4O973-MI
REPORT DOCUMENTATION
PAGE
NO.
Recipient** Acc*t*ton No.
4. Tltte «Mt Subtitle
S. Report Dele
January 1988
CYANAZINE - POSITION DOCUMENT 4
Auttarfe)
EPAf OPP, REGISTRATION DIVISION
•. Herfoonlng Orfanlzartlon Rept. No.
540/09-90-107
». Peifoiii>l«^ Org»nU«tVon Name and Address
EtJVIRONMENEAL PROTECTION AGENCY
OFFICE OF PESTICIDE PROGRAMS
WASHINGTON, D.C. 20460
10. Prof»ct/Ta»k/Work Unit No.
II. Contr»ct(O or Grent(G) No.
(0
(G)
12. Sponsoring Organization Name and Addr«»
SAME AS #9
11. Type of Report & Period Covered
14.
IS. Supplementary Notes
16. Abctract (Limit: 200 word!)
This Position Document addresses the risks and benefits of pesticide products
containing the subject active ingredient. The Agency has determined that the use
of products containing the subject active ingredient may meet or exceed a risk"
criterion described in 40 CFR Part 154. Potential hazards will be examined
further to determine the nature and extent of the risk, and considering the
benefits of the subject active ingredient, whether such risks cause unreasonable
adverse effects on the environment.
17. Document Anelytls e. Descriptors
PESTICIDES, STANDARDS, REGULATIONS, NIANUFACTURING, CHEMISTRY, TOXICOIOGY,
RESIDUES, ECOLOGY, PATH OF POLLUTANTS
6. IdMitlfiers/Open-Ended Terms
c. CO:
!•. AvelU
PUB]
I ANSI-]
EJBD
ARCHIVE
EPA
540-
09-
90-
107
3LE
19. Security CUss (This Report)
UNCLASSIFIED
20. Security Class (This P«fe)
UNCLASSIFIED
21. No
•16'
22. Price
See Inctructlon* on Reverae
OPTIONAL FORM 272 (4-77)
(Formerly NTIS-3S)
Department of Commerce
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540/09-90-107
6560-50
ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF PESTICIDES AND TOXIC SUBSTANCES
[OPP-30000/46B; FRL ]
CYANAZINE; INTENT TO CANCEL REGISTRATIONS; DENIAL
OF APPLICATIONS FOR REGISTRATION; CONCLUSION
OF SPECIAL REVIEW
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice of Final Determination and Intent to Cancel.
SUMMARY: On April 10, 1985, EPA issued a Notice of Initiation
of Special Review of registrations of pesticide products
containing cyanazine. On January 7, 1987, EPA issued a
Notice of Preliminary Determination announcing its preliminary
•
determination that continued use of registered cyanazine
products would be allowed only if registrants modified certain
terms and conditions of registration as described herein.
This Notice concludes the Special Review of pesticide
.products containing cyanazine and announces EPA's final deci-
sion to cancel registrations and deny applications of all
such products unless registrants make specified modifications
to the terms and conditions of their registrations.
87P-1689
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DATE: A request for a hearing by a registrant or applicant must
be received by [insert date 30 days after date of publication in
the FEDERAL REGISTER] or 30 days from receipt by mail of this
Notice, whichever is the later applicable deadline. A request
for a hearing from any other adversely affected person must be
received by [insert date 30 days after date of publication in the
FEDERAL REGISTER].
ADDRESS: Requests for a hearing must be submitted to;
Hearing Clerk (A-110),
Environmental Protection Agency,
401 M St., SW.,
Washington, DC 20460
FOR FURTHER INFORMATION CONTACT:
By mail:
Joanna J. Dizikes,
. Registration -Division -C.TS-2.67c.).,
Office of Pesticide Programs,
Environmental Protection Agency,
401 M St., SW.,
Washington, DC 20460.
Office location and telephone number:
Rm. 1006, CM 12,
1921 Jefferson Davis Highway,
Arlington, VA
(703-557-5096)
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SUPPLEMENTARY INFORMATIONS This Notice is organized into eight
units. Unit I ia the Introduction. It provides the background
information concerning this cancellation action. Units II and
III summarize the risks and the benefits associated with the use
of cyanazine. Unit IV contains the comments of the Scientific
Advisory Panel, the Secretary of Agriculture, and other public
comments and EPA's response to those comments. Unit V describes
the Agency's risk/benefit conclusions, and Unit VI describes the
regulatory actions required to be complied with by this Notice.
Unit VII describes the procedures which will be followed in
implementing the regulatory actions EPA is announcing in this
Notice. Unit VIII describes the public docket established for
the Cyanazine Special Review.
I. INTRODUCTION
A. NOTICE OF SPECIAL REVIEW AND PRELIMINARY NOTICE OF INTENT
TO CANCEL
On April 10, 1965, EPA issued a Notice of Special Review
(also called Position Document 1 or "PD-1") on pesticide products
containing cyanazine (50 PR 14151), following a finding that
cyanazine net or exceeded the risk criteria in 40 CFR 162.11
(a)(3)(ii)(B), which were in effect at that time. The new,
revised risk criteria which appear at 40 CFR 154.7(a)(2) are met
or exceeded a* well.
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The Cyanazine Special Review was based on teratology studies
using oral administration which showed that cyanazine produced
teratogenic effects in the Fischer 344 rat [lowest-observed-effect-
level (LOED-25 mg/kg/day, no-observed-effect-level (NOEL)-IO
mg/kg/dayj and fetotoxic effects in New Zealand white rabbit
(LOEL-2 ing/kg/day, NOEL-1 mg/kg/day). Exposures to mixers/loaders
and applicators were identified as the occupational exposures of
concern.
Dermal absorption and dermal developmental toxicity studies
were submitted to the Agency after the issuance of the Notice of
Special Review on cyanazine. These new data led to refinement of
the risk estimates presented in the Notice of Special Review.
The dermal developmental toxicity study demonstrated a NOEL of
573 mg/kg/day.
-foil-owing review of public comments and available data, the
Agency issued a Notice of Preliminary Determination on January 7,
1987, as well as the Cyanazine Technical Support Document. That
document discussed in detail the Agency's determination regarding
the risks arising from the use of cyanazine and the modifications
to registration which, if adopted, would reduce risks to acceptable
levels. Such modifications involved risk reduction measures and
included requirements for the use of protective gloves, closed
loading systems, and chemical-resistant aprons, as well as label
statements regarding the cleaning of protective gloves, separate
laundering of protective clothing, and the reason cyanazine has
been classified for Restricted use.
