vvEPA
United States
Environmental Protection
Agency
Prevention, Pesticides
And Toxic Substances
(7508W)
Auousi 1Q33
Reregistration
Eligibility Decision (RED)
Amitrole
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
OFFICE OF
PREVENTION, PESTICIDES
AND TOXIC SUBSTANCES
NOV 2 2 1995
CERTIFIED MATT;
Dear Registrant:
I am pleased to announce that the Environmental Protection Agency has completed its
reregistration eligibility review and decisions on the pesticide chemical case amitrole which
includes the active ingredient amitrole (3-amin6-l,2,4-triazole). The enclosed Reregistration
Eligibility Decision (RED) document contains the Agency's evaluation of the data base of
these chemicals, its conclusions of the potential human health and environmental risks of the
current product uses, and its decisions and conditions under which these uses and products
will be eligible for reregistration. The RED includes the data and labeling requirements for
products for reregistration. It also includes requirements for additional data (generic) on the
active ingredients to confirm the risk assessments.
To assist you with a proper response, read the enclosed document entitled "Summary
of Instructions for Responding to the RED." This summary also refers to other enclosed
documents which include further instructions/You must follow all instructions and submit
complete and timely responses. The first set of required responses are due 90 days from
the date of your receipt of this letter. The second set of required responses are due 8
months from the date of your receipt of this letter. Complete and timely responses will
avoid the Agency taking the enforcement action of suspension against your products.
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Please note that this RED was finalized and signed prior to August 3, 1996. On that
date,,the Food Quality Protection Act of 1996 ("FQPA") became effective, amending portions
of both the pesticide law (FIFRA) and the food and drug law (FFDCA). This RED does not
address any issues raised by FQPA, and any tolerance-related statements in the RED did not
take into account any changes in tolerance assessment procedures required under FQPA. To
the extent that this RED indicates that a change in any tolerance is necessary, that
determination will be reassessed by the Agency under the standards set forth in FQPA before
a proposed tolerance is issued. To the extent that the RED does not indicate that a change in a
tolerance is necessary, that tolerance too will be reassessed in the future pursuant to the
requirements of FQPA.
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If you have questions on the product specific data requirements or wish to meet with
the Agency, please contact the Special Review and Reregistration Division representative
Nancy Tonipkins at (703) 308-8172. Address any questions on required generic data to the
Special Review and Reregistration Division representative Mario F. Fiol at (703) 308-8049.
Sincerely yours,
oQ.
Lois A. Rossi, Director
Special Review and
Reregistration Division
Enclosures
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SUMMARY OF INSTRUCTIONS FOR RESPONDING TO
THE REREGISTRATTON EIJGIBILITY DECISION (RED)
1. - DATA CALL-IN (DCI) OR "90-DAY RESPONSE"-If generic data are required for
reregistration, a DCI letter will be enclosed describing such data. If product specific data
are required, a DCI letter will be enclosed listing such requirements. If both generic and
product specific data are required, a combined Generic and Product Specific. DCI letter will
be enclosed describing such data. However, if you are an end-use product registrant only and
have been granted a generic data exemption (GDE) by EPA, you are being sent only the
product specific response forms (2 forms) with the RED. Registrants responsible for generic
data are being sent response forms for bom generic and product specific data requirements (4
forms). You must submit the appropriate response forms (following the instructions
provided) within 90 days of the receipt of this RED/DCI letter; otherwise, your product
may be suspended.
2. TIME EXTENSIONS AND DATA WAIVER REQUESTS-No time extension requests
will be granted for the 90-day response. Time extension requests may be submitted only with
respect to actual data submissions. Requests for time extensions for product specific data
should be submitted in the 90-day response. Requests fo*r data waivers must be submitted as
part of the 90-day response. All data waiver and time extension requests must be accompanied
by a full justification. All waivers and time extensions must be granted by EPA in order to go
into effect.
