malignant tumors in controls
but implied that they did not find any malignant tumors in
the control animals.
ii. The National Cancer Institute. 19T7. In 1977 the
National Cancer Institute (NCI) completed a feeding study
with dimethoate (NCI, 1977 5 . Osbome-Mendel rats of both
sexes, 35 days old, were administered 250 and 125 parts per

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-24-
raillion (ppm) dimethoate in the diet. After 19 days the
doses were reduced to half and the treatment was continued
for an additional 61 weeks. The animals were observed for
115 weeks. The treatment groups consisted of 50 animals of
each sex, and the matched controls consisted of 10 animals.
Hatched controls for aldrin, chlordane, dichlorvos, dieldrin,
and heptachlor were used for evaluation because these
studies were carried out concurrently with the dimethoate
feeding study. Complete histopathology was carried out on
all the animals. 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
pathological evaluation of this study was done at Gulf South
Research Institute. A summary of the survival data and
number of tumor-bearing animals is shown in Table 2.

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TABLE 2 - Dlmethoate chronic feeding study - number and survival of tumor-bearing rat.3
Sex	bosage Group ' Effective dumber Percent frercenl surviving (weeks)
Number—^	TBA-'	5278 115-^
Male
Pooled Control
58
36
62
92
87
47
Hale
Matched Control
10
7
70
100
80
30
Male
Low
50
23
46
98
96
72
Male
High
19
24
49
92
82
58
Female
Pooled Control
60
13
72
97
95
73
Female
Matched Control
10
7
70
100
100
90
Female
Low
17
30
64
98
92
74
Female
High
45
21
47
88
67
51
a/ Total
number of rats in
itially piaoed on
test
minus the number in
ilssing
or autolyzed.

b/ Number
of tumor-bearing
rats.





c/ Denominator for survival percentages was
killed for diagnostic purposes. No animals
the
were
original number of animals
accidentally killed, and
minus those
none were

missing. Study terminated at 115 weeks.

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-26-
NCI (1977) also studied the effects of dimethoate
on 36C3F hybrid mice which were 35 days old. The compound
was administered in the diet at 250 and 500 ppm dose levels,
and the feeding was continued for 69 and 60 weeks, respectively.
Animals were observed for an additional 2U and 3^ weeks
respectively, before sacrifice. All of the animals were
necropsied and examined histopathologically, The data were
statistically analyzed for each organ and tumor type. No
dose-related increase in tumor incidence by site or total in
either sex was found. The pathological evaluation of this
study was carried out at Gul.f South Research Institute. The
data for total-tumor bearing animals are summarized in Table 3-

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K '
TABLE 3 - Dlmethoate chronic feeding study - number and survival oftumor-bearlng mice
Sex	Dosage Group feffeclive dumber freroent percent:" surviving ^weeks)
Number®'	TBA-'	52	70	90s'
Male
Pooled Control
96
31
32 91
92
85
Male
Matched Control
7
6
86 100
100
86
Male
Low
50
11
22 98
81
82
Male
High
50
11
22 96
96
92
Female
Pooled Control
80
11
18 96
90
83
Female
Matched Control
10
3
30 90
90
70
Female
Low
50
15
30 96
96
90
Female
High
19
12
21 91
91
90
a/ total
number of mice initially placed on
test
minus the number missing
or autolyzed.

b/. Number
of tumor-bearing
mice.




c/. Denominator for survival percentages was
billed for diagnostic purposes. No animals
the
were
original number of animals
accidentally killed, and
minus those
none were

missing. Study terminated at 90 weeks.

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-28-
iii. Steiglitz et al. . 1974. Steiglitz et al. (1974)
studied the hematotoxic effects of dimethcate in rats.
Dimethoate was administered to 10-week-cld Wistar rats in
doses of 5, 10, and 15 mg/kg body weight by oral intubation.
Another group was given an intra-muscular dose of 15 mg/kg.
Each test group consisted of 40 animals with two control
groups of 40 animals each. The most important hematological
results included pronounced hyperplasia of the hematopoietic
parenchyma in the bone marrow, and sometimes strong, extraos-
seous myeloid metaplasia. Hyperplasia in the bone marrow
occurred at different levels in all three hematopoietic cell
systems with preferential involvement of granuiocytopoiesis.
Leukocytosis of varying intensity in the peripheral blood
was also found but mainly affected granulocytes. The
highest value exceeded 50,000/ul. The Agency did not base
it RPAR on this third study because the study lacked sufficient
detail. However, the Agency requested registrants and other
interested parties to submit to the Agency information on
these, or similar, effects of dimethoate.
b. The Agency's Conclusion in PD 2/3 Regarding the
Requirement of an Additional Oncogenicity Study. In Position
Document 2/3, the Agency concluded that the rebuttals did
not invalidate the oncogenic risk criterion cited in the
RPAR notice. However, based on re-analysis of the studies
Involved and the rebuttal comments as a whole, the Agency

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-29-
concluded in Position Document 2/3 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.
c. Comments on Requiring an Additional Oncogenicity
Study. The Scientific Advisory Panel (SAP), in its formal
comments, disagreed with the Agency position to require an
additional oncogenicity study. The SAP stated that the
National Cancer Institute bioassay study (NCI, 1977) was a
valid test for the oncogenic potential of jlimethoate.
Although the test was flawed, the SAP did not believe that
t
the NCI study was flawed to the point where it is of no
value in regulatory action. The SAP claimed that this
position was alsc taken by the Agency's Carcinogen Assessment
Group (CAG). For a discussion of flaws in the NCI (1977)
study, see pages 64-66 of the Agency's Position Document 2/3
for Dimethoate and also pages 40 and 41 of the "Transcript
of Proceedings" FIFRA Scientific Advisory Panel, Arlington,
Virginia, November 29, 1979.
American Cyanamid [7(30000/16c)] argued that supportive
evidence is lacking for determining that dimethoate is an
oncogen. American Cyanamid further argued that conclusions
made in the Gibel et al. (1973) study were based on inappropri-
ately grouped data and that the National Cancer Institute
study (NCI, 1977) is an adequate assessment of the oncogenic

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-30-
potential of dimethoate. American Cyanamid urged the Agency
to accept the position taken by the Scientific Advisory
Panel.
d. The Agency's PD 4 Response. The Agency's CAG
(Albert, R.E. , 1980) provided an additional response to the
comments from SAP and American Cyanamid on the oncogenicity
position in Position Document 2/3. wherein the Agency
disagreed with the SAP position that further testing of
dimethoate is not needed. The CAG indicated that if there
were no other relevant considerations, then the negative NCI
bioassay, flawed though it is, in conjunction with a lack of
carcinogenicity of organic phosphate pesticides in general,
might make further testing of dimethoate unnecessary.
However, in the case of dimethoate there is substantial
evidence for mutagenicity of dimethoate, coupled with
suggestive evidence for carcinogenicity in the Gibel et al.
(1973) study which was done on Wistar rats. The NCI bioassay
(NCI, 1977) involved a different strain of rats, namely, the
Osborne-Mendel rat. Furthermore, in these two studies there
was clear evidence of hematopoietic toxicity in the Wistar
rat but not in the Osborne-Mendel rat, thus indicating the
possibility of a different metabolic handling of dimethoate
or a difference in target-organ susceptibility in the two
strains. In its response to the SAP recommendations the CAG
emphasized (Albert, R.E., 1980), that it is not comfortable

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-31-
with the SA? position that no further oncogenicity testing
of dinethcate be required.
Therefore, the Agency rejects the positions of SAP and
American Cyanamid that there is sufficient evidence to
determine that dimethoate is not an oncogen. Moreover,
in order to more fully ascertain whether or not dimethoate
poses a risk of oncogenicity, the Agency will require that a
limited bioassay be conducted on the Wistar rat at the
highest dose level used in the Gibel study (30 mg/kg by
stomach gavage twice a week).
3. Teratogenic. Reproductive and Fetotoxic Effects
Risk—a. Summary of Laboratory Animal Studies Cited in
PD 1—i. Budreau and Singh, 1973. Budreau and Singh (1973)
studied the effect of dimethoate on the reproduction of
Charles River CD-I mice. The insecticide was added to
drinking water at the rate of 60 ppm (1/6 the LD^q) for
five generations. Reproductive performance was evaluated by
mating success and reproduction time. Mating success was
calculated as the proportion of the females mated that had
litters, expressed in percentages. Reproduction time was
the number of elapsed days from the first day when the
females were presented to the male to the day of delivery.
The authors stated that dimethoate treatment significantly
reduced mating success and increased reproduction time.

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Seccnd litter mating success ranged from 33 to
61% (p<0.01) and treated females required significantly
longer periods than controls (p<0.01) to produce first
litters in all generations. Survival rate of total pups
and litters was significantly reduced (p<0.01) in genera-
tions I, III, IV, and V. Histologic examination of the
mammary glands of treated females with high newborn mortality
showed the glands were well developed and contained milk.
The growth rate of dimethoate-treated pups usually fell
behind that of controls, from day 12 after birth. On day
28, average weight was not always significantly different
from controls, mainly because low-weight pups died.
ii. Scheufler, 1975. Scheufler (1975) administered a
single 40 mg/kg dose of dimethoate, intraperitoneally, to
female AB Jena/Halle mice on the day of conception. On the
ninth day of pregnancy the author observed a significant
increase in the number of dead embryos (p<0.01). When
dimethoate was injected daily, at 40 mg/kg during the first
14 days of pregnancy, four times as many implanted embryos
died in comparison to controls. When 40 mg/kg of dimethoate
was administered to female C57BL mice, the number of nonpreg-
nant females was increased to 70% as compared to 20 to 30%
for controls. When dimethoate was applied to DBA-mice, 50%
of the mated females showed no embryos. The author suggested
that dimethoate appears to hinder strongly the development
of embryos prior to implantation.

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-33-
iii. The American Cyanamid Co., 1965. The American
Cyanamid Co (1965(a)) conducted a three generation feeding
study to determine whether dimethoate would interfere with
reproduction or lactation. Albino mice of the CF1 strain
were fed diets containing 5, 15, 50, and 0 (control) ppm of
dimethoate. Animals were approximately one month old at the
start of the test. Weaned pups were fed the same diets as
their parents.
For mating purposes one male and two females were housed
together. Females were housed alone while they cast and
weaned their litters, after which parent animals were mated
again. There were two mating periods. The report concluded
that "reproduction and lactation performance was good for
all groups".
b. Summary of Additional Laboratory Animal Study Cited
in PD 2/3: Khera (undated). New data (Khera undated)
showing a dimethoate formulation to be a mild teratogenic
agent was received by the Agency after the RPAR was issued.
Khera (undated) 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
per day of Cygon IE 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.

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-34.
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
(ps0.05, Student's t 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.
There were no anomalies noted at 3 or 6 mg/kg and hence
a no-observed effect level for all parameters can be set at
6 mg/kg per day of Cygon 4E. The author (Khera) indicated
that the teratogenic effect observed in this study 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.
The same dimethoate formulation, Cygon 4E, was tested at
doses of Q, 3, 6, 12, or 24 mg/kg per day (corresponding to
0, 1.4, 2.8, 5.7, or 11.3 mg/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

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-35-
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 of 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 fetuses examined and the number of litters
having at least one anomalous fetus/number of litters
examined, when compared to controls.
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 nof minor types and of unknown significance".
It should be noted that these effects (wavy ribs), which are
often considered indicators that the the embryotoxic or
fetotoxic dose is approached, occurred at either the maternal
toxic dose or one-half of that dose.
In both studies by Khera, the no-observed effect
level was 6 nig/kg per day for Cygon IE (2.8 mg/kg per day
dioethoate). The oocursance of minor teratogenic effects at
higher doses indicates that Cygon ME has the potential to
interfere with fetal development. Additional studies are

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-36-
required to fully determine the significance of these
findings.
c.	The Agency's Conclusion in PD 2/3 Regarding General
Reproduction and Fetotoxic Effects and Teratogenic Effects.
In Position Document 2/?3» the Agency reviewed the rebuttals
and additional information submitted (Courtney, K. D., 1978;
and Khera, undated). Based on that evaluation, the Agency
concluded that the rebuttals did not invalidate th.e Agency's
original presumption of risk on general reproductive effects
or on fetotoxic effects based on the three studies (Budreau
and Singh, 1973; Scheufler, 1975(a); and American Cyanamid
Co., 1965a) cited in the RPAR notice. In addition, the new
study (Khera, undated) showed Cygon 4E, a dimethoate formula-
tion containing 47.3} dimethoate, to be a mild teratogenic
agent.
d.	Comments on No Observed Effect Level (NOEL).
American Cyanamid [7(30000/16c)] commented that the Budreau
and Singh (1973) study established an effect level and that
for a study to be useful in a risk assessment prooess a no
observable effect level (NOEL) must be established. American
Cyanamid then recommended that the NOEL of 50 ppm in the
diet obtained in their own study (American Cyanamid, 1965a)
be used for risk assessment.
e« The Agency's PD 4 Response. The Agency agrees that
the Budreau and Singh (1973) study is unacceptable for risk

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-37-
assessment, but rejects the recommendation that the NOEL of
50 ppm obtained in the American Cyanamid Study (1965a) be
used for risk assessment of dimethoate. Budreau and Singh
(1973) observed effects on reproduction at 60 ppm, the only
dose level tested. A no observed effect level was not be
established. American Cyanamid (1965a) observed no effects
in their reproduction study in which three dose levels (5
ppm, 15 ppm, and 50 ppm) were used. Although this study
used more than one dose level, none of the doses produced a
significant reproductive effect and thus a no observed
effect level could not be established.
In the absence of a no-effect level for reproductive
effects per se, the Agency will use the NOEL of 2.8 mg/kg
per day from the Khera study for the risk assessment of all
reproductive effects, including fetotoxic and teratogenic
effects, as well as fertility related reproductive effects.
The Agency believes this approach is justifiable
because its concern extends to all adverse reproductive
effects (including teratogenicity, fetotoxic, and reproductive
effects such as reduced fertility) that may result from
exposure to dimethoate. Since the effects in Khera1s
(undated), teratogenicity study were observed at lower levels
than effects in the reproductive studies, the use of the
no-effect level from the teratogenicity study will provide
ample protection for reproductive as well as teratogenic
fetotoxic effects.

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f• Comments on the Meed for Additional Reproductive
Studies. The SAP, in its formal comments, indicated that
additional reproductive studies are necessary to assess the
effect of dimethoate on male reproduction. The Panel noted
positive effects in two studies on reproduction, implying
the possibility of effects on males.
g.	The Agency's PD 4 Response. The Agency believes
that American Cyanamid's multi-generation reproduction study
which showed no adverse effects in males is sufficient to
establish that dimethoate does not have a significant
potential to adversely effect male reproduction. However,
the Agency will require additional teratology studies on the
technical dimethoate in 2 species of laboratory animals as
specified in the proposed guidelines (FR 43, No. 163.
Tuesday, August 22, 1978).
h.	Comments on the Khera (undated) Study. American
Cyanamid [7(30000/l6c)] indicated that:
(1)	No dose-response effect was noted in either
the cat or rat teratology study by Khera.
(2)	The only response noted was in the high dose group
and consisted of an increase in a common anomaly; i.e., wavy
ribs in rats and Polydactyly In cats.
(3)	Dr. Khera, himself, concluded "from the data
available, it cannot be definitely ascertained whether
treatment with 12 mg Cygon 4E per kg has in any way contributed
to the expression of Polydactyly."

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-39-
i. The Agency's PD Response. In response to the
first point, the Agency noted that, in the rat study, there
was a definite do3e-response relationship in terms of a
statistically significant increase in the number of litters
with anomalous fetuses. Looking at each particular anomaly,
there was a signficant increase in the number of fetuses
having wavy ribs and a non-significant increase in fetuses
having extra ribs at a dose level of 12 mg/kg Cygon 4E.
In response to American Cyanamid's second point,
the Agency has concluded that its concern is not alleviated
because the adverse effect noted wa3 merely an increase in
the background rate of normally occurring anomalies. The
occurrence of minor teratogenic effects at higher doses
indicates that Cygon 4E has the potential to interfere with
fetal development. The increase in minor anomalies indicates
that dimethaote may pose a potential to produce adverse
fetotoxic or teratogenic effects in humans.
Cn the third point, the Agency notes that, in the
Khera study, a statistically significant increse in anomalies
occurred at 12 rag/kg Cygon 4E when compared to the controls.
Although the data from the Khera 3tudy is limited and does
not a3se33 the potential for dimethoate to produce fetotoxic/
teratogenic effects at a range of dose levels, this data
does suggest that dimethoate may have the potential to
interfere with normal fetal development.