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This Notice announces the Agency's intent to cancel
registrations and deny applications for registration for all
pesticide products that contain cyanazine as an active ingredient,
unless the terns and conditions of registration are amended as
described in Unit VI. This action is based on the Agency's
determination that the use of cyanazine will result in
unreasonable adverse effects to mixers, loaders, and applicators
of cyanazine unless the required measures are adopted. A
detailed discussion of the basis of this action is contained in
the Notice of Preliminary Determination and the Cyanazine
Technical Support Document issued on January 7, 1987 (52 PR 589).
This Notice constitutes the final Agency action on the Special
Review of cyanazine pesticide products initiated by the results of
the developmental toxicity studies discussed herein.
B. LEGAL BACKGROUND
In order to obtain a registration for a pesticide under the
Federal Insecticide, Fungicide, and Rodenticide Act (PIFRA), as
amended, an applicant for registration must demonstrate that the
pesticide satisfies the statutory standard for registration,
section 3(c)(5) of FIPRA. .That standard requires, among other
things, that the pesticide perform its intended function without
causing "unreasonable adverse effects on the environment." The
term "unreasonable adverse effects on the environment" is defined
under PIPRA section 2(bb) as "any unreasonable risk to man or the
environment, taking into account the economic, social, and
environmental costs and benefits of the use of any pesticide."
This standard requires a finding that the benefits of the use of
the pesticide exceed the risks of use, when the pesticide is used
in compliance with the terms and conditions of registration or in
accordance with widespread and commonly recognized practice.
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The burden of proving that a pesticide satisfies --the
standard for registration rests on the proponents of registration
and continues as long as the registration remains in effect.
Under section 6 of FIFRA, the Administrator nay cancel the
registration of a pesticide or require modification of the terms
and conditions of registration whenever it is determined that the
pesticide appears to cause unreasonable adverse effects on the
environment.
In determining whether the use of a pesticide poses risks
which are greater than the benefits of its use, EPA considers both
possible changes to the terms and conditions of registration
*
which can reduce risks, as well as the impacts of such
modifications on the benefits of use. If EPA determines that
such changes reduce risks to the level where the benefits outweigh
the risks, it may require such changes be made in the terms and
conditions, of -registration.
Alternatively, EPA may determine that no change in the terms
and conditions of a registration will adequately ensure that use
of the pesticide will not pose unreasonable adverse effects. In
that event, the Administrator may issue a Notice of Intent to
Cancel the registration or may hold a hearing to determine
whether it should be cancelled under FIFRA section 6(b). In
determining whether to issue such a notice, the Administrator
must take into account the impact of the action on production and
prices of agricultural commodities, retail food prices, and
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other possible effects on the agricultural economy. At least 60
days before formally issuing such a notice, he must inform the
Secretary of Agriculture in writing of the substance of the
proposed actions and supply the Secretary with an analysis of the
expected impact on the agricultural economy. At the same time,
under FIFRA section 25(d), the Administrator is required to
submit the proposal to the Scientific Advisory Panel for comment
as to the impact on health and the environment of the action
proposed in the cancellation notice. EPA is also required by
law, where appropriate, to consult with the U.S. Department of
the Interior's Office of Endangered Species to see if the proposed
action may affect an endangered species.
Unless expedited procedures are employed, EPA informs the
public of its proposals to issue cancellation notices so that
registrants and other interested persons can also comment or
provide relevant information before a final Notice of Intent to
Cancel is issued. Registrants and other interested persons are
invited to review the data upon which the proposal is based and
to submit data and information to address whether EPA's initial
determination of risk was in error. In addition to evidence
relating to risks, comments may include evidence as to whether
any economic, social, and environmental benefits of use of the
pesticide outweigh the risks of use.
If, after reviewing the comments received, EPA decides to
issue a Notice of Intent to Cancel, any adversely affected person
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may request a hearing to challenge the action. In the hearing,
any party opposing cancellation would have an opportunity to
present evidence, other interested parties could intervene to
present evidence. At the end of the hearing, EPA would decide on
the basis of the evidence presented whether or not to cancel or
restrict the registration of pesticide products. If no hearing
is requested, each registration would be cancelled by operation
of law 30 days after receipt by the registrant or publication in
the FEDERAL REGISTER of the Final Notice, whichever occurs later.
II. DETERMINATION OF RISKS
A. RISK ASSESSMENT AND RISK REDUCTION MEASURES
The Technical Support Document includes a detailed discussion
of the developmental toxicity demonstrated by the cyanazine
studies, which include anophthalmia, microphthalmia, skeletal
variations, diaphragmatic hernia, dilated brain ventricles, and
cleft palate, as well as detailed discussions of the Agency's
exposure assessment and risk assessment.
The Agency's risk assessment indicates that, while the degree
of risk varies depending on the use rate and the number of acres
treated, the risk is unreasonable without the adoption of protective
measures as specified herein.
Traditionally, the Agency prefers the use of an oral NOEL to
assess the developmental toxicity hazard of dietary exposures and
a dermal developmental toxicity NOEL for occupational exposures,
because each NOEL provides information relative to the potential
hazard posed by a pesticide from that chosen route of administrati
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Based. on the NOEL (573 ng/kg/day) from the dermal developmental
toxicity study in rabbits and exposure estimates from a cyanazine
exposure study, margins-of-safety (MOSs) were developed using
the following formula:
Margin-of-Safety (MOS) « Dermal Developmental Toxicity NOEL
Exposure level
The Agency generally considers a MOS of less than 100 for this
biological endpoint to be a matter of concern.