3. APPLICATION FOR REREGISTRATION OR "8-MONTH RESPONSE"-You must
submit the following items for each product within eight months of the date of this letter
(RED issuance date).
a. Application for Reregistration (EPA Form 8570-1). Use only an original
application form. Mark it "Application for Reregistration." Send your Application for
Reregistration (along with the other forms listed in b-e below) to the address listed injtem 5.
b. Five copies of draft labeling which complies with the RED and current regulations
and requirements. Only make labeling changes which are required by the RED and current
regulations (40 CFR 156.10) and policies. Submit any other amendments (such as formulation
changes, or labeling changes not related to reregistration) separately. You may, but are not
required to, delete uses which the RED says are ineligible for reregistration. For further
labeling guidance, refer to the labeling section of the EPA publication "General Information
on Applying for Registration in the U.S., Second Edition, August 1992" (available from the,
National Technical Information Service, publication #PB92-221811; telephone number 703-
487-4650). '
c. Generic or Product Specific Data. Submit all data in a format which complies
with PR Notice 86-5, and/or submit citations of data already submitted and give the EPA
identifier (MRID) numbers. Before citing these studies, you must make sure that they meet
the Agency's acceptance criteria (attached to the DCI).
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d. Two copies of the Cocf -gntial Statement of Formula (CSF) for each basic and
each alternate formulation. The L ,% and CSF which you submit for each product must
comply with P.R. Notice 91-2 by . ring the active ingredient as the nominal
concentration. You have two optic : for submitting *GSF: (1) accept the standard certified
limits (see 40 CFR ง158.175) or (2) provide certified limits that are supported by the analysis
of five batches. If you choose the second option, you must submit or cite the data for the five
batches along with a certification statement as described in 40 CFR ง158.175(e). A copy of
the CSF is enclosed; follow the instructions on its back.
e. Certification With Respect to Data Compensation Requirements. Complete and
sign EPA form 8570-31 for each product.
4. COMMENTS IN RESPONSE TO FEDERAL REGISTER NOHCE-Comrnents
pertaining to the content of the RED may be submitted to the address shown in the Federal
Register Notice which announces the availability of this RED.
5. WHERE TO SEND PRODUCT SPECIFIC PCI RESPONSES (90-DAY) AND
APPLICATIONS FOR REREGISTRATION (8-MONTH RESPONSES)
ByU.S.Mail;
Document Processing Desk (RED-SRRD-PRB)
Office of Pesticide Programs (7504C) ~
EPA, 401 M St. S.W.
Washington, D.C. 20460-0001
* - '
By express;
Document Processing Desk (RED-SRRD-PRB)
Office of Pesticide Programs (7504C)
Room 266A, Crystal Mall 2
1921 Jefferson Davis Hwy,
Arlington, VA 22202 .
6. EPA'S REVIEWS-EPA will screen all submissions for completeness; those which are not
complete will be returned with a request for corrections. EPA will try to respond to data
waiver and time extension requests within 60 days. EPA will also try to respond to all
8-month submissions with a final reregistration determination within 14 months after the RED
has been issued.
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United States
Environmental Protection
Agency
Prevention, Pesticides
And Toxic Substances
(7508W)
EPA-738-F-96-002
August 1996
&EPAI R F n FACTS
.' . I.%.MF ...! f^Y^^ m \J
AMITROLE
Pesticide
Reregistration
Use Profile
Regulatory
History
.All pesticides sold or distributed in the United States must be
registered by EPA, based on scientific studies showing that they can be
used without posing unreasonable risks to people or the environment.
Because of advances in scientific knowledge, the law requires that
pesticides which were first registered before November 1, 1984, be
reregistered to ensure that they meet today's more stringent standards.
In evaluating pesticides for reregistration, EPA obtains and reviews a
complete set of studies from pesticide producers^ describing the human
health and environmental effects of each pesticide. The Agency develops
any mitigation measures or regulatory controls needed to effectively reduce
each pesticide's risks. EPA then reregisters pesticides that can be used
without posing unreasonable risks to human health or the environment.
- When a pesticide is eligible for reregistration, EPA explains the basis
for its decision in a Reregistration Eligibility Decision (RED) document.
This fact sheet summarizes the information in the RED document for
reregistration case 0095, Amitrole.
