United States
Environmental Protection
Agency
Office of
Pesticides and Toxic Substances
Washington, DC 20460
April 1985
vvEPA
Cyanazine
Special Review Position
Document 1
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6560-50
ENVIRONMENTAL PROTECTION AGENCY
[OPP-30000/46]
CYANAZINE
SPECIAL REVIEW OF CERTAIN PESTICIDE PRODUCTS
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: fJThis Notice announces that EPA is initiating a
Special Review ot all pesticide products containing the
H
active ingredient cyanazine.I EPA has determined that
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cyanazine, a registered herbicide, produces teratogenic effects
in laboratory rats and that sufficient exposure to mixer/loaders
and applicators exists so that cyanazine meets or exceeds a risk
criterion described in 40 CFR 162.11. Accordingly, a Special
Review ot products containing cyanazine has been initiated
to determine whether registration of these products should
be permitted to continue and, it so, under what terms and
conditions. During the Special Review process, EPA will
carefully examine the risks and benefits of using cyanazine
and will determine whether additional regulatory actions are
required.
DATE: Comments, evidence to rebut the presumptions in this
Notice, and other relevant information must be received no later
than 45 days from the date this notice is received or until
(insert date 45 days after date of publication in the
FEDERAL REGISTER) (whichever is later) .
85P-361
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ADDRESS: Three copies of written comments identified as
(OPP-30000/46) should be sent by mail to:
Information Services Section,
Program Management and Support Division (TS-757C),
Oftice of Pesticide Programs,
Environmental Protection Agency,
401 M St., SW.,
Washington, D.C. 20460.
In person, bring comments to:
Rrrio 236, CM #2 ,
1921 Jefferson Davis Highway,
Arlington, VA.
Information submitted in any comment concerning this
Notice may be claimed confidential by marking any part or all
of that information as "Confidential Business Information"
(CBI). Information so marked will not be disclosed except in
accordance with procedures set forth in 40 CFR Part 2. A copy
of the comments that do not contain CBI must be submitted
for inclusion in the public record. Information not marked
confidential may be disclosed publicly by EPA without prior
notice to the submitter. All non-CBI written comments will
be available for public inspection in Rm. 236 at the Virginia
address given above, from 8 a.m. to 4 p.m., Monday through
Friday, excluding legal holidays.
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FOR FURTHER INFORMATION CONTACT:
Spencer L. Duffy,
Registration Division (TS-767C),
Office of Pesticide Programs,
Environmental Protection Agency,
401 M St . , SW.,
Washington, D.C. 20460.
Office location and telephone number:
Rm. 728, CM #2,
1921 Jefferson Davis Highway,
Arlington, VA,
(703-557-7421).
SUPPLEMENTARY INFORMATION: The term "Special Review" is the
name now being used by EPA for the process previously called
the Rebuttable Presumption Against Registration (RPAR) process.
Modifications to the process have recently been proposed in
the Federal Register. The Special Review process provides a
mechanism to permit public participation in EPA1s deliberations
prior to issuance of any final notice of intent to cancel
pesticide registrations which may be issued under FItRA Section
6(b). The Special Review process is described at 40 CFR 162.11
and is usually initiated because one or more of the risk criteria
identified in that section have been exceeded, as revealed by
testing of the pesticide's active ingredient.
EPA has determined that a Special Review will be conducted
for all pesticide products containing cyanazine as an active
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ingredient. EPA has also determined that data necessary to
conduct the Agency's risk assessment must be developed on an
accelerated basis, and that precautionary labeling is required
to reduce risk during the Special Review process.
Issuance of this Notice means that potential hazards
associated with the use of cyanazine have been identified. These
hazards will be examined further to determine the nature and
extent of the risk, and considering the benefits of cyanazine,
whether such risks cause unreasonable adverse effects on the
env i ronment.
A document entitled "Guidance tor the Interim Registration
of Pesticide Products Containing Cyanazine" (Guidance Document)
has been issued. (The Guidance Document is also referred to
as a Registration Standard). The Guidance Document is available
to the public from the contact person named above. This Guidance
Document explains the basis for EPA's decision to start a
Special Review and also contains references, background
information, data requirements, and other information pertinent
to the continued registration of pesticides containing cyanazine.