1. Ground boom application. The MOSs presented for ground
boom application assume that the mixer/loader and applicator are
the same person. The MOSs are greater than 100 for all application
rates to corn, cotton, wheat fallow, and milo when protective
gloves are worn during mixing and loading operations and when
adjusting, repairing, or cleaning equipment, as shown in the
following Table 1:
Table 1 — MARGINS-OF-SAFETY FOR GROUND BOOM
APPLICATION1
Corn Cotton Wheat Fallow Milo
Applicator2
No protection3
Gloves3
Gloves/closed cab
7
670
4240
21
1980
12730
11
990
6370
21
1980
12730
1 The MOSs in this table are for the highest use rates.
2 Assumes that mixer/loader and applicator are the same person.
3 The approximately two order of magnitude difference in the
MOSs between the no glove scenario and the glove scenario is
a result of comparing two independent data bases and the effect
of protective gloves on reducing exposure. A worker exposure
study submitted by the registrant contained exposure data only
for handling scenarios in'which gloves were worn. This Table
is not intended to imply that protective gloves can reduce
total dermal exposure by two orders of magnitude.
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2. - Aerial application. Aerial application to corn, grains
sorghum, and wheat fallow is minimal. There are no data showing
that cyanazine is being applied aerially to cotton.
The MOSs for mixer/loaders during aerial use are less than
100 unless protective gloves are worn during mixing and loading
operations and when adjusting, repairing, or cleaning equipment
and a closed loading system is used, as shown in the following
Table 2:
Table 2 — MARGINS-OF-SAFETY FOR AERIAL APPLICATION1
Grain sorghum Corn Wheat Fallow
Applicator (Pilot) 320 170 250
Mixer/Loader
No Protection (open pour) 522
Gloves (open pour) 24 11 12
Gloves/Closed System 1000 440 520
1 The MOSs in this table are for the highest use rates.
3. Chemioation. Corn is the only crop for which chemigation
is listed on the label as an application method. The MOSs for
chemigation are less than 100 unless protective gloves are worn
during mixing and loading operations and when adjusting, repairing,
or cleaning equipment, and a closed loading system is used, as
shown in the following Table 3:
Table 3 — MARGINS-OF-SAFETY FOR CHEMIGATION1
Corn
Applicator
No protection (open pour) 13
Gloves (open pour) 59
Gloves/Closed System 2490
1 The MOSs in this table are for the highest use rate.
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4. Sprav drift. Surrogate exposure studies were used to
estimate exposure to cyanazine through spray drift. -Based on
these exposure estimates, the HOS for a population exposed to
cyanazine by spray drift would be over 1000.
B. OTHER RISK REDPCTION MEASURES
1. Separate laundering. Secondary exposure may occur when
contaminated clothes are brought home. Although data are not
available to quantify such exposure, data do show that cross-
contamination does occur when contaminated clothes are washed
with household laundry. Washing cyanazine-contaminated clothes
separately from household laundry would prevent cross-contamination
of other laundry.
2* Chemical-resistant aprons. While the risk of dermal
exposure to the body from leaning against .tanks during mixing or
loading operations (a common occurrence) and accidental spills
cannot be quantified, it may be significant in light of the
developmental toxicity of cyanazine. Wearing a chemical-
resistant apron while mixing or loading cyanazine would reduce
exposure from accidental contact or spills.
3. Washing of protective gloves. Because hands receive the
largest percentage of the dermal.exposure during mixing/loading,
the Agency believes that protective gloves will be contaminated
on the outside with cyanazine. If protective gloves are washed
with soap and water after use and before being removed from the
hands, the risk of exposure from contaminated gloves will be
reduced.
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4. Restricted Use. Cyanazine products 'have already*been
classified for Restricted Use, as stated in the cyanazine Registra-
tion Standard which was issued in January 1985. The Registration
Standard stated that the reason for this Restricted Use classifi-
cation was that cyanazine had been detected in ground water and
surface water. Label language regarding cyanazine's developmental
toxicity and detection in ground water and surface water was
added to cyanazine labels in accordance with the Registration
Standard, but this language was not explicitly tied to the
Restricted Use requirement.
The Agency's preliminary determination proposed requiring
labels to further state that cyanazine products have specifically
been classified for Restricted Use because cyanazine has been
found in ground water and because it has caused birth defects in
laboratory animals. The Agency based that proposed requirement
on the belief that the reasons a pesticide is classified for
Restricted use should be more prominently displayed on the labels
so that the users and other members of the public can more readily
identify these reasons.
State sponsored monitoring studies, available at the time the
Registration Standard was issued, had located residues of cyanazine
in wells in Iowa, Pennsylvania, Minnesota, Illinois, and Vermont.
Only a small percentage of all the cyanazine samples taken were
positive, at levels close to 1 part per billion (ppb). Also, the
Agency Office of Water Regulations and Standards' STORE! data
base bad reported finding cyanazine in wells. That data base
included reports on 1564 samples, reporting 21 positive samples
(1.3 percent), with the 85th percentile level equal to 0.2 ppb.
(State agencies submit data into the STORE! data base.)
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To provide a more systematic evaluation of cyanazine's
con taaii nation potential, the Agency required the registrant to
conduct a ground water and surface water monitoring study. Those
data have now been submitted and reviewed and are summarized
below.
Two study areas of two counties each were monitored in 1986.
In the hydrogeologically vulnerable East coast, Sussex County,
Delaware and Worcester County, Maryland were sampled. In the
moderately vulnerable Midwest study area, Champaign County,
Illinois and Jones County, Iowa were studied. There were no
positive results in the 400 samples (200 wells each sampled
twice). These results have some consistency with the previously
mentioned monitoring studies which showed 1 percent positives
with findings near and less than 1 ppb.
As a result of the newly generated monitoring data and
the previously .available -data, the Agency no longer believes that
cyanazine has significant ground water contamination potential.
Therefore, EPA no longer believes that ground water contamination
should be a reason for classifying cyanazine for Restricted Use.
Therefore, all cyanazine labels will include a statement that
cyanazine products have been classified for Restricted Use only
because cyanazine has caused birth defects in laboratory animals.
However, because some instances of contamination were reported in
the earlier studies, the Agency believes the ground water advisory
statement should remain on the label.