I : t '"./'
Amitrole is a terrestrial non-food herbicide used primarily in
industrial areas (outdoors), non-agricultural rights-of-way, fencerows,
hedgerows, non-agricultural uncultivated areas, soils, ornamental and/or
shade trees, and ornamental shrubs and vines. There are no tolerances for
any food crop or water which will be used for irritation, drinking or other
domestic purposes. Amitrole's mechanism of action inhibits carotenoid
synthesis, chlorophyll formation, and limited regrowth of buds Amitrole
formulations include a solid/dust (technical) product, a wettable powder (in
water soluble bags), and an emulsifiable concentrate (the registrant has
requested voluntarily cancellation of this product)! Amitrole is solely
applied by fixed boom sprayers attached to tractors, trucks or railway
(ground equipment).
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Amitrole was first registered as a pesticide in the U.S. in 1948. The
EPA issued a Registration Standard March 30, 1984 (PB87-104766). The
Registration Standard besides requiring submission of studies informed
regisitrants that even though amitrole was not used on food crops and there
was no dietary exposure to the chemical the Agency had major concerns for
dermal exposure, with inhalation furnishing only a minor contribution to the
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total body burden. Human exposure, in some circumstances, occurred at
doses which resulted in antithyroid effects in laboratory animals.
Amitrole's use patterns and application techniques met the oncogenicity risk
criterion for Special Review. The Agency determined that it would not
reregister any current product and it would not register any new product
containing amitrole until all pivotal data was reviewed.
On May 15, 1984, the Agency issued a Notice of Special Review
(Position Document-1) of pesticide products containing amitrole. Thfe
Agency's Special Review was initiated to address the use of amitrole on
non-crop sites (highway rights-of-way, primarily) and by homeowners, and
to examine the carcinogenic risk to mixers, loaders and applicators. The
data indicated that amitrole induces thyroid, pituitary and liver tumors in
laboratory animals. The registrant voluntarily acted on a number of .
measures that reduced worker exposure to amitrole. Among these were the
deletion of the high exposure application methods such as knapsack
sprayers, the adoption of a "no-glug" container design for the liquid
formulation to reduce splashing while pouring, the addition of protective
clothing requirements to labels, and packaging of the wettable powder
formulation in water soluble packets. Lastly, the registrant voluntarily
canceled all homeowner products.
During the Special Review phase, two Data Call-ins (DCIs) were
issued by the Agency. A DCI was issued on February 22, 1990 requesting
efficacy, usage and worker exposure monitoring data for both liquid and
powder formulations of.amitrole. A second DCI was issued on August 16,
1991 requesting product chemistry, ecological and environmental fate
studies and toxicology studies.
Based on a risk and benefit assessment, the Agency concluded that
the benefits provided from the use of amitrole (taking into consideration the
measures previously discussed) outweigh the risks. Thus, the Agency on
October 8,1992 issued a Notice of Final Determination (57 FR 46448) of
the Amitrole Special Review. The Agency continued to require: restricted
use (RU) classification, a cancer warning statement on the label, application
methods remain limited to boom sprayers, and protective clothing
requirements remain on the label. The Notice was published in the Federal
Register and comments were invited for 30 days. No comments were
received.
After reviewing all the submitted data and comparing other pesticidal
chemicals also classified as "restricted use," the Agency has determined that
the restricted use classification is no longer appropriate. Amitrole is
classified as a B2-probable human carcinogen. Two thirds of the Agency's
calculated cancer risk of 10"5 to mixers/loaders (assuming handlers wear
long sleeve shirts, long pants, shoes and socks) is from inhalation exposure.
The Agency believes that the likelihood of inhalation exposure is almost
non-existent since the amitrole is packaged in water soluble bags. Focusing
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Human Health
Assessment
only on cancer risk from dermal exposure, the estimated cancer risk
approaches 10"6. Thus, with the low dermal absorption factor (0.5%) (since
the registrant has requested voluntary cancellation of the amitrole use for
ornamental plant nurseries), continued packaging in water soluble bags,
additional protection (although minimal because of the low dermal
absorption) afforded by chemical resistant gloves and chemical resistant
apron, the Agency concluded that the Restricted Use classification could be
rescinded if the registrant agreed to the following conditions: voluntarily
cancel their liquid formulation product; retain the cancer warning label;
retain the boom sprayer as the only application mode; retain the same use
profile as a non-food use pesticide; and provide the Agency with handler
exposure studies for mixers/loaders of water soluble packages to confirm
the Agency's risk assessment and conclusions. In addition, the registrant
understands that any proposed future expansion of their market will require
that a separate risk assessment be performed for any new use/application
method. Furthermore, amitrole labels must carry a ground water advisory
and the registrant must submit additional ecological studies to complete the
Agency's risk assessment.