I . INITIATION OF A SPECIAL REVIEW
A. GENERAL
A pesticide product may be sold or distributed in the
United States only if it is registered or exempt from registra-
tion under the Federal Insecticide, Fungicide, and Rodenticide
Act (FIFRA) (7 U.S.C. 136 e_t seq.) . Before a product can be
registered, it must be shown that it can be used without "un-
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reasonable adverse effects on the environment" (FIFRA section
3(c)(5)), that is, without causing "any unreasonable risk to
man or the environment, taking into account the economic,
social, and environmental costs and benefits of the use of the
pesticide" (FIFRA section 2(bb)). The burden of proving that
a pesticide meets this standard for registration is on the
proponent of initial or continued registration. If at any
time the Agency determines that a pesticide no longer meets
this standard tor registration, the Administrator may
cancel the registration under section 6 of FIFRA.
The Agency has created an administrative process for
fully evaluating whether a pesticide satisfies or continues to
satisfy the statutory standard for registration. This Special
Review process provides an informal procedure through which
EPA may gather and evaluate information about the risks and
benefits of a pesticide's uses. It also provides a means by
which interested members of the public may comment on and
participate in EPA's decision making process. The regulations
governing this process are set forth in 40 CFR 162.11.
A Special Review is begun when EPA determines that a
pesticide meets or exceeds one or more of the risk criteria
set out in the regulations (40 CFR 162 .11 (a) (3)) . The Agency
generally announces the beginning of the Special Review by
issuing a Position Document 1 (PD 1) which is published in
the FEDERAL REGISTER. In addition, registrants of affected
products will receive the PD 1 by certified mail. Registrants
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and other interested persons are invited to scrutinize the
basis for the Agency's decision to initiate the Special Review
and to submit data and information which rebut or support the
Agency's initial determination regarding risk. Commenters
may also suggest methods to reduce risks of use of the pesticide.
In addition to addressing risk issues, commenters are encouraged
to submit evidence and discussions of the biological, economic,
social, and environmental costs and benefits of use of the
pesticide. The public participation stage is described in more
detail in Unit IV. This Notice constitutes Position Document 1
for pesticide products containing cyanazine.
If risk issues are not satisfactorily resolved, EPA will
proceed to evaluate the risks and benefits of cyanazine in order
to determine whether to propose regulatory actions to reduce
the risks. After providing an opportunity for comment by the
Scientific Advisory Panel, the Secretary of Agriculture, registrants,
and the public on those actions and the reasons for them, EPA
will issue an appropriate final notice. If EPA determines that
the risks of use exceed the benefits, EPA will issue a notice of
intent to cancel the registration of products intended for such
use. The notice may state the intention to cancel registrations
outright or may require certain changes in the composition,
packaging, application methods and/or labeling of the product.
These changes would be intended to reduce the risks to levels
that when considered against the benefits will not cause unreason-
able adverse effects to man or the environment.
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A notice initiating a Special Review is not a notice of
intent to cancel the registration of a pesticide, and a Special
Review may or may not lead to cancellation. This Notice initiating
the Special Review for cyanazine products is an announcement ot
EPA's concern about the safety ot the pesticide's use, and only
after carefully considering the risks and benefits of cyanazine
and determining that it appears to cause unreasonable adverse
effects on the environment, would EPA issue a notice of intent
to cancel.
B. PRESUMPTION
EPA has determined that the use of pesticide products
containing cyanazine pose risks which meet or exceed one
ot the risk criteria in 40 CFR 162.11(a) (3) ( ii) ( B) . This
regulation provides that a Special Review shall be conducted
if the use ot a pesticide "produces any other chronic or
delayed toxic effect in test animals at any dosage up to a
level, as determined by the Administrator, which is substantially
higher than that to which humans can reasonably be anticipated
to be exposed, taking into account ample margins of safety."
Studies submitted to the Agency have shown that cyanazine
produces teratogenic and fetotoxic effects in laboratory
animals. Based on these data and on an evaluation of potential
exposure of mixer/loaders and applicators to cyanazine, the
Agency concluded that cyanazine has exceeded the risk criteria
for initiating a Special Review.