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III. DETERMINATION OF BENEFITS^
A. THE EFFECT OP THE RISK REDUCTION MEASURES ON BENEFITS
The Agency expects that the risk reduction measures required
in this Notice will have a negligible effect on the benefits
otherwise associated with the use of pesticide products containing
cyanazine. The requirements involving separate laundering,
washing of gloves, and adding a statement on Restricted Use to
the cyanazine label will have minimal impact on the cost of using
cyanazine pesticide products. The requirements to use protective
gloves and aprons will have a negligible impact on the cost of
use of cyanazine products. In as much as there is not a great
deal of aerial use of cyanazine and most aerial applicators
already have systems which allow for some degree of closed transfer,
the requirement that aerial applicators use closed loading systems
is not expected to have a significant impact on the benefits
Associated vith cyana^tne -use. 'Similarly, there is little use of
cyanazine through chemigation, and the requirement that closed
loading systems be used with chemigation is not expected to
have a significant impact on benefits. None of the modifications
are expected to prevent users from using cyanazine products
wherever such products are currently used. Thus, the Agency
believes that the required modifications will have a negligible
impact on the benefits associated with the use of pesticide
products containing cyanazine.
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B. BENEFITS AND THE TYPES OF APPLICATIONS
1." Ground boom application. The largest use of cyanazine
is for broadleaf and grass weed control in corn, accounting for
about 95 percent of its total annual usage. Approximately 15 to
20 million acres (20 to 25 percent of the total U.S. corn acreage)
of corn are treated annually with cyanazine as either the sole
active ingredient oc tank-mixed with other herbicides. Growers
select cyanazine over other available herbicides for the following
reasons: (a) it has a wide annual bro.adleaf and grass weed
control spectrum; (b) it can be tank-mixed with a number of
herbicides to broaden its weed control spectrum; (c) it has
relatively short persistence in the soil; (d) it has no
rotational crop restrictions; and (e) certain soil types and/or
soil conditions require the use of a short residual herbicide in
order to rotate to different crops. The Agency assumes that the
overall impacts from cancellation of cyanazine use on corn could
have significant impacts to individual users in those areas where
soil conditions preclude the use of more persistent chemicals.
The Agency assumes that since the costs of the required label
modifications to the user are relatively low, no one who is
currently using cyanazine would be kept from its use in the future.
As a result, there would only be a negligible reduction in benefits
in relation to those benefits which are currently realized.
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Only small acreages of wheat fallow, cotton, and sorghum
are treated with cyanazine in the United States. Cyanazine
is used primarily where a broad spectrum of weed control is
desirable without the carry-over associated with many of the
more residual herbicides. As with the impact on benefits to
cyanazine use on corn, the Agency also assumes that there
would only be a negligible reduction in the benefits of
cyanazine use of wheat fallow, cotton, and sorghum as a
result of the required label modifications.
2. Aerial application. Available data indicate that
approximately 70,000 acres of corn are treated aerially with
cyanazine. Aerial application to grain sorghum and wheat
fallow is minimal. There are no data showing that cyanazine
is being applied aerially to cotton. The main benefits from
aerial application are the ability to treat either a large area
in a short period of time or when the soil in the fields is too
wet to allow access with ground equipment. The Agency assumes
that the costs resulting from the label modification which
requires closed systems for transfer of cyanazine will not
create significant hardship or reduction in these benefits
because most aerial applicators already have systems which
allow for some degree of closed transfer.
3. Chcmigation. No significant usage of cyanazine
through chemigation has been reported. The Agency assumes
that the required label modifications will therefore have no
significant effect on the benefits associated with that type
of application.
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IV* COMMENTS OF USDA, SAP, AND PUBLIC
A. COMMENTS FROM USDA AND AGENCY RESPONSE
In accordance with FIFRA section 6, the Agency's prelimi-
nary determination was sent to the U.S. Department of Agriculture
(USDA) for comment.
Comment from OSDA. USDA commented that EPA did not give
a numerical estimate for the benefits of cyanazine use on
corn and that EPA should examine the risks associated with
cyanazine*s alternatives.
Agency response. In the Cyanazine Special Review
Technical Support Document, which was issued with the Agency's
preliminary determination on cyanazine, the Agency assumed that
the overall impacts from concellation of cyanazine on corn would
be low due to the availability of registered alternatives. EPA
did not conduct a quantitative estimate of the benefits of
cyanazine use on corn because EPA concluded that the impacts
on corn farmers will be negligible if the registrant maintains
its registrations with the label modifications proposed by the
Agency in its preliminary determination.
Therefore, the Agency does not expect those who use
cyanazine now to stop using cyanazine and switch to an
alternative herbicide .because of the required modifications
to cyanazine labels. However, as mentioned in the Agency's
Technical Support Document for cyanazine, the following
herbicides may be used as alternatives to cyanazine:
alachlor; atrazine; proroetryn; propachlor; fluometuron; diuron;
and simazine. The risks associated with these alternatives
are given in Unit IV.A.1.-7. of this notice.
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1. Alachlor. Sufficient' toxicity data in laboratory- v
animals are available in the Agency to classify this pesticide
under toxicity category III for acute oral and dermal exposure.
This chemical does not cause eye or skin irritation.
No teratogenic effects were demonstrated when alachlor
was given to pregnant rats. However, administration of
alachlor to rats at 30 rag/kg/day through three successive
generations produced kidney alterations in F2 and F3 offspring.
A reproductive NOEL was established by the Agency at 10 mg/kg/day.
Evidence of a mutagenic effect was not demonstrated in
the several assays (CHO/HGPRT, Salmonella, £. coli, and jJ.
subtilis). Data from chronic feeding studies indicated that
alachlor induced nasal turbinate tumors in rats and bronchiolar
alveolar tumors in female mice. This herbicide is classified
»
as a category B2 oncogen (probable human carcinogen) by the
Agency and a consolidated- Q*- (-cancer potency) -of -8 x 10"2 for
(ing/kg/day)'! human equivalents has been calculated. These
risks are discussed in the Agency's Conclusion of Special
Review for Alachlor signed on December 14, 1987.
2. Atrazine. The available toxicity data support the
classification of atrazine under toxicity category III for
acute oral, dermal, and inhalation exposure. Atrazine is
neither a dermal nor eye irritant.
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A rat developmental toxicity study has been classified
as Supplementary Data because a developmental toxicity NOEL
could not be established. The LOEL was 10 mg/kg/day (lowest
dose tested), based on an increased incidence of runts. A
maternal NOEL was established at 10 mg/kg/day, with decreased
body weight observed at 70 mg/kg/day.
A rabbit developmental toxicity study showed a NOEL of
1 mg/kg/day and a LOEL of 5 mg/kg/day for maternal toxicity,
based on reduced body weight gains. The NOEL for developmental
toxicity was 5 mg/kg/day and the LOEL was 75 mg/kg/day, based
on increased resorptions, reduced fetal weights for both
sexes, and increases in delayed ossification. The rabbit
study is also classified as Supplementary Data.