Toxicitv
In studies using laboratory animals, amitrole technical has been
shown to be in toxicity category IV and HI (practically non-toxic and
slightly toxic, respectively) for acute oral and acute dermal exposure. The
requirement for an acute inhalation study was waived because a 2-year rat
inhalation study is available. Even though this study was not useful for
regulatory purposes it did show that the LC50 is probably at least greater
than 0.5 mg/1 (the highest target concentration tested). Therefore, it is
likely that the acute inhalation is at least toxicity category m. Amitrole is
also in toxicity category ffi for primary eye irritation and toxicity category
IV for primary dermal irrititation (both with rabbits). Amitrole is not a skin
sensitizer in guinea pigs.
'NOTE: For acute oral, dietary, mammalian/avian/aquatic toxicity:
Category I = very highly or highly toxic
Category n = moderately toxic
Category HI = slightly toxic
Category IV = practically non-toxic
Two human studies indicated minimal oral and dermal effects with
amitrole. A dermal absorption study with amitrole (96.4% pure) and
14-C-amitrole (4.03mCi/nmol) indicated that little or no 14-C amitrole was
absorbed over a period of up to 10 hours at dose levels up to 10.0 mg/rat.
Dietary Exposure
Amitrole is a non-food use pesticide. There are no food use patterns,
and since chronic or lifetime exposure is an unlikely scenario, an RfD is not
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required to be established nor did the Agency conduct a dietary risk
assessment. '-..
Carcinogen
Amitrole ha. oeen classified as a Group B2-probable human
carcinogen by the Office of Pesticide Programs Carcinogeniciry Peer
Review Committee (document dated August 30, 1991). This classification
is based on the thyroid tumors seen in the rat (both sexes, multiple strains)
and mouse (both sexes, two strains) and on liver tumors seen in the mouse
(both sexes, multiple strains) as described in studies. The Agency
calculated a Ql* of 0.68 from the thyroid tumor effects as seen in the first
long term toxicological study.
Occupational and Residential Exposure
All products containing amitrole are for occupational use only. There
are no homeowner use products containing amitrole. And although the
Agency has identified inhalation as an appropriate route of exposure on
which to conduct short term and intermediate term risk assessment, the
Agency also believes that in reality there is little likelihood of actual
inhalation exposure from mixing/loading/applying of amitrole. The
inhalation exposure estimates are very conservative because:
(1) amitrole is not volatile, (2) amitrole is only packaged in water soluble
bags (which greatly reduces the chance for incidental inhalation exposure),
(3) the inhalation exposure values presented in Table 3 reflect data from the
Agency's Pesticide Handlers Exposure Database (PHED Vl.l)ป which for
the water soluble packaging data set includes some instances where
detections were not found but a value of half the limit of detection was
assumed, and (4) the Agency assumed 100% adsorption of inhalation
exposure from both the oral developmental toxicity study and the
reproduction study. The assumption of half the limit of detection is a
common Agency practice in establishing exposure/residue values.
As previously discussed, the registrant voluntarily restricted the use
patterns of amitrole to reduce the exposure of amitrole to handlers. The
wettable powder and liquid concentrate formulations were voluntarily
packaged by the registrant to water soluble packets and "no-glug"
containers, respectively. The only current application method is for fixed-
boom sprayers attached to ground equipment such as tractors, trucks or
railroad wagons.
The registrant has recently requested the voluntary cancellation of the
liquid formulation (in no-glug container) and has also requested the use
deletion the only use currently within the scope of the Worker Protection
Standan ornamental plant nurseries.
The three exposure scenarios identified for amitrole are:
(1) Mixing/loading the liquid concentrate formulation (packaged in
no-glug containers) to support ground application. As noted
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previously, the registrant has requested voluntary cancellation
of this product. The Agency has included the mixer/loader,
exposure/risk estimates for this formulation since the voluntary
. cancellation is still in process. -
(2) Mixing/loading the wettable powder formulation (packaged in
water soluble bags) to support ground application, and
(3) Applying as a spray with fixed-boom ground equipment.