1. Toxicological concerns. The data base for the continued
registration of cyanazine includes two studies submitted by
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Shell Oil Company. The first study (MRID 0009102) designed
to test for teratogenicity was conducted using Fischer 344
rats. In this study, rats were dosed daily by gastric intubation
on gestational days 6-15. On the 20th day of gestation rats
were sacrificed and necropsies were performed. Results from
this test showed increased incidence of anophthalmia (no eyes)
and microphthalmia (small eyes), in fetuses at a dose level
of 25 mg/kg/day. A no observed effect level (NOEL) was
established at 10 mg/kg/day. In addition, cyanazine caused
increased incidence of diaphragmatic hernia in fetuses borne
by treated rats. It was not clear, however, at the conclusion
of the test whether the diaphragmatic hernia effect was a
true teratogenic response. The registrant has been asked to
submit by 12/31/85 additional data to clarify the diaphragmatic
hernia issue.
In another study conducted by Shell Oil Company Laboratory,
New Zealand rabbits 3-4 months old were mated at 7-11 months and
dosed with cyanazine (orally via gelatin capsules) 6-18 days
post coitum (p.c.) . The rabbits were sacrified on the 29th day
(p.c.). The results showed cyanazine produced fetotoxic effects
at 2 mg/kg/day. A NOEL was established at 1 mg/kg/day. The
primary fetotoxic response was low litter weights. No terato-
genic effects were observed in this study.
2. Applicator (non-dietary) risk. The Agency has determined
that the principal group of people exposed to cyanazine is
mixer/loader and applicator personnel and that dermal absorption
is the primary route of entry for cyanazine. Data from a
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surrogate study with a pesticide which had similar use patterns
were used because adequate exposure data on cyanazine were
not available to the Agency. These estimates are based on a
completely unprotected agricultural worker and assume 140
acres are treated per day (10 hours) by a 60 kg woman. The
estimates of the amount of cyanazine absorbed by mixer/loaders
and applicators are presented in the table below.
Table 1 Estimates of Cyanazine Absorbed by Workers
Operation Exposure/Absorption
Mixing/loading (Open System) 1.95 mg/kg/day
Application 5.4 mg/kg/day
These exposure estimates suggest levels of exposure to
cyanazine at or near the point where teratogenic and fetotoxic
effects were observed in experimental laboratory animals.
A dermal absorption study requested during the development
of,, the Registration Standard has been completed and was submitted
to the Agency January 16, 1985. The Agency has determined
that this study is unacceptable because of the excessive
amounts of cyanazine which were not accounted for at the low
(0.5 mg) and intermediate (5.0 mg) dose levels. Cyanazine
losses ranged from 13.6-55.0 percent for the low dose level
and from 15.3-23.4 percent for the intermediate dose level.
These losses made it impossible to quantitate accurately
absorption of cyanazine by the skin of the test animals. It
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also prevented evaluation of the significance of the unusual
absorption patterns which occurred during this test.
3. Dietary Risk. Dietary exposures to cyanazine result
from use on corn and other crops which are used for human
food and livestock feed. Ninety six percent of the cyanazine
produced in the United States is applied to corn. A margin
of safety (MOS) for dietary exposure to a teratogen is usually
determined based on a single serving of a given food commodity.
For cyanazine, the single serving for all raw agricultural
commodities is very close to the food factor. (The food
factor is the portion of the diet, usually expressed as a
percentage, which is contributed by a given food based on
the annual average consumption of that food.) Therefore the
theoretical maximum residue contribution (TMRC) as a result
of existing tolerances for each of these commodities can be
used as an exposure estimate. Further, residues of cyanazine
have not been found on crops and the tolerances were set at
the limit of detection of the analytical method. On this
basis, the margins of safety for the teratogenic and/or
maternal and fetotoxic effects can be calculated according
to the following formula:
MOS = No observed effect level (NOEL) (mg/kg)
Exposure (mg/kg)
Based on the above formula, the margins of safety (MOS)
were acceptable for all crops. The Agency therefore determined
that the dietary risk criterion set forth in 40 CFR 162.11
had not been exceeded .
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C. ADDITIONAL DATA
Data considered pivotal to refine the Agency risk
assessment have been required on an expedited basis via the
Registration Standard. These data are needed to clarify the
diaphragmatic hernia issue which may be an additional teratogenic
response and to determine the amount of cyanazine absorbed
upon contact with exposed skin. These data will be discussed
at the time the Agency issues its proposed regulatory decision
in the Position Document 2/3 (PD-2/3).
The following table shows the pivotal data requirements
and the due dates for data on cyanazine.