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-40-
j« Comments on Wavy Rib3. The SAP, in its formal
comments, commented on the teratogenic studies and was
unable to confirm that wavy ribs are a true teratogenic
effect.
k. The Agency's PD 4 Response. The Agency has concluded
that the difference between a "true" teratogenic effect and
an increase in minor anomalies which occur at a normal
background rate should not be relevant for regulatory
purposes. The increased incidence of minor teratogenic
effects indicates that dimethoate may have the potential to
interfere with fetal development. Hence, the Agency's
concern about possible adverse effects to the population at
risk is not diminished. Until such time as the Agency is
able to establish that the adverse effects noted in the
Khera study do not indicate a potential risk for humans, the
Agency will treat these effects as warranting regulatory
concern.
Mutagenicity Riks—a. Summary of Studies Cited
in PD 1 on Dimethoate-Induced Mutations in Submammalian Test
Systems—i. Fahrig, 1973. Fahrig (1973) treated cultures
of Saccharomyces aerevisiae with dimethoate at seven dosage
levels (ranging from 40 mM to 100 mM). The author(s) did
not indicate whether a metabolic activation system had been
included in the test procedures. An induction of mitotic
gone conversions, demonstrating a positive mutagenic effect
was observed.

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-41-
ii.	Hanna and Dyer, 1975. Hanna and Dyer (1975) tested
dimethoate in two bacterial systems by adding 5 to 10 ul of
dimethoate to a layer of the bacterial strain. Positive
results were observed in two strains of Escherichia coli
(E. , coli WP2 uvrA and E. coli WP 67). Negative results
were seen in several E. coli and Salmonella typhimurium
strains.
iii.	Mohn, 1973. Mohn (1973) studied the effect of
dimethoate in _E. coli K-12/galRsl8. Dimethoate was shown to
have mutagenic activity. A significant dose-response
relationship was obtained using five dosage levels (from 1
to 6 X 1Q~^M). The author(s) did not indicate whether a
metabolic activation system had been included in the test
procedures.
iv.	American Cyanamid Co., 1977. American Cyanamid Co.
(1977) investigated the mutagenic potential of dimethoate
using several strains of S_. typhimurium and one strain of E_.
coli. Rat liver microsomal enzymes (S-9) were used for
metabolic activation. Ho mutagenic effects were observed.
Doses ranged from 20 to 100 ug/plate.
v.	Shirasu et al., 1976. Shirasu et al. (1976) studied
the mutagenic effect of dimethoate in the H17 Rec* and
R45~ strains of Bacillus subtilis. No mutagenic activity
was observed under the conditions of the study. The dose of
dimethoate used was not given.

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-42-
vi.	Agarwal et al., 1973. Agarwal et al. (1973)
studied the effect of dimethoate on seed setting and germina-
tion in the bean (Phaseolus vulgaris). Dimethoate in
concentrations of 0.1 and 0.5% by volume were used as foliar
sprays on bean plants in four observation plots. The
spraying was done at the time of bud initiation. Seeds wetre
then collected and soaked up to 46 hours at room temperature.
Dimethoate reduced germination 23 to 28% below controls.
Chromosomal abnormalities including fragments, stickness,
and anaphase bridge formation were seen in 12.8 to 27.5% of
the treated series. No abnormalities were seen in the
controls.
vii.	Amer and Farah. 197**. Amer and Farah (1974)
studied the cytological effects of dimethoate on cotton
(Gossypium barbadense) and beans (Vicia faba). Bean 3eed3
were treated at concentrations of 0.5, 0.25, 0.125, and
0.0625% using both pure and formulated (solution containing
40% active ingredient) dimethoate. Cotton seeds were
treated with the formulated product at concentrations of
0.25, 0.125, and 0.0625% dimethoate. Both pure and formulated
dimethoate greatly inhibited cell division in beans. The
mitotic index for bean seeds treated with pure dimethoate
ranged from 18.4 (0.5% dimethoate) to 62.6 (0.625% dimethoate)
compared with a mitotic index of 94.1 for controls. The
mitotic index for beans treated with formulated dimethoate

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-43-
ranged from 8.0 (0.25J dimethoate) to 42.0 (0.0625% dimethoate)
compared with 56.4 for controls. Chromosomal abnormalities
were also observed for all treated seeds. The percentage of
abnormal mitoses in beans induced by formulated dimethoate
was much higher than that induced by pure dimethoate.
b. Summary of Studies Cited in PD 1 on Dimethoate-Induced
Mutations in Mammalian Test Systems-~i. Gerstengarbe, 1975.
Gerstengarbe (1975) investigated the ability of dimethoate
to induce dominant-lethal mutations in the mouse (Mus
auaculus)¦ Dimethoate was administered intraperitoneally to
male mice of an inbred, AB Jena/Halle strain. One set of
mice received a one-time dose of 80 mg/kg, while another
group received 6.66 mg/kg daily for 30 days. The treated
males were then paired with untreated females. The number
of implantations, resorptions, and living and dead fetuses
on the eighteenth day of gestation was determined. The
living fetuses were weighed and separated according to
sex. A signficant increase in the resorption rate was
detected, indicating damage during spermiogenesis. A
significant increase was observed in the mutation index
indicating that dimethoate, in the case of. AB Jena/Halle
mice, induces dominant-lethal mutations and is capable of
reaching germinal tissue.
ii. Bhunya and 3enera, 1975. Ehunya and 3ehera (1975)
injected adults of both sexes of the mouse (Mus musculus)

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-44-
with 1 cc/100 g body weight of dimethoate (0.5 and 1.0%
solutions). Control animals were injected with distilled
water. Standard cytological slides were prepared from bone
marrow cells of animals sacrificed at 24, 48, and 72 hours
after treatment. The authors stated that in the treated
animals, in addition to other aberrations, centromeric
fission and stretching were predominant. The number of
chromosomes with breakage at the centromere ranged from 1 to
38 per cell. The frequency of aberrations was highest at 24
hours, moderate at 48 hours, and least after 72 hours for
both doses tested. Aberration rates in control animals were
not reported.
c. The Agency's Conclusion in PS 2/3 Regarding Additional
Mutagencity Studies. After reviewing the comments and
rebuttals on the mutagenicity risk presumption, the Agency
concluded in PD 2/3 that the risk had not been rebutted.
Section II c(2) of Position Document 2/3 presented an
analysis of the mutagenicity studies on dimethoate and
attempted to draw conclusions relative to human risk from
dimethoate's ability to induce mutagenic effects. The
Agency concluded that since insufficient data exist upon
which to base a mutagenicity risk assessment, additional
studies are required to estimate the magnitude of the
risk.

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45-
d.	Comment Contending that Dimethoate is not Mutagenic
in the Ames System. In response to the Agency's RPAR Notice
(PD 1) for dimethoate, American Cyanamid Co. submitted a
bacterial assay as their rebuttal (Rebuttal Comment 30000^16:#5A).
American Cyanamid Co. used coli WP-2 uvrA" in their
assay and found that "Dimethoate was not mutagenic" even
at "extremely high dose3". 3ased on their study, American
Cyanmid Co. stated that dimethoate is a non-mutagen because
of it3 "potency" of less than 0.01 revertants/nanomole.
In its Preliminary Notice of Determination Concluding
the RPAR for Dimethoate (PD 2/3), the Agency rejected the
American Cyanamid Co. rebuttal attempt. In their comments
C7 (30OOO/^16c) ] in response to PD 2/3» American Cyanamid Co.
reaffirmed their contention that dimethoate is not mutagenic
in the Ames System and that, based on McCann et al., 1975,
Cyanamid made a determination that chemicals having mutagenic
potencies of less than 0.01 revertants/nanomole can be
classified as non-mutagens in the bacterial Feverse mutation
assay.
e.	The Agency's PD 4 Response. American Cyanamid's
statement that dimethoate is a non-mutagen is not correct by
the criterion that it has a "potency" of less than 0.01
revertants/nanomole. The registrant was attempting to use a
cut-off point derived from an Ames test with a Salmonella
organism (McCann et al., 1975) to describe the potency for

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-45-
an _£. eoli test system in which a clear dose-response was
observed. Clearly, the level of revertants viewed as
indicating a positive response in one test species has
little relevance to the potency determination in a different
test system. The usually accepted criteria for a positive
in an Ames test is a doubling of the- background rate and a
dose-response effect. The important aspect of the £. coli
test in question here is the dose-response observed. The
potency level from the Salmonella sp. study i3 irrelevant.
Furthermore, this particular method of defining a
cut-off point, cited by American Cyanamid, was arbitrarily
chosen by McCann et al. (1975) in order to relate mutagenicity
to carcinogenicity and it appears only in the McCann et al.
(1975) paper. Other more recent methods of defining a
positive mutagenic response do no include any cutoff point
(DeSerres et al., 1979). DeSerres et al. (1979) is currently
considered to be the most valid protocol recommendation for
using the Salmonella/Microsome Mutagenicity Assay.
f. Comments on the Agency's Requirement of a Dominant
Lethal Test. American Cyanamid C7(30000/16c)] in their
comments on PD 2/3 stated that they have no comment on the
requirement for a dominant lethal test except to point out
that a recently published negative report using this procedure
to evaluate dimethoate in the mouse is available as an
abstract (Degraeve et al., 1979).

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-L7-
g. The Agency's PD 4 Response. The Agency has been
unable to cbtair. a copy of the Degraeve study and, therefore,
can not evaluate this study solely on the basis of an
abstract. The Agency will welcome any additional information
on the Degraeve et al. (1979) study, or any other dominant
lethal test using dimethcate, and will evaluate such informa-
tion upon its receipt.
5. Delayed Neurotoxicity--a. Summary of Laboratory
Ar.i.nal Studies Cited in PD 1: American Cyar.amid Co., 1965 .
American Cyar.amid Co. ( 1965b) performed demyeiinarion
studies for dimethcate and its oxygen analog, dimethoxon, in
white leghorn hens estimated to be 1 to 2 years of age.
Although the results appear to show that these chemicals did
r.ct cause myelin degeneration, s closer examination of these
reports indicates that the tests were inconclusive for the
following reasons:
(1)	An LDj-q fcr 2'4 hours, instead of 7 aay3, should
have beer, used in the tests.
(2)	Since hens were given th.e chemicals in their
feed, the dcse received by each hen was not accurately
known. Administration of tne test substance should nave
been cy ir.tubaticr. or gelatin capsule.
(5) Since maximum dcses cf only one-eignth
vers 2ccr.ir.isterec , celayec r.eurctixie effects may net
have d e v e1o ? e d.

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-48-
Th e regimen of the study wa3 such that the study
would not detect delayed neurotoxicity for some compounds
that have a known potential to cause this effect. Either
much higher doses, i.e., the maximally tolerated dose using
atropine, or sub-acute studies for longer periods of time
should have been used.
The Agency did not presume against dimethoate on
the basis of this study, but instead requested registrants
or other interested parties possessing information relevant
to dimethoate associated delayed neurotoxicity effects to
submit such data to the Agency.
b. The Agency's Conclusion in PD 2/3 Regarding Delayed
Neurotoxicity Testing. The Agency concluded in Position
Document 2/3f after reviewing comments submitted in response
to PD 1, 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 neurotoxic effects is warranted.
o, Comments on the Agency's Requirement for Another
Delayed Neurotoxicity Study. The SAP, in its formal comments,
requested the Agency to reevaluate the need for additional
delayed neurotoxicity studies in view of research reported
by T.B. Gaines (1969) entitled "Acute Toxicity of Pesticides"
in which no paralysis was observed in tests conducted with
dimethoate.

-------
49
d. The Agency's PD 4 Response. In response to the SAP
comment concerning the requirement for additional delayed
neurotoxicity studies, the Agency has reevaluated the
American Cyanamid delayed neurotoxicity studies (1965b) and
has reviewed the T.S. Gaines study (1969) entitled "Acute
Toxicity of Pesticides".
In the American Cyanamid Studies (1965b), the chemical
was administered in feed and the dosage received by each hen
was not accurately known. Since maximum doses of only
one-eighth the LD^q were administered, delayed neurotoxicity
effects may not have developed. These studies were inconclu-
sive with regard to dimethoate's delayed neurotoxic potential.
The T.B. Gaines (1969) study entitled "Acute Toxicity of
Pesticides" is primarily a report on the determination of
LE^q values for 98 pesticides and 2 metabolites of DDT
using adult Sherman strain rats treated with a single
dose of the test substance by the oral or dermal route. The
author only briefly reports on the screening tests for
paralytic effects in chicken hens treated with carbamate and
organic phosphorus pesticides.
The author stated that "The method for conducting
the screening tests for the paralytic effects of carbamate
and organic phorphorus pesticides in chickens was the same
as that described by Durham et al. (1956), with the exception
that many of the compounds reported in that paper were

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-50-
tested in White Leghorn chickens because of the unavailability
of the Rhode Island Red breed". The Gaines study indicates
that each test chicken was administered atropine sulfate in
water solution orally at a dosage level of 15 mg/kg to
protect them against the acute effects of the test substances.
9 carbamate and 30 organic phorphorus compounds, including
dimethoate, were tested for paralytic effects. Fifteen
minutes after administration of the atropine sulfate the
chickens were administered the test substance in peanut oil
solution or in suspension by subcutaneous injection under
the right wing. The chickens were checked daily for signs
of paralyis by placing them on the ground and observing
their ability to walk. The author reported that no paralysis
was observed in chickens dosed with dimethoate.
Several important details, such as the number of animals
used, the dosage level for the test substance, and whether
or not histopathology on nervous tissue was carried out,
were not given in the study.
After reevaluating both the American Cyanamid studies
(1965b) and the Gaines (1969) study the Agency concludes
that not enough data are available in these studies to make
a hazard determination. Therefore, the Agency will require
additional delayed neurotoxicity studies in order to
allow the Agency to make a hazard determination for delayed
neurotoxic effects due to exposure to dimethoate.

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-51-
6. Exposure Analysis - Dietary Exposure—a. The
Agency's Exposure Calculation in PD 2/3. The Agency, in
calculating a worst case estimate of the dietary exposure of
the general population to dimethoate in Position Document
2/3, assumed dimethoate residues to be present on food at
the tolerance levels. However, not all crops for which
dimethoate is registered are actually treated with dimethoate.
Therefore, in its calculation of a probable case estimate of
oral exposure, the Agency factored in the percentage of
crops actually treated with dimethoate.
b.	Comment on the Agency's Calculation of Dietary
Exposure. The SAP, in its formal comments, agreed, in
general, with the approach used by the Agency in calculating
dietary exposure, but added that in view of the biodegraaa-
bility of dimethoate it is unlikely that the dietary level
for this compound would approach tolerance levels.
c.	The Agency's PD 4 Response. The Agency agrees with
the SAP. In Position Document 2/3 the Agency stated that
"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. Therefore, it is likely that the Margin of
Safety (MOS) for general population risk is several orders
of magnitude higher than the 875 calculated as a probable
case. However, a lack of data concerning dimethoate residues

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-52-
at harvest precludes estimates of the actual MOS". Risk
from dietary exposure was not viewed by the Agency as a
problem in PD 2/3. A calculation of the dietary exposure
resulting from a single serving of selected food items
confirms that dietary exposure is not a problem. The SAP
has confirmed the Agency's belief that risk from dietary
exposure is not an issue of concern. See Table 4 below for
a comparison of the MOS (including dietary exposure) and the
MOS (excluding dietary exposure) for various users of
dimethoate.)

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Kn
Ui
CMP '
me"»	
SPRAYING
' SlAfi»	
raHBUtb' "
DERMAL AND
INHALATION
EXPOSURE
6hAL '—'
EXPOSURE
TCfrAL
EXPOSURE
H&S
(INCLUDING
ORAL iy
EXPOSURE K*
""MM "
(EXaUDING)
ORAL . .
EXPOSUREK-
Citrus
Ground
(air blast)
21
Appltoators-
Hlxers/loaders
0.39
0.0032
0.03932
7
7
Veg.
Fields
Air
Pilots
0.013
0.0032
0.0162
170
215
Veg.
Fields
Air
F1 aggers
0.013
0.0032
0.0162
170
215
Veg.
Fields
Air
Hlxers/
loaders
0.0062
0.0032
0.0094
298
452
Peoans
Ground
(air blast)
Applloators^'
Mxers/loaders
0.119
0.0032
0.122
23
24
Pone
Ground
(air blast)
Ccmnerolal
Applioators, Ino.
Hlxers/loaders
0.242
0.0032
0.215
12
12
Pane
Ground
Hose Sprayers
0.00017
0.0032
0.0034
823
16,471
Corn
Air
Pilots
0.0083
0.0032
0.012
233
337
Corn
Air
F1aggers
0.008
0.0032
0.011
255
350
Corn
Air
Hiiers/Loaders
0.0063
0.0032
0.010
280
444
Grape
Grouid
Boon highest
00 no.
0.0012
0.0032
0.0041
636
2,333
Grape
Gromd
Highest oona.
(oustom)
Copplestone
nodel
0.0207
0.0032
0.0239
117
135
Grape
Ground
Pust
0.130
0.0032
0-1332

2^3/
U Based on a 2.i} mg/kg
2/ Applicator Is also mixer/loader.
3/ Exposure via Inhalation.