(Exposure data for groundboom equipment is used as a
surrogate for the fixed-boom ground equipment).
The Agency conducted an assessment of the inhalation risks
associated with amitrole following short-term and intermediate-term
exposures to occupational handlers. The Agency has determined that a risk
assessment is not required for short-term and intermediate-term dermal
exposures. Margins of exposure (MOE) for occupational inhalation
exposures were calculated for handlers using the NOELs of 4 mg/kg/day for
short-term and 0.9 mg/kg/day for intermediate-term exposure. Amitrole is
not marketed to homeowners (only application methods is fixed-boom
sprayer), therefore the sole exposure concern is for occupational handlers.
The calculations indicate that with the exception of one scenario, all of the
MOEs for short- and intermediate-term inhalation exposures at baseline
protection (i.e., no respirator) exceed 100 indicating acceptable risk. The
exception is the intermediate-term inhalation exposure of Scenario 1
(mixing/loading the liquid concentrate, which has an MOE of 82).
However, the registrant is voluntarily cancelling this formulation.
Carcinogenic Risks
The Agency conducted an assessment of the carcinogenic risks
associated with amitrole following exposures to occupational handlers
including all currently registered uses, which includes the liquid concentrate
formulation (packaged in a no-glug container) for which the registrant has
recently requested a voluntary cancellation.
The calculations indicate that the risks at baseline protection (i.e.,
long-sleeve shirt, long pants, shoes, and socks) are in the 10's range for
mixing/loading wettable powders (contained in water-soluble packaging)
and application using open-cab groundboom sprayers, the surrogate for
fixed-boom ground sprayers. The calculations indicate that the risks at
baseline protection are greater than 10"4 for mixing/loading liquid
formulations. These calculations do not reflect the exposure reduction
expected to be realized from the mandatory use of "no-glug" containers for
liquid formulations. The registrant has, however, recently requested
voluntary cancellation for this formulation.
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The risk assessment indicates that the risks at baseline protection are
approximately 10'? for mixing/loading the wettable powder formulation
packaged in water soluble bags. Since the risk assessment was conducted
using this assumption, the Agency is requiring that the wettable powder
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Environmental
Assessment
formulation continue to be marketed only in water-soluble packaging. In
addition, since the Agency has low confidence in the data used to assess
exposure to mixers and loaders using water-soluble packaging and amitrole
is a relatively potent carcinogen, additional risk reduction measures for
mixers and loaders is being required The following risk mitigation
measures for mixers and loaders handling the wettable powder amitrole
formulations, should adequately mitigate risk to these workers:
mandatory use of water-soluble packaging for wettable powder
amitrole formulations, and
requiring mixers and loaders to wear a chemical-resistant apron, long-
sleeve shirt, long pants, shoes, socks and chemical-resistant gloves.
There are no amitrole-specific post-application exposure data
available. For many amitro.^ use scenarios, the Agency believes that the
risks from post-application exposures will not pose an unacceptable risk to
persons entering treated areas because, in general, amitrole is used in areas,
such as rights-of-way, industrial areas, permanent landscape plantings, and
other non-crop areas, where frequent or routine prolonged contact with
treated surfaces is unlikely. Therefore, the Agency has determined that
post-application exposures do not appear to pose an unreasonable risk to
persons entering treated areas, as long as entry is not permitted until sprays
have dried. -
Environmental Fate
Acceptable arid supplemental information from environmental fate
studies with respect to the persistence and mobility of amitrdle under
laboratory and field conditions has been reviewed. Persistence classes
discussed in the following sections were based on the groupings (ranging
from non-persistent to persistent) published in Goring etal., (1975) and
McEwen and Steohenson (1979). The environmental fate data base for
amitrole with terrestrial non-food crop use is essentially complete.