In a chronic/oncogenic rat study, an increase in carcinomas
of the mammary glands was observed in females fed 70, 500, or
1000 .parts, per million-(-ppm) for 2-years. There was also an
increase in the incidence of fibroadenomas/carcinomas (1000 ppm)
and all mammary tumors in females receiving 500 and 1000 ppm,
when compared to controls. The Agency has classified atrazine
as a category C carcinogen (possible human carcinogen).
Mammary gland adenocarcinoma incidence data were used to
estimate the Q* of atrazine. The Q* was determined to be
1.24 x 10~l (ag/kg/day)"! in human equivalents.
3. Prometrvn. The available toxicity data place tech-
nical prometryn under toxicity category III for acute oral
and dermal, and toxicity category IV for acute inhalation
exposure. There is no evidence to suggest that prometryn is
a dermal or eye irritant.
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A developmental toxicity NOEL was escao.iisned at 72 wg/kg
in rabbits but no developmental toxicity NOEL could: be ascertained
from a rat teratology study. Although the rat multigeneration
reproduction study was classified as supplementary data, there
is no suggestive evidence of an adverse effect on reproduction
up to and including the highest dose tested, 5 mg/kg/day.
Chronic and oncogenicity data are insufficient to assess
the oncogenic potential of prometryn.
4. Propachlor. Propachlor is moderately toxic to labora-
tory animals. The acute oral and dermal LDSOs are classified
as toxicity category III and IV, respectively. Placement of
propachlor in rabbit eyes produced corneal opacity, ulceration,
iris irritation, chemosis, and conjunctivitis. This herbicide
is also a strong dermal sensitizing agent.
Administration of propachlor to pregnant rats did not
result in developmental toxicity up to and including a dosage
level of 200 mg/kg.
The reproductive and the oncogenic potential cannot be
ascertained since no valid studies are available. It is note-
worthy to mention that propachlor is structurally related to
alachlor (discussed previously), a B2 oncogen.
5. Diuron. Diuron is classified as toxicity category III
for acute oral, dermal, and inhalation exposure, it does not
produce eye or skin irritation. ...
No acceptable teratology studies are available to assess
the developmental toxicity potential of diuron. A multigenera-
tion reproduction study was conducted in rats and decreased
F2b and F3a offspring weights were noted at the single dose
level tested (6.25 mg/kg).
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No acceptable oncogenicity studies are available. However,
diuron was clastogenic in an in vivo cytogenetic assay. Further,
diuron is structurally related to linuron, a category C oncogen
(possible human carcinogen).
6. Fluometuron. Sufficient data are available to suggest
that fluometuron has a low acute toxicity in laboratory animals.
The acute oral and dermal LDSOs and the acute inhalation LC50
belong to toxicity category III. However, fluometuron produces
severe dermal irritation, corneal opacity, and may cause dermal
sensitization.
No data are available to assess the developmental toxicity,
•
reproductive, chronic, mutagenic, and oncogenic potential for
this herbicide.
7. Simazine. Siroazine is structurally related to atrazine
and cyanazine. It is relatively non-toxic to laboratory animals
•
after -acute ^ral- exposure -(toxicity category IV). "However, it
is moderately toxic after inhalation (toxicity category II).
The 80 percent wettable powder formulation produced corneal
opacity and skin irritation.
A developmental toxicity NOEL was established in rabbits
at 75 mg/kg/day with decreased fetal weights and increased
skeletal variations noted at the 200 mg/kg/day. In the rat,
administration of 100 ppra did not exert any adverse reproductive
effect.
Data are Inadequate to assess the chronic toxicity,
oncogenic and mutagenic potentials of siraazine.
In summary, the Agency has a more complete data base for
cyanazine than for most of its alternatives. The most widely
used alternative to cyanazine is atrazine, which may have more
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persistent residues, has been classified as a~categoiTy"^f*"bncogenrr
and leaches through the ground at the same rate as cyanazine.j
B. COMMENTS FROM SAP AND AGENCY RESPONSE
In accordance with FIFRA section 24, the Agency's preliminary
determination was sent to the FIFRA Scientific Advisory Panel
(SAP or Panel) for comment. An open meeting was held with
the SAP on March 24, 1987 to discuss scientific issues being
considered by the Agency in connection with the Special
Review of cyanazine. Specifically, the Agency requested any
comments that the Panel wished to make with regard to the
Agency's use of the dermal developmental toxicity study to
assess the hazards from dermal exposure.
1. SAP comment on maternal toxicitv. The Panel believed
that the dermal developmental toxicity study was an appropriate
data set for determining hazards from dermal exposure. However,
the Panel also believed that the toxic endpoint that should
have been used was the NOEL for dermal maternal systemic
toxicity (96 mg/kg/day), not dermal developmental toxicity
(573 mg/kg/day). The Panel stated that developmental toxicity
occurred only at doses that were maternally toxic, and maternal
systemic toxicity occurred at lower exposures; thus, a lower
MOS existed for adult animals than for the developing fetus.
'Agency response* Oral administration of technical cyanazine
induced developmental toxicity (including malformations) in
rabbits and rats. From the rabbit oral developmental toxicity
data, both maternal and fetal developmental toxicity NOELS were
established at 1 mg/kg/day.
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Dermal application of technical cyanazine produced maternal
toxicity (body weight depression and food consumption reduction)
at 283 mg/kg/day and above. A naternal NOEL was established
at less than 96 mg/kg/day based upon dermal irritation and at
96 mg/kg/day based upon systemic effects. Developmental
toxicity (delayed ossification) was found at 955 mg/kg/day
and a dermal developmental toxicity NOEL was established at
573 mg/kg/day. The NOEL of 573 mg/kg/day for dermal develop-
mental toxicity was used by the Agency to calculate risk in
its preliminary determination.