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-54
7. Exposure Analysis - Occupational Exposure—a. The
Agency's Occupational Exposure Calculations in PD 2/3• In
Position Document 2/3 the Agency revised and expanded the
exposure analysis presented in Position Document 1.
The exposure analysis in PD 2/3 was developed for smaller
subpopulations engaged in the application of dimethoate, who
would experience greater exposure than that identified for
the general population. For example, 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 application, as well as ground application,
may be exposed both dermally and via inhalation. Estimates
of exposure to these subpopulations and the MOS for each
are presented in Table 5.

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TABI.E 5 - Estimates of exposure and margins of safety for various users of dlmethoate-'
1/
CROP
TVPL CF
SPRAYIHG
HQS FOR
SUBGROUP
Combined Dermal and
Inhalation DAILY
EXPOSURE (for fe- ORAL
male mg/kg/day)	EXPOSURE
TOTAL
EXPOSURE
HQS For
Terato-
genic p.
Effects^
in
in
corn
corn
corn
ornanental
ornunental
grai*
graj*
grape
cotton
cotrin
cotton
cotton
citrus
X/ "TratTTIf 2737
air
air
air
ground
ground
ground
ground
ground
air
air
ground
groind
air
pilots
flaggera
mlxers/1oaders
commercl al
high concentration
compressed air
lioine garden high
concentration
Boan highest cono.
highest
cone, (custom)
Coppie3lone model
dust
pilots
mixers/loaders
applicators
mixers/loaders
pilots, ground
crews, mixers/loaders
0.0083
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
o.oom
0.0239
0.1332
0.005
0.00
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TAUIE 5 - tall mates of exposure and margins of safety for various users of dlmettioate^
crop
TYPE CK
SPRAYING
KB FOR
SUBiNOUP
Combined Dermal and
Inhalation DAILY
EXPOSURE (for fe-
male mg/kg/day)
ORAL
EXPOSURE
TOTAL
EXPOSURE
HQS For
Terato-
gen^ p.
Effects-
cltru ,
grand
(air blast)
applIcators
mlxers/loaders
0.39
0.0032
0.3932
7
sorghum
Blr
saine as corn




veg. fields
(tcauato,
broccoli)
air
pilots
flaggera
mixers/loaders
0.013
0.013
0.0062
0.0032
0.0032
0.0032
0.0162
0.0162
0.0094
170
170
298
veg. (Fla)
ground
applicators
0.00005
0.0032
0.0033
B4B
vect r con-
trol (house
fly)
ground
applIcators
0.0019
0.0032
0.0051
. 549
forest pine
(seed or-
chard)
ground
applIcators
0.0008
0.0032
0.0040
700
pecan
til gh cono.
pecan
ground
groixid
(air blast)
podel
applIcators
mixers/loaders
applicators
nlxer3/loaders
0.00041
0.00022
0.119
0.0032
0.0032
0.0032
0.0036
0.00342
0.122
778
B19
23
safflower
air
side as corn




pane
ground
(air blast)
commercial applicators 0.242
Including mixers/loaders
0.0032
0.245
12
P0?"5..
ground
liose sprayers
0.00017
0.0032
0.0034

21 baaed on 2.8 NOtL (Khera mdaLed).

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-57-
The exposure analyses in PD 2/3 considered rebuttal
comments received in reponse to the RPAR notice, data froze
the USDA concerning use and use practices, published studies
concerning worker exposure to dimethoate and related pesticides,
and certain assumptions made by the Agency in the absence of
specific data on dimethoate.
There were no published data available to the Agency
showing the amount of dimethoate an applicator would
be exposed to during aerial application. However, exposure
data were available for another organophosphate, parathion.
Therefore, the Agency used exposure values reported for
parathion aerial application (Gordon et al., 1978) as a
model for estimating human exposure to dimethoate during
aerial application. The following rationale was given for
using parathion values to estimate dimethoate exposure:
(1)	The vapor pressure of parathion and dimethoate
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.).
(3)	The rates of aerial application of parathion and of
dimethoate are similar.

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Since exposure during aerial application can occur
via the respiratory and^or dermal route, the Agency made
calculations of applicator exposure via each of these
routes.
In calculating inhalation exposure, the Agency made
the following assumptions:
(1)	The ambient air concentrations observed for paEathion
(Gordon et al., 1978) are the same as dimethoate at each of
the various sampling sites (e.g., airplane cockpits).
(2)	The applicator's breathing rate will be 1.8 m^
per hour.
(3)	100* of all dimethoate inhaled will be absorbed.
(4)	The applicator will weigh 60 kg (adult female).
(5)	The applicator will wear no special protective
devices (e.g., respirator).
The Agency used the following equation in calculating
the respiratory exposure for dimethoate:
Respiratory Ambient air concentration of 1.8 cr^/hr	Number of
Exposure	dimethoate (ug/nr5) at the	(breathing	hours of
(ug/kg^day) = site in question	X rate)	X exposure/day
60 kg person
For the dermal exposure calculations the Agency made the
following assumptions:
(1) Dermal exposure observed for parathion skin patch
tests (Gordon et al., 1978) are the same for dimethoate.

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-59-
(2)	155 of the applicator's total skin surface will be
exposed.
(3)	10J of the dimethoate coming into contact with the
uncovered skin will be absorbed.
(H) The applicator will weigh 60 kg (adult female).
The following equation was used by the Agency in
calculating the dermal exposure to dimethoate:
Dermal	Concentration of	Number of
Exposure	dimethoate on the	?	hours exposed
(mg/kg/day) = skin (ug/an) X 3000 cm X 10J absorbed X per day
60 kg person
Specific data concerning applicator exposure to dimethoate
applied by boom type equipment in large agricultural
situations and by compressed air equipment (hand pump
sprayers) in home garden application situations in the
United States was not available to the Agency. However,
information concerning applicator exposure to dimethoate in
the Sudan was available (Copplestone et al., 1976). Therefore,
in PD 2/3 the Agency used the dermal and respiratory exposure
of spraymen to dimethoate reported by Copplestone et al.
(1976) as the basis for its calculations of applicator
exposure to dimethoate when boom and compressed air equipment
is used.

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-60-
Th e Agency used the following equations to calculate
the respiratory and dermal exposure resulting from the
ground application of dimethoate:
Respiratory exposure	Number of hours
Respiratory observed in Sudan cencentratin of dimethoate	spraying (USDA/
Exposure = (mg/hr) X used in the U .S.	X states/EPA
concentration of dimethoate	Assesanent Tean
used in the Sudan	on Dimethoate)
bO kg person
Dermal
Exposure
dermal exposure
observed in the-
Sudan (mg/cm/hr )
concentration of dimethoate
X used in the U.S.
concentration of dimethoate
used in the Sudan
X 105 absorption
50 kg person
Specific data concerning applicator exposure to dimethoate
applied by high volume air blast equipment (greater than 300
gal./A), such as that commonly used in citrus, pecans, and
pome fruit orchards, were not available to the Agency.
However, Wolfe et al. (1967) reported the dermal and respira-
tory exposure of workers to several selected pesticides, one
of which was parathion, using air blast equipment. In the
absence of specific dimethoate data, the Agency, in Position
Document 2/3. assumed the exposure values of workers applying
0.052 parathion emulsifiable concentration (E.C.) with air
blast equipment to be the same as that for workers applying
dimethoate. The Agency felt this assumption to be reasonable

-------
-61-
slnce both dimethoate and parathion are organophosphates and
both are emulsifiable concentrates applied at similar
concentrations.
The Agency concluded, in Position Document 2/3, that
potential occupational exposure was greatest for ground
applications of dust formulations on grapes and for ground
applications utilizing air blast equipment on citrus, pome
fruits, and pecans.
b.	Comments on the Inadequacy of the Data Used to
Estimate the Potential Exposure of Air Blast Applicators. A
number of commenters concluded that the data on which the
Agency relied in estimating the potential exposure of air
blast applicators were inadequate. American Cyanamid
[7(30000/160] and the University of California [8(30000/l6c)]
stated that the Copplestone (1976) study referred to in
Position Document 2/3 was an inappropriate model for air
blast exposure, since in that study dimethoate was applied
with a knapsack mist blower. The University of Arizona
[5(30000/16c)] commented that they are concerned about the
small amount of data on which the Agency relied, i.e. "an
old study in Washington State by Dr. Homer Wolfe, and an
incident in Sudan" (Wolfe, 1967 and Copplestone, 1976).
c.	The Agency's PD 4 Response. The Agency responds to
these comments regarding the inadequacy of the data relied
upon in PD 2/3 for estimating potential exposure of air

-------
-62-
blast applicators by pointing out, first of all, that the
data used in the air blast calculations were that of Wolfe
et al. (1967) and not that of Copplestone et al. (1976).
Wolfe et al. reported dermal and respiratory exposure of
workers to several selected pesticides, one of which was
parathion, using air blast equipment. Secondly, the Agency
did not have specific data on dimethoate exposure from air
blast application for calculating exposure in PD 2/3•
Therefore, in the absence of better information, the Agency
extrapolated Wolfe's results with parathion to dimethoate.
It is the Agency's opinion that the data were adequate for
such an extrapolation and that such an extrapolation was
reasonable since both dimethoate and parathion are organophos-
phates and both are emulsifiable concentrates applied at
similar concentrations.
d. Comments on a University of California at Riverside
Field Monitoring Study of Applicator Exposure to Organophosphate
Pesticides Resulting from Use of Oscillating Boom Sprayers
and Air Blast Equipment. The University of Arizona [5(300QQ/16c)],
in their comments on PD 2/3, stated that a study on air
blast sprayer driver exposure is underway at Riverside,
California. This commentor recommended that a decision on
air blast application be delayed until data from this study
are available for scientific review. Additionally, the
University of Arizona stated that it was their understanding
that the study would be completed by August 1980.

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-63-
The Scientific Advisory Panel, in its formal comments,
mentioned testimony by a representative from the State of
California relative to planned research in the near future,
with dimethoate, to assess applicator exposure from air
blast equipment in comparison with oscillating boom type
sprayers.
The University of California at Davis C8)30000/16c)]
stated, in their comments on FD 2/3, that "the Western
Region Pesticide Impact Assessment Program is funding a
study by Professors Gunther and Carman (University of
California, Riverside) to quantify the extent of occupational
exposure of pesticide applicators during actual spraying of
an organic phosphate insecticide on citrus trees. Those
studies will Involve measurements of pesticide vapors and
aerosols in the cab of the spray rig as a result of having
the windows opened, opened and closed on operator judgment
basis, and closed with and without air-conditioning. This
will determine whether operator judgment is sufficient to
limit pesticide exposure or whether a static cab or a more
sophisticated system involving charcoal filters and air-condi-
tioning units should be required. The principal investigators
are willing to expand the experimental design to permit
exposure comparisons between air blast and oscillating boom
applications, providing adequate funding is available".

-------
-64-
Th e California Citrus Quality Council [9(30000/16c)]
stated that "The citrus industry of California i3 supportive
of exposure studies now being undertaken at The Citrus
Research Center of the University of California in Riverside
to quantify applicator exposures associated with oscillating
boom equipment and would fully endorse an extension of these
studies to include evaluations with air blast equipped with
various provisions for applicator protection and operated
under variant field conditions'*.
e. The Agency'3 PD4 Response. The Agency agrees that
actual data on applicator exposure to dimethoate would be
more useful than estimates derived from an evaluation of
other organophosphate pesticides. The Agency understands
that the monitoring phase and the analysis of the data of
the current study at the University of California are likely
to be completed in early 1981. The Agency welcomes any
additional information resulting from the current study at
the University of California at Riverside.
8. Risk of Alternatives to Dimethoate—a. Summary of
the Agency's Toxicology Review of Alternatives to Dimethoate.
The Agency's purpose for reviewing alternatives for a
particular pesticide is not to make an in-depth review of an
alternative but to indicate whether or not suitable alterna-
tives exist at each use site for the pesticide in question.
In its toxicology review of the alternatives to dimethoate

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-65-
the Agency reviewed available toxicity data from published
and unpublished Substitute Chemical Program reports, proprie-
tary data from pesticide petitions, and published literature.
The basic conclusion of the Agency's review was that for the
sites in which dinethoate is used, there are many alternatives.
In FD 2/3 the Agency proposed the cancellation of
air blast application of dimethoate on citrus, pome fruit,
and pecans. When cancellation of a use is considered by
the Agency, a review of possible alternatives for the uses in
question is conducted. A summary of the Agency's toxicological
review of the alternatives for air blast application of
dinethoate in citrus, pome fruit, and pecans is given
below.
i. Alternatives to Dimethoate Use on Citrus. The
Agency considered malathion, phosphamidon, formetanate,
rotenone, demeton, mevinphos and parathion as the major
alternatives to dimethoate use on citrus.
1.	Malathion. Malathion is low in toxicity and has
not been shown to cause adverse reproductive effects when
tested in a teratology test. Recent National Cancer Institute
studies have indicated no significant carcinogenic potential
from malathion. Malathion was registered many years ago,
but adequate multi-generation studies have not been performed.
2.	Phosphamidon. Phosphamidon- is more acutely toxic
than dimethoate. A recent National Cancer Institute study

-------
-66-
indicated that phosphamidon was not carcinogenic in B6C3F1
mice but the data were insufficient to allow interpretation
in the rat. Data on reproductive effects are either
lacking or carried out at Industrial Bio-Test. Validation
of the Industrial Bio-Test studies has not been done.
Phosphamidon, like malathion, was registered a number of
years ago.
3.	Formetanate. Formetanate is a much more acutely
toxic compound than dimethoate with an oral	around 20
mg/kg. Although available data indicate no significant
adverse effects, the presence of Industrial Bio-Test data
limits the usefulness of these studies.
4.	Hotenone. Minimal data are available on rotenone's
reproductive effects. Preliminary data suggested that
rotenone was carcinogenic but evaluation of all of the
carcinogenicity data does not indicate an oncogenicity
hazard. Although there are some studies that indicate
potential teratogenic problems, these studies are seriously
flawed and need to be re-done before we can determine if
there is a teratogenicity problem.
5.	Demeton. Demeton is a highly toxic organophosphate
(acute oral	below 20 mg/kg). There appears to be no
multi-generation study and the only teratogenic study
seems inadequate to assess teratogenic or fetotoxic hazard.
No chronic or carcinogenic studies have been reported.

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-67-
6.	Mevinphos. Mevinphos, like demeton, is a highly
toxic organophosphate. Available teratogenic, reproduction,
and chronic studies indicate no adverse effects.
7.	Parathion. Parathion is a highly toxic organophosphate
by all routes of exposure. A recent oncogenic study by NCI
indicated positive findings. A preliminary risk assessment
on the oncogenic effects is being carried out.
ii. Alternatives to Dimethoate Use on Pome Fruit
(apples). The Agency considered cyhexatin (plictran),
guthion (azinphosmethyl), propargite, and demeton as alterna-
tives to dimethoate use on pone fruits.
1.	Cyhexatin. This compound has not demonstrated
any adverse effects in laboratory animals in chronic feeding
studies and reproduction and teratology studies.
2.	Azinphosmethyl (Guthion). Both guthion and demeton
are highly toxic organophosphates with acute oral LD^0
below 20 mg/kg. Guthion was not teratogenic or fetotoxic in
doses up to 5 mg/kg/day (the maternal toxic dose) in
rats or mice. A recent National Cancer Institute study
concluded that "under the conditions of this bioassay,
neoplasms of the thyroid and pancreatic islets suggest but
do not provide sufficient evidence for the carcinogenicity
of azinphosmethyl in male Osborne-Mendel rats. Azinphosmethyl
was not shown to be carcinogenic in female Osborne-Mendel
rats or in B6C3F1 mice of either sex". The Agency is

-------
-68-
reviewing this study and a risk assessment may be carried
out based on the positive oncogenic response.
3.	Propargite. This compound has not demonstrated any
adverse effects in laboratory animals in chronic feeding
studies and reproduction and teratology studies.
4.	Demeton. See write up under Citrus above.
iii. Alternatives to Dimethoate Use on Pecans. The
Agency considered phosalone and dialifor as alternatives to
dimethoate use on pecans.
1. Phosalone. Phosalone is slightly more acutely toxic
than dimethoate. The available data do not indicate that
this compound produces adverse reproduction or teratogenic
effects.
2* Dialifor. Dialifor caused no malformations in a
teratology test, but the systemic NOEL was 1.0 mg/kg. The
vast majority of toxicity data supporting dialifor was
carried out at Industrial Bio-Test and is still unvalidated.
Conclusions about the reliability of these data cannot be
made at this time.
b, Comments on the Risks of Alternatives to Dimethoate.
The SAP, in their formal comments, stated that it is
likely that substitute pesticides which may be more hazardous
than dimethoate may be selected for use in air blast equipment
if dimethoate is not available.