The following information is derived from acceptable environmental
fate studies reviewed by the Agency. The studies determining laboratory
persistence (degradation and metabolism processes) indicate amitrole is
slightly to moderately persistent [aerobic soil half-life (t1/2) ซ22-26 days;
aerobic aquatic half-life of ซ57 days] with degradation primarily through
biotic processes such as microbid-mediated metabolism. Abiotic
hydrolysis is not a significant degradation process. Amitrole was reportedly
stable to photodegradation in water and was shown to photodegrade slowly
on soil with a t^ of >30 days. Results of the anaerobic aquatic metabolism
study demonstrate that amitrole is persistent with a t1/2 of >1 year. In an
aerobic aquatic metabolism study, amitrole was moderately persistent with
an experimentally-determined tw of ซ57 days for a flooded sandy loam
sediment Results of terrestrial field dissipation studies in Washington and
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Oregon show amitrole dissipating fairly rapidly under field conditions with
DT50s ranging from ซ17-21 days.
The mobility of amitrole was evaluated with batch equilibrium studies
and amitrole was determined to be mobile in silty clay, sandy loam, sand,
and silt soils (Kds ranged from 0,152-0.922 ml/g). The reported vapor
pressure of amitrole is 4.4 x 10"' mm Hg (5.9 x 10"5 Pa) and the estimated
Henry's Law Constant of 1.6 x 10"15 atm-mVmol are low; therefore,
volatilization and subsequent photodegradation in air are not considered
probable routes of dissipation.
, The bioaccumulation in fish study was not submitted; however, the
high solubility (280 g/1) and low octanol/water partition coefficient
(log %. = -0.15) indicate limited potential for bioaccumulation in fish.
Amitrole is mobile, somewhat persistent and may have the potential
to contaminate ground water. This assessment is based on the acceptable
environmental fate studies which indicate amitrole has a significant number
of characteristics in common with pesticides that are known to leach to
ground water./Amitrole is stable to hydrolysis, and aerobic soil and
anaerobic aquatic metabolism and field dissipation data indicate that it is
somewhat persistent Amitrole is classified as mobile because the low Kd
and K^. values indicate it will not strongly adsorb to soil. Pesticides with
similar properties have been found in ground water.
Amitrole may contaminate surface" water from runoff or spray drift
associated with ground spray application. Amitrole is stable to degradation
from abiotic hydrolysis and aqueous photolysis, and is slightly to
moderately persistent (aerobic soil metabolism tV2 ป22-26 days; aerobic
aquatic metabolism t^ ป57 days) in aerobic environments. Amitrole does
not adsorb significantly to soil particles and may be transported in the
dissolved phase by runoff to surface water bodies; Amitrole's primary route
of dissipation is microbial-mediated metabolism; however, amitrole is
stable in anaerobic environments.
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Ecological Effects
The acute risk to nontarget animals (birds, insects, mammals, fish and
aquatic invertebrates) is predicted to be low. Chronic risk to mammals was
identified; however, the chronic risk to other nontarget animals (birds, fish
and aquatic invertebrates) was not determined because chronic ecological
effect data were not available.
Studies indicate that amitrole is practically non-toxic to avian species
on an acute oral and subacute basis. For birds, it is important to note that
the LCjo values used to calculate the RQs were greater that the highest dose
tested (5,000 ppm). The Agency considers amitrole to represent low acute
risk to birds. At this time chronic risk to birds cannot be assessed, because
avian reproduction data are not available.
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Amitrole is practically non-toxic to small mammals on an acute oral
basis. The RQs for small herbivores and insectivores (0.13 to 0.29)
exceeded by small margins the LOCs for endangered species (0.1) and
restricted use (0.2). Amitrole however, may be hazardous to mammalian
reproduction in localized areas. Using the acceptable two-generation rat
reproduction study, the risk assessment indicates use of amitrole has the
potential for chronic risk to mammalian species and may also chronically
affect endangered mammalian species. The mammalian exposure
asssessments use residue levels which represent the maximum estimated
values, and the residues are expected to be lower on most food items.
Amitrole residues are predicted to decline by microbial-mediated
metabolism, physical removal by washoff and other dissipation pathways.
The amitrole residue levels on food items in treated areas are not known
because the treated areas are limited to nonagricultural use sites (rights-of
way, fencerows? hedgerows, etc.) and the extent of exposure may be
limited. ^
There is sufficient information to characterize amitrole as relatively
non-toxic to bees.
The toxicity of amitrole to most aquatic organisms tested to date
range from practically non-toxic (freshwater fmfish) to moderately toxic
(marine invertebrates). Chronic risk to freshwater fish can not be assessed
because the fish life-cycle data are not available at this time.