Table 2
Pivotal Data
Pivotal Data Required Submission Date
Teratogenicity study December 31, 1985
Dermal absorption study July 31, 1985
(study submitted
1/16/85 was found
to be unacceptable)
D. ADDITIONAL CONCERNS
The Agency is concerned about ground and surface water
contamination from agricultural uses of cyanazine. Cyanazine
has the potential to move (leach) through the soil and contaminate
ground water which may be used as drinking water. Cyanazine
has been found in surface and ground water as a result of
agricultural use. The Agency does not have the data necessary
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to assess the health risks associated with consuming drinking
water which has been contaminated with cyanazine. However,
ground water data have been requested via the Registration
Standard and are due in June 1986. In the interim, to address
cyanazine's potential to contaminate, drink ing water, label
changes have been imposed which advise users not to apply
cyanazine to highly permeable soils or where the water table
is close to the surface.
E. CURRENT REGULATORY ACTIONS
Because the Agency has determined that cyanazine produces
teratogenic etfects in laboratory animals at concentrations to
which mixer/loaders and applicators may be exposed, the Guidance
Document requires that an appropriate warning be added to the
pesticide label regarding cyanazine's potential to cause birth
defects in laboratory animals. The Guidance Document also
requires the registrant to change the label to include the
"Restricted Use" classification which limits the use of the
pesticide to certified applicators or to persons directly
under their supervision. The registrant, however, has not
yet committed to implement these requirements. The Agency
will take appropriate actions to ensure compliance with
these requirements.
All currently registered cyanazine products will remain
registered while the Special Review is in progress. In addition,
the Agency is deterring final decisions on the reregistration of
any products containing cyanazine as a sole active ingredient until
the Special Review is concluded. The Agency is requiring data
sufficient to recalculate existing tolerances which will include
the combined residues of the parent compound and all metabolites
that contain the triazine moietv.
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F. COMMENTS ON THE INITIATION OF THE SPECIAL REVIEW
Prior to the initiation of a Special Review, the sole
registrant of the active ingredient was given notification of
the Agency's determination that one of the criteria to initiate
a Special Review may have been met. This notification included
information on the toxicity findings, route of exposure and
related general information. The registrant was allowed
30 days following receipt of the notification to rebut the
Agency's conclusions. The registrant responded to the
notification requesting the Special Review be delayed until
all teratogenicity data were submitted but failed to rebut the
Agency's presumption of teratogenicity for cyanazine.
G. REBUTTAL CRITERIA
All registrants, applicants tor registration, and other
interested members of the public are invited to submit evidence
either to support or to rebut the presumption that cyanazine
causes teratogenic effects in rats and may cause such effects
in humans. Under 40 CFR 162.11(a) (4 ) (iii) the presumption
initiating a Special Review may be rebutted by proving, in
the case of acute and chronic toxicity criteria, "that the
determination by the Agency that the pesticide meets or exceeds
any of the criteria tor risk was in error."
H. BENEFITS INFORMATION
The Agency will conduct a comprehensive benefits review
and analysis for cyanazine during the Special Review process
and will consider that information in setting forth the Agency's
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proposed regulatory decision in the Position Document 2/3. A
preliminary analysis of the benefits of cyanazine has been
performed and is presented here.
Ninety-six percent of the cyanazine produced in the U.S.
is used as a herbicide on corn. About 3 percent is used on
cotton and less than 1 percent is used on sorghum and wheat.
About 14-16 percent of the total U.S. corn acreage was treated
with cyanazine in 1982. Most of the cyanazine produced is
applied in the corn belt states (IL, IN, IA, MO, OH) and a
lesser amount applied in the Northern Plain States (KS, NE,
and SD). About 3 percent is used on cotton mainly as a post-
emergent, directed spray herbicide.
Growers selected cyanazine over other currently available
corn herbicides for the following resasons:
(1) Cyanazine has a wide annual broadleaf and grassy
type weed control spectrum.
(2) It can be tank-mixed with a number of herbicides
(atrazine, butylate, alachlor and metolachlor) to broaden its
weed control spectrum.
(3) Because of its relatively short persistence in the
soil, cyanazine reduces the carryover effect of other more
persistent triazine herbicides on subsequent crops.
(4) Cyanazine, unlike some of its alternatives, has no
rotational crop restrictions.
There are several alternatives to cyanazine and data show
no significant increase in production cost it they are used.
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However, the alternative herbicides have a narrower weed
control spectrum than cyanazine and may produce carryover
eftects when mixed with other more persistent herbicides such
as atrazine.