A Peer Review Committee consisting of representatives
from different Agency Offices met to discuss the comments
raised by the SAP. The Peer Review Committee concluded that
the use of the maternal NOEL from a developmental toxicity
study in calculating the MOS may not be justified because:
a. In general, maternal toxicity end points determined
from a developmental toxicity study (body weight, organ
weight, food consumption, clinical signs) are insensitive
parameters that do not reflect a true NOEL. Based upon the
weight-of-evidence, determination of maternal toxicity requires
scientific judgement on a case-by-case basis.
b. Developmental toxicity manifestations may or may not
be associated with maternal toxicity because the mechanisms
by which toxicity is manifested are different.
c. As a screening test, a developmental toxicity study
is designed primarily to assess effects on the developing
organism and does not allow characterization of subtle changes
in systemic toxicity due to an inadequate length of exposure
(10 days).
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d. Manifestations of maternal systemic toxicity may result
froo repeated exposures whereas manifestations of developmental
toxicity aore likely result from a single exposure. Therefore,
NOELS for maternal systemic toxicity and for developmental
toxicity may not reflect comparable lengths of time during
which exposure occurred.
2. SAP comment on label language. The SAP believes that
the Agency is correct in requiring the label changes to reduce
applicator exposure, but that it should not state that birth
defects are the reason since developmental toxicity occurred
at maternally toxic doses and maternal systemic toxicity
occurred at lower exposures.
Agency response. The SAP recommendation relative to
"maternal toxicity occurred at lower doses than developmental
toxicity" applied only to the dermal developmental toxicity
data. By the oral route of administration, developmental
toxicity an'd maternal toxicity are observed at the same dose
level (both NOELs are established at 1 mg/kg/day and both
LOELs are established at 2 mg/kg/day). The Agency's "Guideline
for the Health Assessment of Suspect Developmental Toxicants
(1986)" states that "when developmental effects are produced
only at aaternally toxic doses, the types of developmental
effects should be examined carefully, and not discounted as
being secondary to maternal toxicity. Current information is
inadequate to assume that developmental effects at maternally
toxic doses result only from the maternal toxicity; rather,
when the lowest observed effect level is the same for the
adult and developing organisms, it may simply indicate that both
are sensitive to that dose level."
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The developmental toxicity hazard of cyanazine was
demonstrated by the oral route of administration (structural
abnormalities including malformations) at maternally toxic
doses, (indicating that both the mothers and developing
organisms may be equally sensitive to that dose level), and
confirmed by the dermal route of administration (developmental
delay, altered growth) at doses higher than those producing
maternal toxicity. Therefore, the developmental toxicity
hazard of cyanazine is still of concern and failure to state
that "... cyanazine has caused birth defects in laboratory
animals ... " is not justified, consequently, the Agency
supports its original position of requiring this advisory
statement on cyanazine labels.
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C. COMMENTS FROM THE PUBLIC AND AGENCY RESPONSE'
The only public comment submitted in response to the
Agency's preliminary determination which challenged the
Agency's position was submitted by the cyanazine registrant,
E. I. Du Pont De Nemours Company (Du Pont). The Cyanazine
Technical Support Document, which was issued with the Agency's
preliminary determination, cited Shell Chemical Company,
Setre Chemical Company, and R. F. Lindsey and Sons as the
registrants for cyanazine. However, since the preparation of
the Technical Support Document, Setre and Lindsey have volun-
tarily cancelled their cyanazine registrations, and Du Pont
has purchased Shell's cyanazine registrations.
1. Du Pont comment on birth defects label. Du Pont believed
that there was no basis for concern from exposures associated
with present use labels and that the statement regarding birth
defects should be removed from the label.. -Also., Dupojit..stated
that maternal toxicity was always seen at doses lower than
those showing fetotoxicity, and therefore, cyanazine was not
a true "teratogen" and should be of no concern.
Agency response. By the dermal route of administration,
structural anomalies (not malformations) are observed in rabbits
at doses higher than those producing maternal toxicity. However,
by the oral route of administration, manifestations of develop-
mental toxicity, including malformations: anophthalmia/micro-
ophthalmia; dilated brain ventricles; and diaphragmatic hernia,
are observed in both rabbits and rats. Although these manifesta-
tions occur at a dose level which also produces some evidence
of maternal toxicity, they cannot be considered as secondary
to maternal toxicity.
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Current information is inadequate to assume that developmental
effects at maternally toxic doses result only from maternal
toxicity; rather, when the lowest effect is the same .for the
adult and developing organisms, it simply indicates that both
are sensitive to that dose level. Therefore, the association
between developmental toxicity manifestations in both rats
and rabbits by the oral route of administration and cyanazine
cannot be ruled out. Based upon these data, there is evidence
to suggest that cyanazine is a developmental toxicant (multi-
species evidence of similar findings).
Du Font's statement, "maternal toxicity was always seen
at doses lower than those showing fetotoxicity," is misleading.
This is true for the dermal but not for the oral studies in
which maternal toxicity and fetotoxicity occurred at the same
dosage level.
2. Du Pont comment on separate laundering. Ou Pont agreed
that cross-contamination may occur when contaminated clothing
is washed with household laundry and that separate laundering
is a "prudent precaution* to take with all pesticide contaminated
clothing. However, Du Pont questioned "the imposition of a
requirement to launder cyanazine-contaminated clothing separately
from household laundry in lieu of data specific to cyanazine."
Du Pont believed that "this requirement should be added to
cyanazine labels at the time this change is mandated for all
pesticide labeling, unless specific data warrant otherwise."
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Aoencv response* The Agency lioucs that Du Pont .agrees
that it would be prudent to wash cyanazine-contaminated
clothing separately from household laundry. The Agency believes
that by stating such on the label it is more likely that this
precaution will be taken. That label language is being required
to be added to cyanazine labels at this time in order to
reduce potential exposure and because the Agency has just
completed its review of worker exposure to this chemical.
3. Du Pont comment on chemical-resistant aprons. Du Pont
disagreed with the Agency's position regarding the use of
chemical-resistant aprons. In opposition to a statement which
was made in the Agency's preliminary determination, Du Pont
stated that there were data to quantify the risks associated
with dermal exposures resulting from leaning against mixing
tanks and accidental spills; Du Pont stated that the cyanazine
exposure study which was used by the Agency to calculate some
of the risks presented in the preliminary determination
employed all common practices in mixing and loading, including
leaning against the spray tanks. Also, Du Pont believed that
chemical-resistant aprons were bulky and cumbersome to wear
and proposed the following label language, instead of requiring
the use of chemical-resistant aprons:
In case of accidental exposure, remove contaminated
.' . , » • •'
clothing and wash skin thoroughly with soap and
water. Replace contaminated garments with clean,
freshly laundered clothing before returning to
pesticide handling operations.