-------
-69-
The Cooperative Extension Service of the University
of Georgia ClA(3000Q/16c)], in their comments on PD 2/3,
stated that "while there are alternative materials (FR, p.
66560), most effective alternatives have a much higher acute
toxicity than dimethoate. This particularly will effect
small pecan growers and homeowners who have trees in areas -
where materials of high acute toxicity should not be used".
The Extension Service of Oregon State University
[y(3000/l6c)] and the Hood River Grower-Shipper Association,
Hood River, Oregon [6(3Q0Q0/16c)] stated, in their comments
on PD 2/3, "Dimethoate is one of only three systemic insecti-
cides registered for use on bearing apple trees. Of the
three, dimethoate has the lowest mammalian	toxicity
at 215 rag/kg, compared to 6.2 mg/kg for demeton (Systox) and
24 mg/kg for phosphamidon. This makes dimethoate the least
toxic systemic presently registered for use on apples".
American Cyanamid Co., [7(30000/16c)] commented that
"should the Agency cancel air blast application of dimethoate,
applications would most probably be made using parathion.
This alternative would be an unacceptably high risk situation".
The Cooperative Extension of the University of California
at Davis [8(30000/16c)] commented that California's treatment
guide for citrus crops lists six alternatives to dimethoate
for thrips control. The listed alternative materials are
sabadilla, parathion, dioxathion, azinpnosmethyl, phosphamidon,

-------
-70-
and ryaaia. This commentor stated that dimethoate, with its
4-day reentry interval, is the material of choice because a
relatively safe, short-lived material is necessary for
thrips control since the chemical is applied over ripe
fruit.
c. The Agency's PD 4 Response. The Agency agrees that
cancellation of the air blast use of dimethoate on citrus,
pome fruits, and pecans may result in the air blast applica-
tion of alternative pesticides registered for these same
uses. The Agency is also aware that cancellation of this
application method will probably not lead to the use of
dimethoate on these crops by another method of application,
e.g., oscillating boom sprayer. In addition, the Agency is
aware that there is a high probability that, at least in
some cases, the alternative pesticide may be an organophosphate
of higher acute toxicity. The following key lists definitions
of abbreviations used in Tables 6 and 7:
CAR - Carcinogenic effects.
CNS - Central nervous system effects - includes effects
such as headaches, tremor, drowsiness, convulsions, hypnosis,
anesthesia.
IHL (Inhalation) -- Inhalation in chamber, by cannulation,
or through mask.
IMS (Intramuscular) — Administration into the muscle by
hypodermic needle.

-------
INV (Intravenous) — Administration directly into the
vein by hypodermic needle.
IRP (Intraperitoneal) ~ Administration into the peritoneal
cavity.
LCLo (Lethal Concentration Low) — the lowest concentra-
tion of a substance in air, other than LC50, which has been
reported to have caused death in humans or animals.
LC50 (Lethal Concentration Fifty) — a calculated
concentration of a substance in air, exposure to which for a
specified length of time is expected to cause the death of
50% of an entire defined experimental animal population.
LDLo (Lethal Dose Low) — the lowest dose (other than
LD50) of a substance introduced by any route, other than
inhalation, over any given period of time in one or more
divided portions and reported to have caused death in humans
or animals.
LD50 (Lethal Dose Fifty) — a calculated dose of a
substance which is expected to cause the death of 50% of
entire defined experimental animal population. It is
determined from the exposure to the substance by any route
other than inhalation of a significant number from that
population.
NEC - Neoplastic effects.
ORAL ~ Per os; intragastric, feeding, cr introduction
with drinking water.

-------
-72-
PNS - Peripheral nervous system effects.
SCU (Subcutaneous) — Administration under the skin.
SKIN — Application directly onto the skin, either
intact or abraded. Used both for systemic and primary
irritant effects.
TCLo (Toxic Concentration Low) — the lowest concentration
of a substance in air to which humans or animals have been
exposed for any given period of time that has produced any
toxic effect in humans or produced a carcinogenic, neoplatic,
teratogenic, or mutagenic toxic effect in animals or humans.
TDLo (Toxic Dose Low) — the lowest dose of a substance
introduced by any route, other than inhalation, over any
given period of time and reported to produce any toxic
effect in humans or to produce carcinogenic, neoplastigenic,
teratogenic, or mutagenic, or mutagenic effects in humans or
animals.
TER - Teratogenic effects - nontransmissible changes
produced in the offspring.
7FX - Toxic effects - used to introduce the pathology
or the principal organ system affected.
UNK (Unreported) — Dose, but not route, is specified
in the reference.
Table 6 summarizes the toxicological information for
dimethoate and chemical alternatives to dimethoate. The
information in Table 6 was derived from the "NIOSH 1978
Registry of Toxic Effects of Chemical Substances".

-------
I
CHEMICAL
TADI.E 6 - Suimartzatton or toxlcologlcal Information for dlmethoate and chemical alternatives to dlmethoate
Irritant	TOXIC DOSE
Effects 	OKIE	SRHI	IRF 	—Sill	TFV	Iffi-
(Eye)
LD50
TpLo LlX.o Lb50 LD50 TPl.o
LD50
TBT
LDLo LD50 LM.o LD50 LDio TDt.o LC&O l,cTo~
unir
TKo
DIHtnUATE
-a
Aquatic
ToxlolLy
Rating
TLra 96 ro-
under lppm
NCI Bioassay
Results
Negative
linn an
30
gg^g
Rat
152
mg/kg
Rat
50
utg/kg
TFX-CAR
"Rat	RaE
353 100
mg/kg mg/kg
hat
350
mg/kg
"RSI—
150
mg/kg
House
60
mg/kg
Dog
<100
Mouse
15
mg/kg
Mouse
60
¦"frfog
"TEE	
176
mg/kg
TFX-CAR
Rat
250
ae/kg
Rabbit
300
IM/k|L
Culnea
Pig
350
Qjtnea
Pl8
650
mg/kg
HonsteF
200
nig
ilcken
37
Hanster
60
lnB/kB	
Mammal
15
mg
22
Bird
7 mg/kg
Cat
300
mfi/ka

-------
TABLE 6 - Sunmarlzatlon of to»tcologlcal Information for dlmethoate arxl chemical alternatives to dliaethoate (cont.)
irritant '	'	'	TOXIC DOSE"	' ' ~~ ~	~
CIILHICAL
Effects
(Eye)
I.D50
T5RHT
SKIN
~W"
TDLo LtXo IPSO t-P50 TpLc
~W
VP50 L^o
~isr
"IFb
1BT
TlfiiT
ID50 LDj.o lteO tblo TDLo 1.C50 LCLo tteo
HAUTHIOH
Aquatic
Toxlolty Rating
Tljn 96:10-under
Ippn
NCI Bioassay
Results
Negative
HIOSHIAHI'JON
Rat
685
se
775
pig/kg
Sine a
Inea
P»g
570
mg/kg
tanestto
Animal
500
Rat
17
mg/kg
Rat
Rat
3>I0
Big/kg
House
ouse
193
-SiBfta
Rat
1000
Rat
50
Guinea
Pig
550
Big/kg
use
1811
Hisuan
50
Big/kg
Ran
857
Big/k
Rabbit Rabbit
120 <1100
pig/kg mg/kg
Rat
125
Rat
26
TO/kg
Manunal
500
. '"gfoB

-------
TABI.E 6 - Summarization of toxlcologlcal Ipfonnatlop for dlpethoate and chemical alternatives to dlmethoate (oont.)
CHEMICAL
Irritant
Effects
(Eye)
LD50
OhAL
~W
TKo"
SKIM
im.
3S°I
TfiF
TOXIC POSE
"TEto	nS5o~
~53T
TECT
	TRV	
Lbgfl Ltt-o"
tkit
$
TIE
nc
LtfO Uto
UNK
"TD55
PlIQSPtlAMIDON
(cent.)
NCI Bloassay
Completed
9/78
<1
Ln .
FOHMETANATE
House
6
nig/kg
cnicken
9040
Jig
iid
2
mg/kg
Rat
20
mg/kg
House
16
me/kg
Dog
19
FjgfkB	
Chicken
21500
ug
nr
13
i^/^g
Hsuse
6
pg/^a
Human
5
Rabbit
267
Rat
160
Dg/O /
ja	
Rabbit
10200
"Jt^a

-------
TABLE 6 - Sunmarlzatlon of toilcologlcal Information for dlmethoate and chemical alternatives to dlmethoate (oont.)
jrFjtant
CIIIMJCAI.
Effects

ORAL

SKIN
IRP
SCU
INV IMS 1IIL UNK

(Eye)
LKtt
TpLo
tDLo
Lb$o
LD50
TDi.o LD50 LM.o
LD50 l.M.o LD50 Ltf.o TCLo LC50 LCLo LK0
ROTENONE

Rat
132
mg/kg



Rat
2800
ug/kg
Rat
91
mg/kg
TFX-NEO

Selected by
NCI for
Carclnogenlsls

Mouse
350
mg/kg



House
2800
ug/kg


Bloassay 9/78

Hanmal
50
mg/kg










Hunan
50
mg/kg




DfcHE'fON

Rat
1700
ug/kg


Rat
8100
ug/kg
Rat
3
mg/kg

Rat Rat
1750 3
ug/kg mg/kg


House
7800
ug/kg



House
<1
mg/kg
House
10
mg/kg
TFX-TER
House
3900
Mg/kg
Guinea
P»g
¦SSh
9
¦SM.
Duck
7
01
ru
Bird
7
nig/kg
Wunari
210
ug/kg
Wild
Bird
1800

-------
CHEMICAL
TABU 6 - Suimarlzatlon of toxIcoloRlcal Information for dlmethoate and chemical alternatives to dlmethoate (oont.)
Irritant	TOXIC DOSE	
Effeota	oKaT	SETS	TBF	5ED	ISV	HE
(Eye) TbSO tbt.o LbLo IJ05Q two TdLo LbgQ LtLo LbgQ LbLo Lb50 LbLo ~TtI
TTUT
tess—mr
TMT
TRg
DEMETCN
(cont.)
I
Rabbit Rabbit
24	3250
ma/kg ug/kg
Dog
3650
u&^ka
MEVINP1I0S
Rat
1
mg/kg
House
4
g/kg
Rat Rat
<1200 890
ug/kg ug/kg
	
Chicken
7520
-Sfra"—
Bird
3
mg/kg	
House House
1000 3
ug/kg mg/kg
Rat
1211
ug/kg
House
Cat
3900
u6^kB
Rat
14
PPH/1H
iise
1180
ug/kg
House
680
"g'fcg
Harcnal
690
ug/kg
TFX-PN5
Human
5
mg/kg
Rabbit
4700
ug/kg
Gerbll
450
"B^B

-------
TABI.E 6 - Sunmarlzatlon of toxlcologlcal	information Tor dlmethoate and chemical alternatives to dlmethoate (oont.)
irritant	TOXtC KBT	
Effects
(Eye)
CHtMlCAL
LD50
ORAL
w
LDLo
SKIN
w
IRP
TB5J5	TfiCT
TB55"
"SoT
"IfiV"
LDLo LDgfl l blo ~ng(r
T®~
TETo"
IHL
"TETo CC58 Rlo~
TjfiiT
TBff
CYIIEXATIN
(Plictran)
-a I
I
AZINPIIOSMET1M.
(Guthlon)
Aquatto Toxicity
Rating
TIjd 96:under
lppm
NCI Bloassay
Results
Indefinite
Rat
190
mi
Rabbi
500
mg/kg
Guinea
"8
780
Big/kg
wg/kg
uucicen
651
mg/kg
Rat
16
mg/kg
Guinea
Pig
80
mg/kg
Chicken
277
rrr
Bird
8
mg/kg
Rat
13
Domestic"
Animal
150
mg/kg
Rat
220
mg/kg
Rat
7500
ug/kg
Tat	
rng/m3/
1H
—RaT
15
mg/kg
Human
5
ouse
5
mg/kg
House
65000
ug/kg
House
5
mg/kg
House
8
mg/kg

-------
TABLE 6 - SinmarlzatIon of toxlcologlcal Information Tor dlmethoate and aheiolcal alternatives to dlnethoate (coot.)
Irritant		TOTIiTKEE	
CHEMICAL
Effects	: ORAL	SKIM	IRP	SSi	ISV	IIS	ITE	DhfiT
(Eye) lt>5fl TdLo IHo LKO Lb50 THo Lb50 LbLo LKO LDLo LKO [.bio TCLo L«0 LCLo LKO
PROPARGITE
P1IOSAI.ONE
[mixed with
Kei thane
(1:2)]
-J ; DIAL IFOR
-I* I
PABATHION
Rat
1180
pig/kg
Rat
600
Duse
175
mg/kg
Rat
5
Fg/k8
House
39
mg/kg
Dog
91
mi
Rabbi
35
mg/kg
Dog
2
mg/kg
Rat
250
mg/kg
Hanster
100
mg/kg
TFX-TER
Rabbit
115
"6^6
Rat
2
Dig/kg
fiat
6600
ug/kg
Rat
1500
ug/kg



Rat
3
Dig/kg
Rat
6
mg/kg
Rat
oig/«r*/
2H
House
6
mg/kg

Rat
3550
Ug/kg
House
3500
mg/kg
TFX-TER
House
30
mg/kg
House
17100
ug/kg

House
7200
Ug/kg

Dog
12
pig/kg

-------
! TABLE 6 - Summarization or toxlcologlcal Information	Tor dlmethoate and chemical	alternatives to dioiethoate (coot.)
	Irritant	TOXIC DOSE
, CHtMiCAL Effects OBE 5KTH	TET &5J	IHV TfB ITiE DHIT
	(Eve) TD50 TDLo l.DLo IPSO I.D50 Tbto LD50 LM.o	IPSO UXo LD50 LDLo TDLo LC5Q " LfcLo Id50
PARAT1II0N
(cont.)
1
O '
Rabbit
Rabbit

Rabbit
10
10

5° ,
mg/kg
rag/kg

mg/iu/



211
Guinea
Guinea
Guinea
Guinea
P»8
Pig
PlB
P»B
e
600
12
lH ,
mg/kg
mg/kg
mg/kg
mg/m /



211
Duck
23M0
"B/kg
Dcmestlo
Animal
fig
Cat
3
Hanuual
6
nr
Bird
2
mg/kg
Wild
Bird
1800
"g^B
Woman
5670
ug/kg
TFX-CNS
Human
290
ug/kg

-------
TABI.E 6 - Sunnarlzatlon or toxicological Information lor dimethoate and chemical alternatives to dimethoate (cont.)
Irritant	~	TOXIC POSE
Effects
(Eye)
CHEMICAL
LD50
~MfT
TDLo
LDi.o
SklH
LD50
"W
TD50 TBTxT
LD50
"MT
"W
TDLo TdS5 LDLo O)50~
IMS "
TECT
"THET
"TECo [C5S LCLcT
"W
1D50
SABADIU.A

DIOXATIIION
NCI Dloassay
Results
Negative
Rabbit
25 nig
mild
Rat
1000
jsaM.
Human
50
mg/kg
Rat
20
mg/kg
~KaE
63
mg/kg
Mouse
7500
"B^kg
Rat
30
mg/kg
Rat
1398,
mg/ar/
1H
Mouse
50
mg/kg
Mouse
33
mg/kg
Dog
10
mg/kg
"House
310
mg/ur/
1H
Guinea
Pig
10
g/kg
nig/kg
Cfiicke
170
mg/kg
Human
50
mg/kg
Rabbit
85

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TAB1.E 6 - Summarization of toxlcoloalcal Information Cof dlmethoate and ohenlcal alternatives to dlmethoate (cont.)
	TrrTCSKt		TOXIC USE	
CHEMCAL Effeota	ORAL	SiOM	IRP	ScD	IfN	lifi	flSI	DfiiT
	(Eye) ~T550 iDLo LMo IbgO lb50 Itto LKfl Uto lbS6 LHo U66 IbLo TbLo l(SQ Lclo Lbjtt
RYANIA	Rat	Rat
750	750
	 "g'frB	"8^8	
House
650
	FB^kB
rQ	DOg
150
Rabbit
650
Guinea
Pig
25000
Jj&M-
Hinan
113
pig^kg

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-83-
Table 7 is a summary of the ranges of the toxic doses for
each of the chemicals in Table 6.