In addition to submitting evidence to rebut the presumptions
of risk in the Special Review, 40 CFR 162.11(a)(5)(iii) provides
that a registrant or applicant "may submit evidence as to whether
the economic, social and environmental benefits of the use of
the pesticide subject to the presumption outweigh the risk of
use." if the presumption of risk is not rebutted, the benefits
evidence submitted by registrants, applicants, and other inter-
ested persons will be considered by the Agency when determining
the appropriate regulatory action.
Registrants, applicants or other interested persons who
desire to submit benefits information should consider submitting
information on the following subjects along with any other
relevant information they desire:
1. Identification of the biological and economic importance
of cyanazine uses including market studies and estimated quantities
applied for those uses.
2. Identification of alternative chemical and nonchemical
methods of control tor all registered uses and application tech-
niques including any health effects and potential for water
contamination associated with use of the alternatives.
3. Determination of any change in costs to cyanazine users
tor obtaining equivalent disease control with available substitute
products or management techniques.
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4. Assessment of the expected changes in the level of
efficacy, crop yield, crop quality, crop injury, herbicide-
resistant weed species, and environmental impacts associated
with the use of alternative control measures.
5. Identification of increased or reduced risks associated
with the mixing, loading, applying and disposing of alternative
chemicals, and ot other hazards associated with their potential
increase in use if cyanazine were not available as well as
descriptions of the application equipment types, protective
clothing and mixing/loading and disposing procedures for the
alternative chemicals.
6. Identification of cultural and spray application
practices, and other factors that affect farmworker exposure
to cyanazi ne.
7. Identification of any alternative cultural or integrated
pest management practices which are enhanced or limited by
use of cyanazine.
II . REBUTTAL SUBMISSION PROCEDURES
All registrants and applicants for registration are
being notified by certified mail of the Special Review being
initiated on their products containing cyanazine.
The registrants and applicants tor registration will
have 45 days from the date this notice is received or until
(insert date 45 days after date of publication in the FEDERAL
REGISTER) (whichever is later) to submit evidence in rebuttal
to the Agency's presumption. Other interested parties may
submit comments during the same period.
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1II• DUTY TO SUBMIT INFORMATION ON ADVERSE EFFECTS
Registrants are required by section 6(a)(2) of FIFRA to
submit any additional information regarding unreasonable adverse
effects on man or the environment which comes to their attention
at any time. Registrants of cyanazine products must immediately
submit any published or unpublished information, studies,
reports, analyses, or reanalyses regarding any cyanazine effects
in animal species or humans, and claimed or verified accidents
to humans, domestic animals, or wildlife which have not been
previously submitted to EPA. These data should be submitted
with a cover letter specifically identifying the information
as being submitted under section 6(a)(2) of FIFRA. Registrants
should notify EPA of any studies on cyanazine currently in
progress, their purpose, the protocol, the approximate completion
date, a summary of all results observed to date, the name and
address of the laboratory performing the studies, and a
statement as to whether these studies are being conducted in
accordance with the Good Laboratory Practices specified in
40 CFR Part 160, published in the FEDERAL REGISTER of
November 29, 1983 (48 FR 53946).
IV. PUBLIC COMMENT OPPORTUNITY
During the time allowed for submission of rebuttal
evidence, specific comments are solicited on the presumptions
set forth in this Notice and in the Registration Standard. In
particular, any documented episodes of adverse effects on
humans or domestic animals should be submitted to the Agency
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as soon as possible. Any information as to any laboratory
studies in progress or completed should be submitted to the
Agency as soon as possible with a statement as to whether
those studies are in compliance with the Good Laboratory
Practices specified in 40 CFR Part 160. Specifically, infor-
mation on any adverse toxicological effects of cyanazine, its
impurities, metabolites, and degradation products is solicited.
Similarly, submission of any studies or comments on the benefits
from the use of cyanazine is requested. All comments and
information and analyses, which come to the attention of EPA,
may serve as a basis tor final determination of regulatory
action following the Special Review.
All comments and information should be sent to the
address given above, preferably in triplicate, to facilitate
the work of EPA and others interested in inspecting them.
The comments and information should bear the identifying
notation [OPP-30000/46].
During the comment period, interested members of the
public or registrants may request a meeting to discuss the
risk issues and methods of reducing risks. Any records
pertaining to such meetings, including minutes, agendas, and
comments received will be filed under docket number [OPP-30000/46'
Dated:
Director,
Office of Pesticide Programs.
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