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Aoencv response. The Agency has no indication that
chemical-resistant aprons are difficult to wear and has imposed
this requirement on other pesticide registrations. The Agency
does not agree with Du Font's proposed label language because
it is unlikely that when an accidental spill occurs, a pesticide
operator would be in a situation where it is convenient to
immediately remove his/her clothing, put on clean clothing,
and resume his/her duties.
4. Du Pont comment on Restricted Use classification.
Du Pont also believed that cyanazine should be reclassified
from Restricted Use to general use. Du Pont based their
position on the beliefs that: cyanazine is not a teratogen
in the absence of maternal effects; the Agency's requirements
for additional protective clothing and closed loading systems
will provide adequate occupational MOS.r and recently collected
ground water samples did not contain detectable residues of
cyanazine or the amide metabolite SD 20258.
Agency response. The Agency agrees with Du Pont's comment that
it is not appropriate to classify cyanazine for Restricted
Use due to ground water concerns. As discussed in Unit II.B.4.
of this Notice, new monitoring data have shown that out of
400 samples from 200 wells in two East Coast counties and two
Midwest counties, no detectable levels of cyanazine were
found. However, the Agency continues to believe that cyanazine
poses developmentally toxic concerns and that Restricted Use
is an appropriate requirement to mitigate this concern.
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The Agency has found that when a pesticide is classified
for Restricted Use, the pesticide operators are better educated'
in the proper use of a pesticide. Therefore, it is more likely
that label directions will be complied with, and practices
are less likely to occur which may result in unreasonable
exposures to mixers/loaders or applicators. Therefore,
cyanazine will remain classified for Restricted Use because
of its developmental toxicity.
V. RISK/BENEFIT CONCLUSIONS
As discussed in Unit II. of this Notice, the Agency has
found that there are substantial risks associated with the
currently registered use patterns of pesticide products con-
taining cyanazine. The Agency has also determined that there
are modifications available that can significantly reduce
these risks. The Agency has further determined in Unit III.
of this Notice that adoption of. these modifications -will have
a negligible effect on the benefits associated with the use
of pesticide products containing cyanazine. The Agency
therefore believes that current use patterns generally cause
unreasonable adverse effects upon the environment and that
cyanazine products should be cancelled unless the following
modifications are made:
1. For ground boom applications, the label must require:
a. the use of protective gloves; b. use of chemical-resistant
aprons; c. separate laundering of cyanazine-contaminated clothes;
and d. washing of protective gloves. In addition, the label
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must include a statement explaining that cyanazine products
have been classified for Restricted Use because cyanazine has
caused birth defects in laboratory animals.
2. For aerial applications and chemigation, the label
must require: a. the use of protective gloves; b. a closed
loading system; c. use of chemical-resistant aprons; d.
separate laundering of cyanazine-contaminated clothes; and e.
washing of protective gloves. In addition, the label must
include a statement explaining that cyanazine products have
been classified for Restricted Use because cyanazine has
caused birth defects in laboratory animals. The labels of
product formulations which cannot be used in a closed loading
system must contain language prohibiting the use of those
formulations via aerial application and chemigation.
VI. COMPLIANCE WITH THIS NOTICE
A. DEFINITIONS
The following terms are defined for the purposes of this
Unit.
1. "Manufacturer" refers-to any registrant who, as
defined, sells or distributes a pesticide product containing
cyanazine. . '- •*
2. 'Distribute and sell" and grammatical variants refer to
the distribution, sale, offering for sale, holding for sale,
shipping, delivering for shipment, or receiving and (having so
received) delivering or offering to deliver a pesticide product.
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B. REQUIREMENTS FOR COMPLYING WITH THIS'NOTICE-
A.manufacturer of any pesticide product containing cyanaz'ine
must submit an application to amend the registration of the
product within 30 days of publication in the FEDERAL -REGISTER
or receipt of this Notice, whichever is later, to be allowed
to continue to sell and distribute the product. The application
must propose to amend the registration of the product to include
the following terms and conditions and modifications to labeling:
a. Require the use of protective gloves when mixing or
loading cyanazine or when adjusting, repairing, or cleaning
equipment.
b. Require the following precaution concerning the washing
of protective gloves:
Protective gloves must be washed
with soap and water after use
and before removing from the hands.
c. "Require the use of closed systems in connection with
aerial use and chemigation (product formulations which cannot
be used in a closed loading system must prohibit aerial use
and chemigation).
d. Require use of a chemical resistant apron when mixing or
loading.
e. Require that all "Restricted Use" statements include a
statement that cyanazine products have been classified for Restricted
Use because cyanazine has caused birth defects in laboratory
animals.
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f. Include the following precaution concerning the washing
of contaminated clothing:
Cyanazine-contaminated clothing should
be laundered separately from household
laundry to prevent cross-contamination
of other laundry. Heavily contaminated
or drenched clothing and protective equip-
ment must be discarded or destroyed in
accordance with state and local regulations.
C. EXISTING STOCKS AND DISPOSAL PROVISIONS
Under the authority of FIFRA Section 6(a)(l), EPA will
establish certain limitations on the sale, distribution and
use of existing stocks of cyanazine pesticide products subject
to any final cancellation notice. EPA defines the term
"existing stocks" to mean any quantity .of cyanazine pesticide
products in the United States on the effective date of final
cancellation of a cyanazine registration or on the effective
date an application for amendment of registration as provided
for in Section VLB of this Notice is granted by the Agency.
Such existing stocks include cyanazine products that have
been formulated, packaged and labeled and are being held for
shipment or release or have been shipped or released into commerce,
As stated earlier in this Notice, EPA believes certain
modifications to the terms and conditions of registration are
necessary in order to prevent the use of cyanazine products
from causing an unreasonable adverse effect upon the environ-
ment. In order to allow for the modifications to be made or
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to allow for substitution of alternative control7methods, EPA
will allow sale and distribution of existing stocks of cyanazine
for up to sit aonths after final cancellation or approval of
an amendment to the registration. Existing stocks nay be
sold or distributed, by the registrant or by any other person,
after this six-month period only if the stocks have been
relabeled to reflect the modifications identified in this
Notice.