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TAB1.E 7 - Similar izat I on or the ranges of the toxla doses of dtmethoate and chemical alternatives to dlmethoate
Irritant		—			TOXIC KflE
CHEMICAL
Effects

ORAL

SKIN
IRP

SCU
INV


IKS

ihL
UNK

(Eye)
LD50
TDLo
LDLo
Lb50
LW6
TDLo
LD50 LDLo
Lteb
LdLo
LD50
LdLo
TDLo
LC50 Lao
LD60
Dlmetlioa' e

7-M00
mg/kg
50
trig/kg
CAR
300
mg/kg
353-
650
mg/kg
45-100
mg/kg

60-350
mg/kg
450
mg/kg



176
mg/kg
CAR

250
mg/kg
Halathlon

500-
685
mg/kg

50-857
mg/kg
4100-
114
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TABLE 7 -
Sunnarlzatlon of
the ranges of the toxio doses of dlnethoate and chemical alternatives to dlmethoate (oont.)




Irritant





TOXIC DOSE






CHEMICAL
Effects

ORAL

SKIN
IRP

SCU
INV
IKS
M.1

UNK

(Eye)
LbW
TDl.o
LDLo
Lt)50
Lb50
YbLo LKO
LDLo
USA
LM.O I.D50 IdLo TDLo
LC50
LCLo
Lb$o
Proparglte

1160
mg/kg


250
mg/kg








Phosalone

175-
600
mg/kg











Dt all for

5-91
mg/kg

100
mgkg
TER
115
mg/kg








ParuLhlon

2-10
mg/ kg
5.6
mg/kg
CMS
.21
mg/ kg
1.8-
600
mg/kg
1.5-
12
mg/kg
3500
mg/kg
TER
30
mg/kg
3-
17.1
mg/kg
3 6-7.2
mg/kg mg/kg

10-
mg/n^/
2H
6
mg/kg
Sub Kill la

1000
Dig/kg

50
mg/kg

7.5
mg/kg







Dioxathlon
25 mg
mild
10-170
mg/kg

50
mg/kg
63-05
mg/kg
30-33
mg/kg




310-
1398,
ne/or/
1H


Ryanla

150-
2500
mg/kg

113
mg/kg
750
mg/kg









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-86-
Th e potential for exposure to the alternatives to
dimethoate is an important facto? in evaluating the risk
from the alternatives relative to the risk from dimethoate..
The Agency concludes, in a similar fashion to the conclusion
in Appendix C of the Chlorobenzilate Position Document 2/3
on alternatives to chlorobenzilate's air blast use on
citrus, that: (1) regardless of the pesticide used in the
citrus air blast equipment, the dermal and inhalation
exposure would be assumed to be similar and (2) unless the
Agency had dermal penetration data to indicate otherwise,
the dermal dose of these alternatives would be assumed to be
similar.
The major alternatives to dimethoate use on citrus,
pome fruits, and pecans are:
(1)	Citrus. formetanate, malathion, phosphamidon,
demeton, and mevinphos. None of these pesticides have
identifiable adverse chronic or delayed toxic effects,
although a complete data base is lacking for many of these
compounds.
(2)	Pome fruit, azinphosmethyl, cyhexatin, propargite,
and demeton. Available data indicates that, with the
exception of azinphosmethyl which is under review, these
pesticides do not appear more hazardous than dimethoate.
Azinphosmethyl is more acutely toxic than dimethoate
and, based on a recent National Cancer Institute study, may

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-87-
pose a carcinogenic risk. Moreover, azinphosmethyl is a
restricted use pesticide and can only be used by trained
pesticide applicators.
(3) Pecans. Phosalone and dialifor. Phosalone is
slightly more acutely toxic than dimethoate. Agency records
indicate that phosalone 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
ooncerning the reliability of these data cannot be made
at this time.
Although the validity of the data ooncerning dialifor is
in question, available data indicate that these major
alternatives to dimethoate for use on citrus, pome fruit,
and pecans pose at least as great a hazard as dimethaote.
Since a complete data base is lacking for many of
the alternative compounds and test data for others has not
been validated, the Agency oahnot determine whether the risk
posed by alternative chemicals will be greater than that
posed by dimethoate. However, one of the factors which has
led the Agency to reconsider its PD 2/3 decision to cancel

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-88-
the air blast use is the possibility that farmers who ovm
air blast equipment may switch to alternative compounds
which are at least as hazardous as dimethoate.
B. Comments Relating to Benefits
1. Summary of the Agency's Benefit Analysis in PD 2/3.
In assessing the benefits of the continued use of dimethoate,
the Agency evaluated the economic, social, and environmental
effects which would result should any or all uses of the
pesticide be cancelled. The benefits of continued use were
weighed against the attendant risks.
The PD 2/3 benefit analysis included a quantitative
assessment of the impact of a variety of possible EPA
regulatory actions on the cost of production, and the
potential loss in farm income. Consumer impacts were
evaluated qualitatively. The data which provided the
basis for the benefit analysis were derived from information
supplied by American Cyanamid, the U.S. Department of
Agriculture, and other interested parties.
In Position Document 2/3, the Agency estimated annual
dimethoate use at 2.8 million pounds A.I. (active ingredient)
applied to about 4.7 million agricultural acres. The
benefit analysis provided estimates of annual use and
economic impacts of a potential cancellation action for the
following classes of use sites: grains, field crops, fruits
and nuts, vegetables, and other use sites.

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-89-
Since comments received on the benefit analysis in
Position Document 2/3 only addressed the use ana benefits of
dimethoate on fruits and nuts, this document will only
summarize the Agency's benefit analysis for those use
sites.
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. 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 58 percent of the
California grape acreage was treated with dimethoate.
For apples, pears, and pecans several effective alterna-
tives for dimethoate are available; the efficacy and perfor-
mance 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, at least
$551,000 for citrus, $3.9 - $10.7 million for grapes, and
$745,800 for pecans. Since only minor amounts of dimethoate
are used on pears, the cancellation of dimethoate for this
use would have negligible effects upon total production
oosts.
Changes in the value of production would either be
negligible or not expected for apples, pears, and pecans.
Annual grape production losses in California, of $40,600 are

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-90-
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 $3.94 - $10.74 million,
or $12.55 - $34.22 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.
Even though significant economic impacts would be
experienced by some U.S. fruit and nut producers (e.g.,
$3.94 - $10.74 million for grape growers, $745,800 for pecan
growers, etc.), consumer Impacts are not expected for pears
and apples due to the small proportion of the total U.S.
production affected. Prioe 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 data.

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91
2. Summary and Analysis of Comments Received in PD2/3—
a. Air Blast Application of Dimethoate for Citrus, Pome
Fruit, and Pecans—i. Comments on the Need for and Extent
of Air Blast Application for Citrus, Pome Fruit, and Pecans.
Several commenters addressed the use and benefits of air
blast application of dimethoate on citrus, pome fruit, and
pecans as follows:
The College of Agriculture of the University of Arizona
[5(30000/16c)] commented that most (90S) of the applications
of dimethoate on citrus are by air blast ground spraying
and many new sprayers were purchased in 1978 and 1979.
Aerial application, continued the commenter, does not
provide adequate canopy penetration, requiring a second
aerial application a few days later, thus doubling costs
and the amount of insecticide used as well as increasing
exposure.
The California Citrus Quality Council t9(30000/16c)]
indicated that air blast application of dimethoate is the
predominant application method in California for control of
aphids and citrus thrips.
The University of California Extension Service at Davis
[8(30000/16c>] submitted extensive comments on the need for
and extent of use of dimethoate and of air blast equipment
for citrus. They estimated that in the San Joaquin Valley,
70S of first applications for trip oontrol on citrus are

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-52-
dimethoate applied with air blast equipment. This commentor
further stated that air blast equipment is used almost
exclusively in the treatment of apples, pears, and other
fruit and nut crops in California. Note was made that the
pear and apple crops use much less dimethoate than the
citrus crops.
The University of California at Davis also stated that
air blast equipment in many cases is preferred over aerial
application and is steadily replacing fixed and even oscil-
lating boom sprayers for fruit and nut tree crops. The
reasons for preferring air blast equipment include speedier
application times which enables better timing of applications,
lower volumes while maintaining efficacy, lesser amounts of
active ingredient, lower application costs, and better
coverage.
The Cooperative Extension Service of the University of
Georgia [1(300D0/I6c)] indicated that "virtually all
pesticide applications to Lpome fruit in Georgia] are
made with air blast sprayers." The Georgia Extension
Service in Tifton, Georgia [1A (30000/l6c)], also emphasized
that the prohibition of dimethoate air blast applications
would be the same as cancellation of the chemical for pome
fruits and pecans in Georgia.
William R. Gale [3(30000/l6c)] indicated that 98* of the
commercial use of dimethoate on pome fruits is by air blast
equipment.

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-93-
Oregon State University Extension Service [4(30000/
16c)] commented that "practically all commercial appli-
cations of pesticides in apple orchards, including dimethoate,
are made by air blast sprayer." Prohibiting the use of
dimethoate by air blast equipment would virtually eliminate
its commercial use in this area.
The Hood River Grower-Shipper Association [6(30000/16c)]
repeated the concerns of the Oregon State Extension Service.
The College of Agriculture of the University of Idaho
[10(30000/16c)3 indicated that "a relatively small percentage
of Idaho apple and pear acreage is treated with dimethoate,
since insecticides which do not reduce predator mite popula-
tions are usually preferred." However, they stated that
virtually all pesticide application in Idaho commercial
orchards is by air blast equipment. They also discussed
alternate application methods, including aerial, hand gun
spraying, oscillating boom sprayers, and overhead sprinklers,
and concluded that "air blast application has definite
advantages in efficacy, economy, and, in some instances,
safety."
The Cooperative Extension Service of Washington State
University Ell(3O000/16c)3 oommented that virtually all
applications of dimethoate on apples in central Washington
is by air blast equipment. Prohibiting the use of dimethoate
in air blast equipment would virtually eliminate the use of
the chemical on apples in central Washington.

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-94-
ii* The Agency's PD *1 Response. None of the comments
provided specific new information that causes the Agency to
revise its original estimates on the economic benefits of
dimethoate or the economic impact of cancelling dimethoate
use on citrus, pome fruit, and pecans. The Agency was
unable to estimate the quality or yield losses due to a lack
of necessary data. The $551,000 economic impact on citrus
growers, estimated in PD 2/3? is an increase in costs.
Output effects could not be measured. Therefore the
Ag ency's original estimate of the economic benefits of
dimethoate use on citrus, pome fruit, and pecans remains
unchanged. The comments do emphasize, however, the extensive
use of air blast application on these crops, and the Agency
agrees with the commenters that air blast appears -to be the
predominant mode of application of dimethoate for the
control of certain insect pests on these crops.
The University of Arizona argued that aerial application
to citrus requires a second application compared to air
blast. From this argument one would presume that air
blast only requires a single application. The Univeristy of
California however, estimated "that in the San Joaquin
Valley, 70S of the first applications of dimethoate for
thrips control on citrus are applied with air blast equipment".
This statement would lead one to bel>«ye that a second
application is required, at least in the San Joaquin

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-95-
Valley. The Agency re-reviewed the information in the
USDA/EPA Assessment Team Report on Dimethoate. A summary of
the number of applications of dimethoate to citrus by aerial
ana ground application indicates that on an average 1 to 2
applications of the pesticide, whether applied by ground
equipment or by aerial application, are made to citrus
crops.
b. Citrus—i. Comments on Air Blast Application of
Dimethoate for Control of Aphids and Citrus Thrips. The
College of Agriculture of the University of Arizona [5(3000/16c)]
commented that dimethoate use in Arizona is almost exclusively
confined to citrus, some for the control of aphids, but most
for citrus thrips. The commenter stated that 90S of the
applications of dimethoate are by air blast ground spraying.
Aerial application, continued the commenter, does not
provide adequate canopy penetration, requiring a second
aerial application a few days later, thus doubling costs and
the amount of insecticide used as well as increasing exposure.
ii. The Agency's PD 4 Response. The Agency agrees with
the commenter that ground application of dimethoate, whether
it be boom sprayer or air blast sprayer, does tend to give
better penetration of the canopy of citrus trees than does
aerial application. The Agency also agrees that for stem
feeding pests, such as mites and scale insects, applications
that penetrate the canopy are more effective. However,

-------
-96-
where the pest is a peripheral feeder, such as terminal
feeding aphids or thrips, aerial applications can be used
and are used when conditions do not permit utilizing air
blast equipment.
Thus, this comment provides no specific new information
that causes the Agency to revise its original estimates on
the economic benefits of dimethoate use on citrus.
c. Pome Fruits—i. Comments on the Use of Dimethoate
for Control of Rosy Apple Aphids. William R. Gale [3(3OOO0/16c)]
commented that the states of Oregon and Washington need
dimethoate for control of rosy apple aphids for occasions
when other insesticides will not work.
Oregon State University Extension Service [4(300DD/16c)3
commented that:
Insecticides for rosy apple aphid
control in the spring are often mixed
with fungicides for disease control.
Tank mixing of water-dispersible powders
with emulsifiable concentrates containing
petroleum solvents often causes phytotox-
icity to fruit and foliage. Dimethoate
is the only systemic aphicide in a
water-dispersible formulation which may
be more safely applied as a tank mix
with water-dispersible fungicides.

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-97-
Control of rosy apple aphid and woolly
apple aphid is often difficult due to
the difficulty of contacting the insects.
Rosy apple aphids distort and roll
leaves and are protected from wetting in
the rolled leaves, while woolly aphid
aerial colonies secrete a cottony wax
over their bodies which repels water
sprays. In controlling these species,
it is often necessary to use a systemic
insecticide such as diraethoate applied
thoroughly to the foliage by ground
dispersal equipment. Dimethoate is
needed as a necessary alternative in
control of these pests in commercial
apple orchards,
ii. The Agency's PD *4 Response. The Agency agrees
with these commenters on the usefulness of dimethoate in
controlling the rose apple aphids. The Agency is not
proposing to cancel the use of dimethoate on apples.
Moreover, the Agency has decided not to pursue cancellation
of air blast application at this time. The Agency will
re-assess its decision on the air blast use when the results
of exposure studies are received and evaluated.

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-98-
i i i . Comments P.erardinq the 5 er i s t r a t. i or, of Phosphrr i con
Having. Beer Withdrawn. The Cooperative Extension Service of
Washington State University [1I(3000C/i6c)] forwarded
comments from its Tree Fruit Research Center indicating the
increased need for dimethoate on apples, since the registra-
tion of phcsphamidon, a widely-used insecticide for aphids
and white apple leafhopper, has been withdrawn,
iv. The Agency's PD 4 Response. The Agency does not
have any information indicating that the registration of
phosphamidon has been withdrawn. A check of the records
indicates that phosphamidon is still registered with the
Agency and would therefore be allowed for use.
d • Pecans—i. Comments on the Impact cf A Minor
Increase ir. the Cost of Pecan Production. The Cooperative
Research Service of the University of Georgia at Athens
[l(30000/16c)] and at Tifton [1A(30000/16c)] commented that
"While the effects cf cancellation might be negligible or
slight on a nationwide basis (FR, p. 6656C), a minor increase
in the cost of production eight mean the difference in
whether or not some small pecan growers can economically
manage their arthropod pests".
ii. The Agency's PD 4 Response. In PD 2/3 the Agency
had estimated decreased farm income for pecans would be
$14.31 oer impacted acre if dimethoate were cancelled fcr
use on pecans. However, the Agency's prcposal was not to

-------
cancel the use of c ir.cthcjte but r~thcr to prohibit one
particular application method. Dirr.etnoate would have still
been available for use on pecans but by a mode of application
other than air blast. In addition, phosalor.e and cialifor
are available as alternatives to dinethcate. The use of
dimethoate with an alternative mode of application or the
substitution of the alternative compound would only result
in a minor increase in the cost of production. Although
this slight cost increase might have an impact on some
small pecan growers, the Agency does not believe in general
such an impact would be substantial at the user level.
C. Connients Relating to Regulatory Options
1. Summary of the A-gency's Regulatory Options i;;
PD 2/3. The development of the regulatory options designed
to reduce the risks accompanying the use of dinethoate
focused on means to reduce the level of human exposure to
dinethoate. 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 application, as well
as ground applicators, may all be exposed both dermally and
via inhalation.

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- i 00-
The Agency cons idered each of these exposure situ 8-ions,
and identified several categories of regulatory options wr.ich
induce various methods of risk reduction. Those regulatory
options considered were as follows:
(15 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 neurotox-
icity studies, and (b) amend the terms and conditions of
certain registrations.
(4)	Continue registration of all uses but (a) require
additional oncogenicity, mutagenicity, and delayed neurotox-
icity studies, (b) amend the terms and conditions of
certain registrations, and (c) rs^uire comprehensive studies
to determine the amount of exposure incurred during all air
blast application situations.
(5)	Continue the registration of cost uses but (a)
require additional oncogenicity, mutagenicity, and delayed
neurotoxicity studies, Co) amend the terms and conditions of
certain registrations, (c) require comprehensive studies to
determine the amount of exposure incurred during all air
blast situations, and (d) cancel the use of all dust formula-
tions.

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- I 01-
( 6 ; Cent i rue i st- at i or. cf most u:'.'5 but (a) r •:;; i ~ •:•
~r. i : i: c r 22 cr? e n :c1ty . rr u t a ~er. 1 c i t y , arc c ei s y e : neur<•; t ov -
icity studies, (t) a.T.enc the terns and conditions of ce'tain
registrstions. (c) specifically prohibit the use of air
blast equipment wher. treating citrus, pecans, and pone
fruit, (d) requi-e corn pr e her. s i ve studies to deter mine the
amount of exposure incurred during all air blast situations
not covered in (c) above, (e) specifically warn female
worke-s involved m air blast application practices of the
potential teratogenic effects of dimethoate, and (f) cancel
the use of all dust formulations.
(7) Cancel all uses.
In PD 2/3 the Agency proposed ^dopt 10" and inpi events-
tion of regulato-y option number 6 above. This option was
selected because it represented 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 this option the
Agency proposed 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.

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-1 02-
2. Summary and Analysis of Comments Received in PD 2/3--
a. Cancel Dust Formulations—-i ¦ Summary of the Agency's
Conclusions in PD 2/3. In Position Document 2/3 the Agency
concluded that the risk resulting from the use of dust
formulations of dimethoate outweighed the benefits derived
from the use of the dust formulations. Dimethoate in
the form of a wettable powder is the choice alternative to
the dust formulation. Because the wettable powder formula-
tion results in lower applicator exposure, the total risk
for the wettable powder formulation would be less than that
of the dust formulation. The Agency, therefore, proposed
eliminating the use of all dust formulations of dimethoate.
The dust formulations are intra-state labels for which
applications for Federal Registration are pending. Intra-state
applicants who have previously submitted a Notice of Applica-
tion for Federal Registration are permitted to sell and
distribute affected pesticide products solely in intra-state
commerce, pending a final decision concerning Federal
Registration.
ii• Comments on the Elimination of Dust Formulations.
The U.S. Department of Agriculture and the Scientific
Advisory Panel agreed, in their comments, with the Agency's
decision to eliminate the registration for dust formulations
of dimethoate in order to reduce applicator risk.

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-103-
i ii. The Agency's PD K Response. The Agency will
proceed with its proposed elimination of the use of all
dust formulations of dimethoate.
b. Require Protective Clothing and Equipment—i.
Summary of the Agency's Conclusion in PD 2/3. In Position
Document 2/3, the Agency concluded that potential mutagenic
and reproductive/teratogenic risks are too high relative to
the benefits associated with the use of dimethoate. However,
the Agency also concluded that the benefits of dimethoate
use would outweigh the risks, if specific changes in applica-
tion practices were implemented to reduce dermal and respira-
tory exposure. The Agency, therefore, proposed the require-
ment of protective clothing for applicators of all dimethoate
products and for all uses of dimethoate, and the requirement
of respirators for pilots and mixer/loaders.
ii. Comments on Requiring Protective Clothing for
Applicators of All Dimethoate Products and All Uses. The
Agency received several comments relating to the recommendation
to require protective clothing for all products and all
uses.
The Department of Agriculture, in their comments
supports the modification of labeling to include protective
clothing and equipment for applicators.
American Cyanamid [7(30000/l6c)] commented that a
significant benefit in reducing exposure can be achieved

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-104-
through the use of protective clothing and for certain uses
is preferred. For certain uses, however, American Cyanamid
contended that this requirement is an extra precaution that
will not significantly increase the margin of safety. The
commenter cites CYGQN* 2E systemic insecticide formulations
for fly vector control and insect control on ornamental
plants as an example. American Cyanamid stated that the
margin of safety as calculated by the EPA, for the fly
vector control use is 1,^74 and that this is achieved
without discomforting the applicator with rubber gloves,
boots, etc. Protective clothing for this use raises the
margin of safety to 3,111. American Cyanamid stated that
although protective clothing is advisable, its requirement
in this case is arbitrary.
American Cyanamid also stated that for other uses
simple devices such as a canvas covering for the applicator
area on the rig may be preferable to protective clothing and
that in excessively hot temperatures applicators would more
likely exercise this safety precaution than they would the
use of protective clothing.
The Nebraska Aviation Trades Association [2(30000/16c)]
stated that the required protective clothing would hinder
the pilots in flying the aircraft, and that the use of
closed mixing and loading equipment would make this requirement
unnecessary for applicators.

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-105-
The California Citrus Quality Council [9(30C00/l6c)j
also stated that the use of closed mixing and loading
equipment would obviate the need for protective clothing,
and that drivers are exposed only to the diluted spray
material and are, in addition, protected by cab enclosures
or other protective provisions.
iii. The Agency's PD M Response. In Position Document
2/3 the Agency calculated the MOS for the various uses of
dimethoate from the estimated exposure for those uses. The
assumptions which were made in order to arrive at the
exposure estimates, and thus, to calculate the MOS are
stated in Position Document 2/3. Table 8 shows the Agency's
calculations of applicator exposure and margins of safety
for various uses of dimethoate under curent practices (no
protective clothing and equipment) and with protective
clothing and equipment.

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TABI.E 8 - Applicator exposure and margins of safety for various users of dlmethoate exoludlni
udlng dietary
exfoSune—
(oral) eipoaure^-'
U
CROP
TYPE OF
SPRAYING SUBGROUP
OGHBIIED DERHAL
AND IMIALATION
EXPOSURE
HQS UNDER
CURRENT
PRACTICES^
(DERHAL AND
INIIAI.ATION
MIEN PROTEC-
TIVE CLOTHING
	13 REQUIRED)
HQS WHEN
PROTECTIVE
aOTHING IS
REQUIRED
TOTAL EXPOSURE
MIEN PROTECTIVE
CLOTHING AND
RESPIRATORS ARE
REQUIRED	
HQS MIEN
PROTECTIVE
CLOTHING AND
RESPIRATORS
ARE REQURIED
C>
5T-
corn	al r
corn	air
corn	air
ornamental	ground
ornamental	ground
I i
grape
grape
grape
cotton
cot I jn
cotton
cotton
citrus
groind
grand
grand
air
air
ground
ground
air
pilots
naggers
mixers/loaders
coranerlaal
high aonoentraotlon
canpressed air
home garden high
concentration
Boon highest cona.
highest oonc.
(custom)
Gopplestone model
dust
pilots
mlxers/loaders
appl loators
mixers/loaders
pilots, ground
crews, ntxers/loaders
0.008)
0.008
0.0063
0.00012
0.000152
0.0012
0.0207
0.130
0.0017
0.0095
0.0078
0.00033
sane as corn
337
350
111
23,333
18,121
2,333
135
1,617
295
359
8,185
0.00806
0.0013
0.000037
0.000015
0.0001
0.006
0.130
0.0016
0.00065
0.0021
0.00011
317
651
75,676
62,222
7,000
167
22
1,759
1,308
1,167
25,151
_ J |
T7 This table was Table VII in Position Docunent 2/3.
21 Based on a 2.8 mg/kg NOEL (Khera impubllshed).
3/ Exposire is via Inhalation .
0.00086
0.00088
0.00002
0.00003
0.00023
0.0038
0.013
0.00017
0.00011
0.00115
0.00007
3,256
3.182
110,000
93.330
12,171
737
215
16,171
20,000
1,931
10,000

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TABLE B - Applicator exposure and aarglns of safety for various users of dlaethoate excluding dietary (otil) exposure^ (cont.)
CROP
TKPE OF
SPRAYING
SUBGROUP
COMBINED DERMAL
AND INHALATION
EXPOSURE
MOS UNDER
CURRENT .
PRACTICUS^'
EXPOSURE
(DERMAL AMD
INHALATION
UllEN PROTEC-
TIVE CLOTHING
IS REQUIRED)
MOS MIEN
PROTECTIVE
CLOTH INC IS
REQUIRED
TOTAL EXPOSURE
MIEN PROTECTIVE
CLOTHING AND
RESPIRATORS ARE
REQUIRED
HOS WHEN
PROTECTIVE
CLOTH INC AND
RESPIRATORS
ARE REQURIED
ci tru«
ground
(air blaat
node 1)
4/
applicators—
alxera/loadera
0. 39
7
0.078
36
0.071
39
Borgliua
al r
¦ait aa corn






veg.
fields
(tomato,
broccoli)
air
pilots
flaggars
alxere/loaders
0.013
0.011
0.0062
213
215
432
0.0128
0.0043
219
631
0.014
0.00088
2,000
3,182
veg. (ria)
ground
spplicators
0.00005
56,000
0.00001
280,000
0.000007
400,000
vector
control
(houae fly)
ground
applicators
0.0019
1,474
0.0009
3.111
0.00032
8,750
forest
ploe
(seed
orchard )
ground
applicators
0.0008
3.300
0.00023
11,200
0.00014
20,000
pecan
ground
(air blaat)
applicators
¦liera/loaders
0.119
24
0.0252
111
0.0232
121
safflt <«r
air
ssaa aa corn






pons
ground
(air blast
aodel
coaaarcisl applicators
including mixers/
loadara
0.242
12
0.0527
S3
0.0483
38
poae
ground
hoes sprayers
0.00017
16.471
0.00003
36.000
0.000032
87,300
If Based on a 2.8 mg/kg NOEL (Khera uopubliahcd).
4/ Applicator la also aiier/loader.


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TABLE 8 - Applicator exposure and margins of safety lor various users of dlmethoate excludlm
iidlng dietary
urMt—
(oral) exposure^ (cont.)
CROP
TYPE CF
SPRAYING
SUBGROUP
CCHBIICD DERMAL
AND IMIA1.ATION
EXPOSURE
HQS UNDER
CURRENT .
PRACTICES^
(DERMAL AND
INHAMTION
WIIEH PROTEC-
TIVE CLOTHING
IS REQUIRED)
HQS UHEN
PROTECTIWE
CLOTHING 13
REQUIRED
TOTAL EXPOSURE
UI1EM PROTECTIVE
CLOTHING AND
RESPIRATORS ARE
REQUIRED
HQS MIEN
PROTECTIVE
CLOTHING ANU
RESPIRATORS
ARE REQURIED
o
soybean
tiieat
tobacco
high cone.
alfalfa
High conc.
air
air
ground
ground
same as com
sane as corn
applicators
Including Mixers/
loaders
0.000*12
applicators IncluJlng 0.00052
mixers/loaders
veg. fields ground
(lettuce)
applicators
mixers/loaders
0.0002
0.00026
T7 ITils table was Table VII in Position Docunent 2/3.
2/ Based on a 2.0 mg/kg NOEL (Khera unpublished).
6,667
538
11,000
10.769
0.00013
0.00163
0.00007
0.00009
21,538
1,718
NO.000
0.00008
0.00097
0.000013
0.000051
35,000
2.B87
65,116
51.852

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-109-
Frorn Table 8 we can see that there are certain use
situations where, based on these exposure estimates, protective
clothing would not significantly increase the estimated
margin of safety. The Agency would therefore tend to agree,
to a certain extent, with American Cyanamid's comments that
for certain uses the MOS would not substantially increase
with protective clothing. However, it would not only be
impractical but nearly impossible to develop labeling to
show all the various use areas and/or conditions where
protective clothing would and would not significantly
increase the margin of safety for the applicator.
With regard to American Cyanamid's contention that
simple devices such as canvas coverings for the applicator
area on the rig are preferred by applicators in excessively
hot weather, the Agency would also tend to agree with
American Cyanamid. However, in the absence of field data
measuring the efficacy of such devices in reducing exposure
to applicators, the Agency will proceed with requiring
protective clothing, but encourages the development of field
data for such devices. The Agency would be receptive to
modifying labeling if data showing the risk reducing potential
of this method are provided.
Therefore, while it agrees to some extent with American
Cyanamid, the Agency will require the use of protective
clothing for all uses. However, pilots will not be required

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-110-
to wear protective clothing while engaging in flying the
aiFcraft. The Agency has re-evaluated the requirements for
protective equipment and clothing for aircraft pilots and
has decided that protective clothing and equipment would in
itself be a hazard to pilots engaged in flying the aircraft.
Pilots will not therefore be required to wear protective
clothing and equipment while flying the aircraft, however
the Agency encourages the use of aircraft equipped with
positive ventilation equipment. Pilots involved in the
mixing-loading operation will be required to wear protective
clothing and equipment during that operation.
With regard to the comments of the California Citrus
Quality Council on mixer/loader exposure and protective
clothing, the Agency does not feel that the efficacy of
closed mixing and loading systems have thus far demonstrated
that they would obviate the need for protective clothing.
Recent industry submissions on closed systems suggest that
protective clothing may not be necessary, however, field
monitoring studies need to be carried out to determine
the level of exposure to applicators using this type of
equipment. In the meantime the Agency will require protective
clothing even for closed mixing and loading systems.
c. Require Automatic Flagging—i. Summary of the
Agency's Conclusion in PD 2/3. In Position Document 2/3»
the Agency determined that the potential risks to human

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-111-
flaggers are too high relative to the benefits associated
with the use of dimethoate. Therefore, the Agency proposed
to eliminate the risk by requiring the use of automatic
flagging equipment for all aerial application situations.
ii. Comments Opposing the Use of Automatic Flagging
Devices. The Scientific Advisory Panel (SAP), in their
comments, objected to the proposed prohibition of the
conventional use of human flaggers to mark swaths in
aerial spraying and the associated requirement for use of
automatic flagging devices. The Panel stated that insufficient
research has been accomplished to indicate that the technique
would be an effective regulatory procedure to reduce risks
to man and the environment. The Panel recommended that
the Agency determine the limitations of automatic flagging
in various agricultural situations before making the use of
these devices an absolute requirement. The Panel also
encouraged the Agency to promote research on flagging
devices to expedite their development and availability to
farmers.
The Department of Agriculture suggested, in their
formal comments, that the Agency not prohibit the use of
human flaggers, but require protective clothing and equipment
to minimize any exposure the flaggers may experience. The
Department of Agriculture also recommended additional
studies of actual exposure of all workers during aerial
application.