EPA also will allow use of existing stocks for up to 1
year after final cancellation or approval of an amendment to
the registration. Existing stocks may be used after this
one-year period only in accordance with the modifications
identified in this Notice. Any disposal of existing stocks
not relabeled in accordance with this Notice must be in
accordance with the requirements of the Resource Conservation
and Recovery Act.
- Any existing stocks provisions involved in voluntary
cancellation of a cyanazine product prior to the publication
of the final Notice is not affected by this provision.
>
VII. PROCEDURAL MATTERS
This Notice announces EPA's intent to cancel the registrations
of pesticide products that contain cyanazine. This Unit explains
how .current registrants may apply to amend their registrations
to comply with the terms and conditions discussed in Unit V.
of this Notice.
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Urider sections 6(b) and 3(c)(6) of FIFRA, applicants,
registrants, and certain other adversely affected persons are
also entitled to respond to this Notice by requesting a
hearing on the actions that EPA is initiating. Unless a
hearing is properly requested with regard to a particular
registration or application, this action will become final by
operation of law.
This Unit of the Notice explains how such persons may
request a hearing on EPA's final cancellation and denial
Notice (and the consequences of requesting a hearing or failing
to request a hearing in accordance with these procedures).
A. PROCEDURES FOR AMENDING THE TERMS AND CONDITIONS OF
REGISTRATION TO AVOID CANCELLATION OR DENIAL OF APPLICATION
Registrants affected by the cancellation actions set forth
in this Notice may avoid cancellation by filing for an application
for an amended registration which contains the label modifications
detailed in Unit VLB. of this Notice. This appliation must
be filed within 30 days of receipt of this Notice or within
30 days from the publication of this Notice, whichever occurs
later. Applicants for a registration subject to this Notice
must file an amended application for registration within the
applicable 30-day period to avoid denial of their pending
application.
Applications must be submitted to:
Robert J. Taylor,
Product Manager 25,
Registration Division (TS-767C),
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Office of /isticide Programs,
Environmental Protection Agency,
401 M St., SW.,
Washington, DC 20460,
(703-557-1800).
B. PROCEDURES FOR REODESTING A HEARING
To contest the cancellation action set forth in this Notice,
Federal registrants or applicants may request a hearing within
30 days of receipt of this Notice, or within 30 days from
publication of this Notice, whichever occurs later. Any
other person adversely affected by the action described in
*
this Notice may request a hearing within 30 days of publication
Of this Notice in the FEDERAL REGISTER.
A registrant or other adversely affected party who requests
a hearing must file the request in accordance with the proce-
dures established by FIFRA and EPA's Rules of Practice Governing
Hearings under 40 CFR Part 164. These procedures require,
among other things, that all requests must identify the
specific pesticide product(s) for which a hearing is requested,
and that all requests must be received by the Hearing Clerk
within the applicable 30-day period. Failure to comply with
these requirements may result in denial of the request for a
hearing. Requests for a hearing -should also be accompanied
by objections that are specific for each use of each pesticide
product(s) for which a hearing is requested.
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Reguests for a hearing must be submitted to:
Hearing Clerk (A-110),
Environmental Protection Agency,
401 M St., SW.,
Washington, DC 20460.
1. Consequences of filing a timely and effective hearing
request. If a hearing on the action initiated by this Notice
is requested in a timely and effective manner, the hearing
will be governed by EPA's Rules of Practice for hearings
under FIFRA section 6 (40 CFR Part 164), as modified below.
The hearing will be limited to the specific uses and specific
product registrations for which the hearing is requested.
In the event of a hearing, the specific use or uses of
the specific registered product which is the subject of the
hearing request will not be cancelled except pursuant to an
order of the Administrator at the conclusion of the hearing.
2. Consequences of failure to file in a timely and
effective manner. If a hearing concerning the registration
of a specific pesticide product subject to this Notice is not
requested by the end of the applicable 30-day period, registra-
tion of that product will be cancelled, unless the registrant
files a request for an amended registration within the statutory
period provided herein. (See Unit VI of this Notice.)
If the registration of a product covered by this Notice
is cancelled by operation of law, the sale and distribution of
existing stocks is governed by the provisions of Unit VI of this
Notice.
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C. SEPARATION OF FUNCTIONS
EPA's Rules of Practice forbid anyone who nay take-part
in deciding this case, at any stage of the proceeding, from
discussing the merits of the proceeding ejc parte with any
party or with any person who has been connected with the
preparation or presentation of the proceeding as an advocate
or in any investigative or expert capacity, or with any of
their representatives (40 CFR 164.7).
Accordingly, the following EPA offices, and the staffs
thereof, are designated as the judicial staff to perform the
judicial function of EPA in any administrative hearing arising
from this Notice of Intent to Cancel: the Office of the Adminis-
trative Law Judge, the Office of the Judicial Officer, the
Administrator, and the Deputy Administrator. None of the persons
designated as the judicial staff may have any ex parte communi-
cation on the merits of any of the issues involved in this
proceeding, with the trial staff or any interested person not
employed by EPA, without fully complying with the applicable
regulations.
VIII. PUBLIC DOCKET
Pursuant to 40 CPR 154.15, the Agency has established a
public docket (OPP-30000/46B) for the Cyanazine Special Review.
This public docket includes:
(1) This Notice.
(2) Any other notices pertinent to the cyanazine Special
Review.
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(3) Non-CBI documents copies of written comments or
other.materials submitted to the Agency in response to this
Notice, and any other Notice, regarding cyanazine submitted
at any time during the Special Review process by any-person
outside government.
(4) A transcript of any public meeting held by'the Agency
for the purpose of gathering information on cyanazine.
(5) Memoranda describing each meeting held during the Special
Review process between Agency personnel and any person outside
government pertaining to cyanazine.
(6) A current index of materials in the cyanazine public
docket.
On a monthly basis, the Agency will distribute a compendium
of indices for newly received comments and documents that have
been placed in the public docket for this Special Review. This
compendium will be distributed by mail to those members of the
•p-ubii-c-vho have - sped fical-ly -requested such material for this
Special Review, pursuant to 40 CFR 154.15(f)(3).
Dated; ^S 7^*_<_ ? "?
,
i i.ce of Pesticides and
Toxic Substances
CERTIFIED TO BE A TSUI
COPY OF THE
So/dm,
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