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-1 12-
American Cyanamid [7(30000/16c)] suggested alternative
labeling requiring human flaggers to use "proper flagging
techniques to avoid exposure from drift." Cyanamid added
that the use of automatic flag paper dispensers must be
discontinued after the plants reach a height that makes it
difficult to see the paper. They further urged the Agency
to accept the analysis and comments presented by the National
Agricultural Aviation Association at the SAP meeting regarding
automatic flagging.
Mr. Harold Collins, Director of the National Agricultural
Aviation Association made a presentation before the Scientific
Advisory Panel on November 29, 19T9> in which he addressed
the recommendation that automatic flagging equipment be
used to the exclusion of ground flaggers.
Mr. Collins stated that automatic flagging equipment
is expensive, and that some types can cost as much as
$50,000 per aircraft. There are less expensive flagging
devices than the $50,000 device, but many of these become
impractical or unusable later in a spray season. Mr. Collins
further commented that the "ag" aircraft industry would find
it inappropriate to even continue spraying dimethoate in
some situations if they were required to go to equipment
that is as expensive as $50,000.
Mr. Collins questioned the necessity to eliminate
the possibility of flagging since there are methods of

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-113-
human flagging which are acceptable which should minimize
the potential exposure.
Mr. Collins stated that there are circumstances that
make automatic flagging systems impractical. For example,
a system which uses paper is designed to mark the last
or the edge of the last spray run (or the end of a spray
run midfield) becomes impractical as the crop matures
and obscures the paper from view. Automatic flagging is
not necessarily adequate until you get into equipment like
the electronic equipment which is accurate to about five
meters at the current time. However, these electronic
devices are a new and innovative aid, and they are very
expensive.
Mr. Collins commented that if it was found that protec-
tive clothing was required with dimethoate use, he did not
believe that the National Agricultural Aviation Association
would object to it.
The University of California (8(30000/16c)) commented
that the technology for efficient mechanical flagging
or marking is not well-advanced. They stated that proper
protective clothing and equipment might reduce the exposure
to persons serving as flaggers for aerial application.
The California Citrus Quality Council (9(30000/16c))
commented that "practical procedures for automatic flagging
have not been adequately developed and have not been generally

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-114-
adopteci by licensed pilots and their organizations....
(P)rovision should be made for the continued use of workers
as flaggers, since, properly positioned and protected, they
are not at untenable risk in this occupational exposure."
iii. The Agency's PD 4 Response. The Agency has
decided not to prohibit the use of human flaggers during
aerial application of dimethoate, but to encourage the use
of automatic devices, when feasible. When human flaggers
are used, precautions, such as the wearing of protective
clothing, will be required to minimize the exposure of
applicators to dimethoate.
d. Prohibit Air Blast Application on Citrus, Pome
Fruits, and Pecans—i. Summary of the Agency's Conclusions
in PD 2/3. In Position Document 2/3, the Agency concluded,
in the case of the citrus, pome fruits, and pecan uses of
dimethoate, that the use of available protective clothing
and equipment will net reduce the risk experienced by
applicators using air blast equipment to an acceptable
level. The Agency, therefore, proposed the prohibition of
air blast application equipment when treating citrus, pome
fruits, and pecans with dimethoate.
In Position Document 2/3» the Agency projected that
if air blast application of dimethoate on citrus were
cancelled, some dimethoate users would use aerial application,
a few might switch to other ground application techniques,

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-115-
and some would use alternate pesticides. Because of a lack
of data it was not possible to determine the relative
adoption ratios of these three strategies and their associated
economic impacts. Thus, the impact of restricting air
blast application was estimated to range from zero impact to
the same impact as cancellation (more than $551 ,000/year).
Yield and quality losses were not considered in the $551,000
impact.
ii• Comments on Exposure with of Air Blast Application
for Citrus. Pome Fruit, and Pecans Compared to Alternative
ADplication Techniaues Compared to Alternative Application
Techniques. The Agency received comments on this proposed
regulatory action from the Scientific Advisory Panel, U.S.
Department of Agriculture, University of Georgia El(30000/16c)],
William R. Gale of Oregon [3(30000/16c)], Oregon State
University £4(30000/160)], University of Arizona [5(30000
-------
issue, not the operating pressure and spray volume. A
functional definition proposed by the Council characterizes
air blast equipment for tree crops as that application
method which uses a directionalized air stream with velocities
of 50 miles per hour (m.p.h.) or greater to move entrained
spray droplets towards a target area.
The University of California at Davis [8(3000Q/16c)]
also proposed a definition of air blast equipment based
on velocity of the air stream, not on pressure or volume.
The California Citrus Quality Council [9(30000/16°)]
further commented that air blast applicators with a variety
of conditions of pressure, velocity, and volume do not
invariably provide greater applicator exposure than applica-
tion with manual equipment or with stationary or oscillating
booms. Variations in exposure relate more to ground speeds,
the direction, magnitude, and constancy of natural air
movement of the equipment, humidity/temperature factors,
etc., than to the type of equipment. The Council predicted,
in fact, that the greatest potential for exposure was in
manual ground spraying and that oscillating booms with their
recurrent forward sweep of the spray pattern, slower ground
speeds, and broader range of droplet size have greater
potential for exposure than air blast units which involve
faster ground speeds and more forcibly project the spray
into the target area at a set angle of 90 degrees in relation

-------
-1 17-
to the movement of the equipment. Applicator exposure could
be minimized, according to the Council, by using simple
canopies or cab enclosures.
Finally, the California Citrus Quality Council supported
applicator exposure studies underway in California and
indicated that, unless such exposure studies show the
exposure to be substantial and not reducible by simple
canopies or oab enclosures, that the citrus growers would
protest the prohibition of air blast application of dimethoate.
iii. The Agency's PD 4 Response. All of the comments
received by the Agency on this issue disagreed with the
recommended option to cancel the air blast use of dimethoate
for citrus, pome fruits, and pecans. However, none of these
comments contained any new information regarding application
exposure resulting from this use of cimetnoate. Many of the
comments recommended that field monito-ir.g studies be
carried out in order to refine the Agency's exposure estimates.
The Agency agrees that additional dats is necessary
to refine the Agency's exposure estimates for the air blast
uses of dimethoate. In the absence of app-cpriate data to
adequately compare applicator exposure frc: me use of air
blast equipment with the exposure resulting from other
application methods, such as the oscillating boom sprayers,
the Agency believes that the cancellation of the air blast
use is premature. Hence, the Agency has reconsidered its

-------
-1 18-
pcsition anc will not cancel the airblast use of dimethoate
at this time.
This conclusion is supported by information indicating
that a large number of farmers perfer the use of air blast
equipment, and own such equipment. Hence, they are likely
to use substitute pesticides which may be at least as
hazardous as dimethoate with this air blast equipment if
dimethoate is not available. The Agency also recognizes
that dimethoate is a valuable pesticide component of integrated
pest management (IPM) programs for citrus insect pests and
that such programs are almost totally based around the use
of air blast equipment to apply reduced dosages ana selective
coverage. In view of these considerations, the Agency will
retain the air blast use at this time. The Agency will,
however, require the submission of exposure information in
accordance with the protocols and timetables set forth in
Chapter III of this document, and will use this data, in
conjunction with any other available information, to re-assess
the exposure potential of the air blast method and the
attendant risks posed to humans.
e. Warning Statement for Female Applicators—i.
Summary of the Agency's Conclusion in PD 2/3« In Position	
Document 2/3, the Agency stated its concern for women
applicators applying dimethoate via sir blast equipment
during pregnancy. The Agency proposed to require that all

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-119-
products containing dimethoate which can be or are intended
to be used with air blast equipment must bear s statement or.
the label warning female workers that dimethoate causes
birth defects in laboratory animals. The label warning
proposed by the Agency reads as follows:
Warning to Female Workers (in 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.
ii- Comments on ReouirinR a More Direct Warning. The
Department of Agriculture suggested that a more direct
warning such as "Pregnant women should avoid exposure", be
used to alert female workers using air blast equipment of
possible hazards resulting from exposure to dimethoate
during pregnancy.
iii. The Agency's PD 4 Response. The label warning
statement proposed by the Agency in PD 2/3 concludes with
the statement: "Exposure to this product during pregnancy
should be avoided". The Agency believes this statement is a
sufficiently direct warning, however the Agency has decided
not to require this label modification.

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-120-
iy. Comments Urging the Agency to Withdraw the Requirement
for a Warning Statement to Female Applicators. American
Cyanamid [7(30000/16e)3 recommended that the Agency withdr&w
the requirement for a warning statement to female applicators.
In the opinion of American Cyanamid, the requirement is not
supported by the facts in Dr. Khera's paper and a warning
statement describing other than acute hazards would represent
a change in the Agency's policy. American Cyanamid also
stated that the Science Advisory Panel rejected the teratology
warning statements on labels.
v. The Agency's PD 4 Response. The Agency has decided
to drop the requirement for a warning statement to female
applicators. This decision was based on the Agency's
conclusion that the available data on teratogenicity does
not indicate that dimethoate poses a significant teratogenic
risk. Therefore, because of the limited extent of our data
at this time the Agency will not require a warning to female
applicators.
D. Comments Relating to Testing Requirements
1.' Summary of the Agency's PD 2/3 Position. In Position
Document 2/3 the Agency identified several areas requiring
additional testing and directed registrants to submit the
data discussed below.
a. Oncogenicity. The Agency determined that available
evidence for oncogenicity is suggestive and warrants further

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-121
study. Therefore, the Agency directed registrants to
conduct an oncogenicity bioassay using dimethoate in the
same strain of mice and rats as that of the Gibel study.
The Agency stated that this study shall be completed and
submitted within three years of the Agency's final determina-
tion (Position Document M) for dimethoate. The Agency
further stated that protocols for this oncogenicity bioassay
shall be submitted to the Agency within 90 days of receipt
of the Agency's final Notice of Determination (PD 4) for
dimethoate.
b. Mutagenicity. The Agency also determined that
insufficient data exists upon which to base a mutagenicity
risk assessment. The Agency concluded that additional
testing is required. Therefore, the Agency directed regis-
trants to provide adequate test data concerning dimethoate's
ability to cause gene mutation in animal cells. The Agency
stated that registrants shall also conduct a dominant lethal
study in mice as well as studies designed to detect spindle
effects which may result in numerical chromsomal aberrations.
Protocols for these studies shall be submitted to the Agency
within 90 days of receipt of the Agency's final Notice of
Determination for dimethoate. Tests shall be completed and
submitted within eighteen (18) months of receipt of the
Agency's final Notice of Determination for dimethoate. The
Agency also stated that further testing may be required

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-122-
based on the results of the studies discussed above in order
tc properly evaluate mutagenic potential and/or risk.
c.	Delayed Neurotoxicity. The Agency determined that
insufficient data are available to determine whether dimethoate
can induce delayed neurotoxic effects. Therefore, the
Agency directed registrants to conduct appropriate neurotox-
icity testing in accordance with the final registration
guidelines. Protocols for these studies shall be submitted
to the Agency within 90 days of receipt of the Agency's
final Notice of Determination for dimethoate. These test
shall be completed and submitted within eighteen (18) months
of receipt of the Agency's final Notice of Determination for
dimethoate.
d.	Applicator Exposure Data. The Agency determined
that 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 directed registrants to conduct approp-
riate field 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 proposed test protocols
for gathering applicator exposure data to the Agency within

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-123-
90 days of receipt of the Agency's final Notice of Determina-
tion for dimethoate and shall complete all such tests and
submit all exposure data to the Agency within 18 months of
receipt of the Agency's final Notice of Determination for
dimethoate.
2. Summary and Analysis of Comments Received or. PD
2/3~a. Oncogenicity Testing—i. The Agency's Position on
PD 2/3. In Position Document 2/3, the Agency concluded that
additional data were required concerning the oncogenic
potential of dimethoate.
ii.	Comments Objecting to Additional Oncogenicity
Testing~ The Scientific Advisory Panel (SAP), in its formal
comments, objected to this additional testing requirement,
stating that the negative NCI bioassay, flawed though it is,
in conjunction with a lack of carcinogenicity of organic
phosphate pesticides in general, makes further testing of
dimethoate unnecessary.
American Cyanamid [7(30000/16c)3 supported the SAP
position against further oncogenicity testing.
iii.	The Agency's PD Response. The Agency's Cancer
Assessment Group (CAG), in a recent review (Albert, R.E.,
1980) of the SAP position, concluded that there is substantial
evidence for the mutagenicity of dimethoate, coupled with
suggestive evidence for carcinogenicity in the 1973 Gibel
study done on Wistar rats. The NCI bioassay involved a

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-124-
different strain of rats, namely, the Osborne-Mendel rat.
In addition, the evidence of hematopietic toxicity in the
Wistar rat but not in the Osbourne-Mendel rat indicates the
possibility of a different metabolic handling of aimethoate
or target organ susceptability in the two strains.
Therefore, the Agency has decided to retain the requirement
for an oncogenic study on the Wistar rat at the highest dose
level used in the Gibel study of 30 mg/kg giver, by stomach
gavage twice a week.
b. Reproduction Testing—i. The Agency's Position of
PD 2/3. The Agency did not propose any additional testing
for reproductive effects in Position Document 2/3-
ii. Comments Indicating the Need for Additional
Reproductive Studies. The Scientific Advisory Panel, in its
formal comments, indicated that additional reproduction
studies are necessary to assess the effect of dimethoate on
male reproduction. The Panel stated that it noted positive
effects in two studies on reproduction implying the possibility
of effects on males. Therefore, the SAP suggested that the
Agency require a reproductive test to determine dose-response
effects on females (e.g. prevalence of pregnancy, pre and
post implantation loss, survival and growth of young, etc.)
and on males (e.g. spermatogenesis, seminal vesicle size,
etc.).

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-125-
iii. The Agancy's PD 4 Response. The Agency rejects
the Scientific Advisory Panel's recommendation since American
Cyanamid's multigeneration reproduction study has shown no
adverse effects in males. The Agency will not require
additional reproduction testing but will require an additional
teratogenicity study on technical dimethoate using 2 species
of laboratory animals in accordance with proposed guidelines
(FR 43, No. 163, Tuesday, August 22, 1978).
c. Mutagenicity Testing—i.. The Agency's Position in
PD 2/3. In Position Document 2/3, the Agency concluded that
additional data were required concerning the mutagenic
potential of dimethoate. The data required included data
concerning dimethoate's ability to cause gene mutation in
animal cells; a dominant lethal study in mice; and spindle
effects studies.
ii.	Comments Requesting that the Spindle Effects
aaBB|||||||||||iai||||IH||||^^
Testing Requirement be Delected. Amerioan Cyanamid
[7(30000/16c)3 requested that the spindle effects testing
requirement be deleted in the absence of guidelines.
iii.	The Agency's PD 4 Response. The Agency rejects
American Cyanamid's request to delete the requirement for
spindle effects testing and will require these tests. The
Agency is currently developing a policy for spindle effects
and until that policy is available will provide advice and
evaluate testing procedures for spindle effects.

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-126-
iv.	Comments Urging the Use of Mutagenicity Tests
Presently Proposed in the Pesticide Registration Guidelines.
American Cyanamid suggested that dimethoate be evaluated
using mutagenicity tests presently proposed in the pesticide
registration guidelines.
v.	The Agency's PD 4 Response. The following studies
represent only the minimum requirements for data on the
potential heritable effects of Dimethoate. This is a subset
of the studies proposed in the pesticide registration
guidelines.
(1)	A mammalian in vitro point mutation test.
(2)	A sensitive sub-mammalian point mutation test.
(Bacteria, fungi, insect).
(3)	A primary DNA damage test (i.e., sister chromatid
exchange or unscheduled DNA synthesis).
(^i) A mammalian in vitro cytogenics test. If this
suggests a positive result, a dominant lethal or heritable
translocation test may be required.
After results from these test systems and other toxicology
disciplines have been considered, additional testing may be
required to further characterize or quantify the potential
genetic risks.
Although the Agency's mutagenic testing requirements
are not final, the standards for these test should be based
on the principles set forth therein (FR 43, NO. 163, Tuesday,

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August 22, 1978). Protocols and choices of test systems
should be accompanied by a scientific rationale. Substitutions
of test systems for those listed above will be considered
after discussion with the Agency.
The requirements should be considered an interim
guide and not final Agency policy. However, the Agency does
consider the above testing scheme to be a reasonable minimum
requirement.
The Agency has established the mutagenic potential of
dimethoate by means of the screening studies listed above
and is now requiring additional testing to quantify risk to
humans. The studies being required at this time are: 1)
gene mutation study in mammalian system; 2) a dominant
lethal study in mice; and 3) studies designed to detect
spinde effects, i.e., an jLn vivo bone marrow cytogenetic
study.
vi. Comments Recommending that Mutagenic Assays be
Conducted in Accordance with the SAP Recommendation on
the Guidelines. The Scientific Advisory Panel (SAP), in its	
formal comments, recommended that mutagenic assays be
conducted in accordance with their recommendations on the
guidelines, previously submitted to the Agency (May 31,
1978; Review of Proposed Rule Making on Subpart F, Guidelines
for Registering Pesticides in the United States).

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vii.	The /	ency's PD 4 Response. The Agency recognizes
the fact that t	e final form of the guidelines has not been
established yet	The Agency feels that, since the published
reports on dime	hoate, while not completely validated, have
pointed up ares	in which dimethoate could be a oore potent
mutagen thar. nc	indicated, the testing can be directed at
specific aspect	of mutagenicity.
The Agency	s currently reviewing the SAP's recommenda-
tions on the Gu	delines. Until the completion of this
review, the mut	genie assays should be conducted in accordance
with the Agency	s proposed testing Guidelines where appropriate
or by procedure	recommended by consultation with the
Agency.
viii.	Comm	nts Suggesting that the SAP Recommendations
on Spindle Effe	ts be Followed. The SAP suggested that the
Agency follow t	eir previously submitted recommendations on
spindle effects	(November 30, 1979; Review of FIFRA Section
6(6) (7) action	n Benomyl and Thiophanate-methyl).
ix.	The Ag	ncy's PD 4 Response. The Agency has recently
completed guide	ines on mutagenicity risk assessment.
Those quideline	were published in the FEDERAL REGISTER on
November 13, 19	3 (^5 FR 7^98*0. This document has considered
earlier SAP com	snts in reaching a position on mutagenicity
risk assessment	^including spindle effects).

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x. Comments on Using Bone Harrow Derived Cells in
Spindle Effect Assays. The SAP recommended using bone
marrow derived cells in spindle effect assays.
The Agency's PD H Response. The Agency agrees that
an _in vivo bone marrow cytogenetic analysis may be of
assistance, particularly since one of the unvalidated papers
(Bhunya and Behera, 1975) indicated that dimethoate may
affect chromosomes in bone marrow cells.
d. Delayed-Neurotoxicity Testing—i. The Agency's
Position in PD 2/3. In Position Document 2/3, the Agency
concluded that additional data were required concerning the
potential of dimethoate to produce delayed neurotoxic
effects.
ii• Comments Urging Re-evaluation of the Requirement
for Another Delayed Neurotoxicity Study. The Scientific
Advisory Panel (SAP), in its formal comments, recommended
that the Agency re-evaluate the requirement for another
delayed neurotoxicity study in light of a study by T.B.
Gaines (1969).
iii. The Agency's PD Response. The Agency has
re-evaluated the American Cyanamid acute neurotoxicity study
and the Gaines study. Since the dose in the American
Cyanamid study was administered in feed instead of by
gavage, the dose may not have been sufficiently large to
determine dimethoate's neurotoxic potential.

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The Gaines study, while indicating no neurotoxic
effects of dimethoate, did not give important details, such
as dosage used, number of animals used, and whether or not
histopathology on the nerves was carried out. After reevalu-
ating both the American Cyanamid (1965b) studies and the
Gaines (1969 study the Agency concludes that not enough data
is available in these studies to make a hazard determination.
Therefore, the Agency has decided to retain the requirement
that a delayed neurotoxicity study be performed in accordance
with EPA's proposed pesticide registration guidelines (FR
43, No. 163, Tuesday, August 22, 1978).
e. Applicator Exposure Studies—i. The Agency's
Position in PD 2/3. In Position Document 2/3, the Agency
concluded that additional exposure studies were needed to
determine worker dermal and inhalation exposure during the
application of dimethoate with air blast equipment.
ii. Comments on Additional Applicator Exposure Studies.
No comments were received which objected to additional
exposure studies of air blast applications. In fact several
commenters, including SAP, Arizona [5(30000/16C)], California
[8(300D0/16c)3, California Citrus Quality Council [9(30000/16c)],
and Idaho [10(30000/16c)], recommended that the Agency
support and consider research planned by the University of
California on applicator exposure during air blast use on
citrus.

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iii. The Agency PD 4 Response. Additional field
monitoring studies will be required to determine the exposure
to applicators during application of dimethoate with air
blast equipment and to determine the exposure to flaggers
wearing protective clothing during aerial application.
Registrants are directed to conduct appropriate field
studies to determine worker exposure (dermal and inhalation)
during application of dimethoate using air blast type
application equipment and flagger exposure (dermal and
inhalation) during aerial application. Registrants shall
gather such data for each crop where air blast equipment is
used or on crops deemed representative of such applicator
exposure situations, and also for aerial application.
Registrants shall submit proposed test protocols for gathering
applicator exposure data to the Agency with 90 days of
receipt of the Agency 3(c)(2)(B) letter concerning dimethoate
and shall complete all such tests and submit all exposure
data to the Agency within eighteen (18) months of receipt of
the Agency's 3(c)(2)(B) letter for dimethoate. The Agency's
3(c)(2)(B) letter setting forth additional testing requirements
for dimethoate will be issued shortly after publication of
the Agency's final Notioe of Determination for dimethoate.
The exposure study currently underway at the University
of California (Riverside) may satisfy part of this requirement
for air blast equipment. Therefore, data from that study
should be submitted to the Agency as soon as possible
following the conclusions of the study.

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III. CONCLUSIONS
After reviewing comments from the Secretary of Agriculture,
the Scientific Advisory Panel, and others who commented on
EPA's findings and recommendations concerning dimethoate as
set forth in PD 2/3, the Agency has decided to implement the
Proposed Regulatory Option as put forward in PD 2/3 and
restated in Chapter I of this document with the following
modifications:
(1)	The Agency will not cancel the air blast application
of dimethoate on citrus, pome fruits, and pecans. However,
the Agency will require an exposure study of dimethoate
applicators using contemporary air blast equipment to allow
a better assessment, than is currently available, of the
applicators' potential risk from dimethoate in air blast use
situations. After the results from the exposure studies
become available, the Agency will reevaluate air blast
application of dimethoate.
(2)	The Agency will not require a label change to
require automatic flagging. Instead the following label
statement will be required on all products intended for
aerial application:
Automatic flagging devices should be
used whenever feasible.
If Human Flaggers are employed they must
wear the protective clothing and respirator
specified on this label.

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'".or., the Agency will review an exposure study cf
ficE'.ger'

c*c:ec::ve c Io t h i r. =: cu'ir
c " . - c JL
c;r.s:r.ca:e to allow 2 tetter assessner.'
the fl eg gers ' potential r:s k fr cr: dime tr.oate in tne aerial
use situation.
(3) Tne Agency will exer.pt pilots from the protective
clothing anc equipment r equ ir err.en t when flying the aircraft.
(J ; Tne Agency will net require the la'c-el warning
statement for ferr.ale applicators. However, the Agency will
require an seditions! teratology study on technical cirr.ethoat'
The Agency's final ce termi n at ion for cirr,ethoate is as
foil cws .
A. Regulatory Actions
1.	Unconditional cenial of all applications for registra-
tion of dir.ethoate products for use in dust formulations.
2.	Cancellation and cenial of registrations of dimet heats
products for ail uses, ur.less the registrants or applicants
for registration modify the labeling of dimethcate products
to include tne following:
Required Clothing and Equipment
for Application	
All applicators, including homeowners
and flaggers, and all personnel involved
with the mixing, loading, ana transferring
operations, must wear the protective

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clothing ard equipment enumerated below.
Pilots are exenpt f-on this requirement.
The protective clotnmg and equipment to
be wc-rr is as follows:
a. Impe-meable gloves (for example,
rubber or plastic covered gloves),
b . Rub ber or synthetic rub ber boots or
beet covers.
c.	Lcng-sleeved shirt end long pants
made of closely woven fabric.
d.	Vide-fcrimmed hat.
e.	Respirators must be worn by flaggers
and rr.ixer/loaders .
3. Cancellation and denial cf registration of cimethoate
products labeled for aerial application unless the registrants
or applicants for registration modify the terms and conditions
of registration to include the following statements:
AUTOMATIC FLAGGING DEVICES SHOULD BE
JSED WHENEVER FEASIBLE
IF HUMAN FLAGGERS ARE EMPLOYED THEY
MUST WEAr, THE PROTECTIVE CLOTHING AND
RESPIRATOR SPECIFIED ON THIS LABEL.
In adcition to these actions, the Agency has determined,
under the authority cf section 3(c)(2)(B), that additional
data are required to maintain the registrations of dimethoate

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- . JP-
prccjc :s in e f f e••	. The request for thi s aata is incepencent
c f tne Agency' s <	termi nations regarding the tertr.matic r. of
:r.is ?.PA R . H e n c. ¦	trie 3(c)(2)(c) data requirements c £ n not
c-e contested in i	a cm i r. i s t r a t i ve nearir.g cr. all e r.ging t:~.e
terms cf a cancel	a t i o n notice. The additional studies
w.nicn the Agency	s requiring are summa:-i zee below.
E.	Testing requirements
. A dimethc	te oncogenicity stucy using the same
strains of mice	d rats used ty Gibel et al . ( 1973 ).
The proposec pro:	ccl for this study must be submitted
within $0 cays of	receipt cf tne Agency's 3(c)(2)(E) letter
concerning cineth	ate. This study must be completed witr.m
three years of re	eipt cf the Agency's 3(c)(2)(B) letter
concerning dimeth	ate (PDs).
2.	Mutagenic	ty tests, including gene mutation studies
in mammalian syst	ns, a dominant lethal study in mice, 2p.c
studies designed	o detect spindle effects, i.e., an _i_n vivc
bone marrow cytog	netic study. The protocol for these
studies must be s	emitted within 90 days cf receipt of tne
Agency's 3(c)(2)'	) letter concerning dime the ate. These
tests must be com	Letec anc submitted within eighteen
months of receipt	sf the Agency's 3(c)(2)(B) letter concerning
d ime thoate.
3.	Delayed n	jrotoxicitv tests which must be conducted,
in accordance wit	ErA's proposed pesticide registration

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guidelines. The protocol for these tests oust be submitted
within 90 days of receipt of the Agency's 3(c)(2)(B) letter
concerning dimethoate. These tests must be completed within
eighteen months of receipt of the Agency's 3(c)(2)(B) letter
concerning dimethoate.
Teratology tests on the technical dimethoate
using 2 species of laboratory animals in accordance with the
proposed registration guidelines published in the FEDERAL
REGISTER of August 22, 1978 (43 FR 37336). The protocol for
these tests must be submitted within 90 days of receipt of
the Agency's 3(c)(2)(B) letter concerning dimethoate. These
tests must be completed within eighteen months of receipt of
the Agency's 3(c)(2)(B) letter concerning dimethoate.
5. Exposure studies to determine worker dermal and
inhalation exposure during the application of dimethoate
with air blast equipment and dermal and inhalation exposure
for flaggers during aerial application of dimethoate.
Exposure data must be gathered for each crop where air blast
equipment is used or on crops deemed representative of such
applicator exposure situations. Registrants and applicants
must submit proposed test protocols for gathering applicator
exposure data within 90 days of receipt of the Agency's
3(c)(2)(B) letter and must complete all such tests and
submit all exposure data within eighteen months of receipt
of the Agency's 3(c)(2)(B) letter for dimethoate The

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Agency will reevaluate air blast application of dimethoate
after the results of the exposure studies become available.
The Agency's 3(c)(2)(B) letter for dimethaote will be
issued shortly after publication of the Agency'3 final
Notice of Determination for dimethoate.

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BI3LI0GRAPHY
(1)	Agarwal, K.B. , H.N. Mehrotra, and B.K. Paul. 1973-
Effect of organic insecticides on cytology of bean (Phaseolus
vulgaris L.). Labdev J. Sci. Tech. 11-8(3-4): 67-69.
(2)	Albert, R.E. 1980. Memo; CAG response to the SAP
recommendation on further oncogenicity testing on dimethoate,
dated April 8, 1980. From Soy E. Albert, M.D., Chairman,
Carcinogen Assessment Group (RDI-589), to Peter McGrath,
Director, Hazard Evaluation Division.
(3)	Amer, S.M., and O.R. Farah. 1974. Cytological
effects of pesticides. VI. Effect of the insecticide
"Rogor" on the mitosis of Vicia faba and Gcssypium barbadense.
Cytologia 39:507-514.
(4)	American Cyanamid Co. 1965a. Successive generation
studies in mice. American Cyanamid Co., Princeton, N.J.
(unpublished).
(5)	American Cyanamid Co. 1965b. Dimethoate: Demyeli-
nation studies in white leghorn hens. American Cyanamid
Co., Princeton, N.J. (unpublished).
(6)	American Cyanamid Co. 1977. Mutagenicity testing
of CL 12,880 (dimethoate). American Cyanamid Co., Princeton,
N.J. (unpublished).
(7)	Bhunya, S.P., and J. Behera. 1975. Centromeric
sensitivity of mouse chromosomes to the systemic insecti-
cide dimethoate (Rogor). Cur. Sci. 44(23):859-860.

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-1 39-
(8)	Budreau, C.H., and R.P. Singh. 1973. Effect of
fenthion and diaethoate on reproduction in the mouse.
Toxicol. App. Phara. 26:29-38.
(9)	Copplestone, J.F., Z.T. Fakri, J.W. Miles, C.A.
Mitchell, Y. Osman, and H.R. Wolfe. 1976. Exposure to
pesticides in agriculture: a survey of spraymen using
dinethoate in the Sudan. Bull. World Health Organ. 54:217-23.
(10)	Courtney, K.D. 1978. Memo: Response to Rebuttal
on dimethoate, dated June 30, 1978. From K. Diane Courtney,
ETO, HERL, RTP, to William Waugh, Project Manager, SPRD.
(11)	Degraeve, N., J. Moutschen, M. Moutschen-Dahmen,
J. Gilot-Delhalle, A. Colizzi, N. Housbrechts and M.C.
Cholett. 1979. Genetic effects of organophosphate insecti-
cides in mouse. Mutation Research 64(2):131 (abstract
only).
(12)	deSerres, F.J., and M.D. Shelby. 1979. Recommenda-
tions on data production and analysis using the Salmonella/
Microsome Mutagenicity Assay. Environmental Mutagenesis
1:87-92.
(13)	Durham, W.F., T.B. Gaines, and W.J. Hayes, Jr.
1956. Paralytic and related effects of certain organic
phosphorus compounds. AMA Arch. Ind. Health 13:326-330.
(14)	Fahrig, R. 1973. Evidence of a genetic effect of
organophosphorus insecticides. (Transl. from German.)
Naturwissenchaften 60:50-51.

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-1 40-
(15)	Gaines, T.B., 1969. Acute Toxicity of Pesticides.
Toxicology and Applied Pharm. 14:515-534.
(16)	Geratengarbe, S. 1975. Mutagenesis caused by
dimethoate — identified by means of the dominant lethal
test in the mouse (Mus musculu3 L.). (Transl. from German.)
Arch. Sci. J., Univ. Halle, M Series.
(17)	Gibel, W., Kh. Lohs, G.P. Wildner, D. Ziebarth,
and R. Stieglitz. 1973- Experimental study on cancerogenic,
hematotoxic and hepatotoxic activity of organophosphorus
pesticides. (Transl. from German.) Arch. Tumor Res.
41(4):311-328.
(18)	Gordon, M., 3. Cohen, E. Richter, M. Luria, and J.
Schoenberg. 1978. Parathion exposures in agricultural
spray pilots and ground crews. Aerospace Medical Association,
Annual Scientific Meeting, Mew Orleans, Louisiana.
(19)	Hanna, P.J., and K.F. Dyer. 1975. Mutagenicity
of organophosphorus compounds in bacteria and Drosophila.
Mut. Res. 28:405-420.
(20)	Khera, K.S. undated. Evaluation of dimethoate
(Cygon 4E) for teratogenic activity in the cat. (unpublished).
(21)	McCann, J., E. Choi, E. Yamasaki, and B. N. Ames.
1975. Detection of carcinogens mutagens in teh Salmonella/
microsome test: Assay of 300 chemical. Prac. Nat. Acad.
Sci. USA 72(12) :5135-5139.

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(22)	Mohn, G. 1973- Mutagenic activity of monofunctional
alkylating agents including organophosphorus insecticides.
Mut. Res. 20:7-15.
(23)	NCI. U.S. Department of Health, Education, and
Welfare, National Cancer Institute. 1977. Bioassay of
dimethoate for possible carcinogenicity: Carcinogenesis
technical report no. 4. Bethesda, Md.
(24)	Scheufler, H. 1975a. Effects of relatively high
doses of dimethoate and trichlorophone on the embryogenesis
of laboratory mice. (Transl. from German.) Biol. Rdsch.
13(*O:238-240.
(25)	Shiraau, Y., M. Moriya, K. Kato, A. Furuhashi, and
T. Kada. 1976. Mutagenicity screening of pesticides in the
microbial system. Mut. Res. 40:19-30.
(26)	Steiglitz, R., W. Gibel, and H. Stobbe. 1974.
Experimental study on haematotoxic and leukaemogenic effects
of trichlorophone and dimethoate. Acta Haematol, 52:70-76.
(27)	Wolfe, H.R., W.F. Durham, and J.F. Armstrong.
1967- Exposure of workers to pesticides. Arch. Environ.
Health 14:622-633.
The documents cited in this bibliography, as well
as other documents which make up the Administrative Record
for the Agency's actions on dimethoate, are available
for inspection on normal working days between the hours of 8
a.m. to 4.30 p.m. in the offices of the Special Pesticide

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Seview Division, 1921 Jefferson Davis Highway, Crystal Mall
Building #2, Room 720, Arlington, Virginia 22202.
Da ted :

Steven D. Jellinek ^
Assistant Administrator for
Pesticides and Tox'^c Substances

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