There is sufficient information to characterize amitrole as slightiy
toxic to aquatic invertebrates. However, the chronic risk to freshwater ...
invertebrates will be assessed once the invertebrate life cycle study is
reviewed. ,
The acute risk from applications of amitrole is expected to be low to
freshwater and marine/estuarine organisms. The risk quotients determined
from application rates ranging from 3.6-8.0 Ibs ai/A are less than the levels
of concern for the tested aquatic animals at all use rates, except for
marine/estuarine invertebrates. The RQ for mysid shrimp was 0.137
, (8 Ibs ai/acre) which exceeded the LOCs for endangered species (0.05) and
restricted use (0.1) by a small margin. In this assessment, the screening
model GENEEC was used to model runoff from non-agricultural use sites
for amitrole. The GENEEC model was based on an agricultural use.
scenario and is a conservative estimate of exposure from surface runoff
because agricultural land uses are intensive and may cover large areas.
The conclusion of low acute risk to estuarine crustaceans is based not
only on the fact that the LOCs were exceeded by a small margin, but also
because amitrole is used on non-agricultural use sites. In addition to
marginal LOG exceedances and non-agricultural uses, the amount of
amitrole applied annually in the United States is relatively small. Usage
information for amitrole in the U.S. is between 40,000 and 60,000 pounds
of the active ingredient on an annual basis. Furthermore, endangered
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Additional Data
estuarine invertebrates are not currently listed by the United States Fish
Wildlife Service (USFWS).
The available information indicates that amitrole affects the
vegetative vigor of both monbcots and dicots at very low levels (<0.01 Ibs
ai/A). The risks to non-target plants from sheet and channelized runoff was
not determined with certainty because plant toxicity data were limited
(seedling emergence .data are not available). Qualitatively, amitrole's broad
spectrum plant control due to its mode of action (i.e., inhibition of
carotenoid synthesis) suggests exposure of amitrole may impact non-target
plants. Based on me 3.6 to 8.0 Ibs. ai/A use rates of amitrole, risk quotients
exceed the levels of concern for terrestrial and semi-aquatic plants (1.0).
Risk quotients are based on EG2Js from the dry weight parameter for wheat
(monocot) and pepper (dicot) from the vegetative vigor study. The wheat
and pepper plant EC2Ss were the most sensitive plants tested and the lowest
levels for the available plant toxicity data.
Because the risk assessment is incomplete for non-target terrestrial
and aquatic plants, terrestrial (seedling emergence) and aquatic plant (all
five species) testing is being required to confirm and complete the
Agency's risk assessment and conclusions.
The generic data base supporting the reregistration of amitrole for the
el egible uses has been reviewed and determined to be substantially
complete for all uses. Nevertheless, the following studies are required to be
conducted on the generic active ingredient: Guidelines 17-4(a) and (b),
Avian reproduction studies and, Guideline 72-4(b), Aquatic Invertebrate
Life Cycle with Daphnia Magna. Furthermore, the following confirmatory
studies are required in order to complete the Agency's risk assessment and
conclusions: Guideline 123-l(a), Terrestial Plant Testing: Seedling
Emergence only. Guideline 123-2 Aquatic Plant Testing: All five species,
and Guideline 23 1 and 232 Handler exposure study to provide dermal and
inhalation data on mixers and loaders during the use of water-soluble
packages.
The Agency is also requiring product-specific data including product
chemistry and acute toxicity studies, revised Confidential Statements of
Formula (GSFs), and revised labeling for reregistration.
3rodlICt Labeling All amitrole end-use products must comply with EPA's current
hanges Required pesticide product labeling requirements and with the following. Fora
, comprehensive list of labeling requirements, please see the amitrole RED
document.
Labeling Requirements for Manufacturing-Use Products
To remain in compliance with FIFRA, manufacturing use product; (MP)
labeling must be revised to comply with all current Agency (EPA)
regulations, PR Notices and applicable policies. An MP registrant may, at
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his/her discretion, add one of the following statements to an MP label under
"Directions for Use" to permit the reformulation of the product for a
specific use or all additional uses supported by a formulator or user group:
(a) "This product may be used to formulate products for specific
use(s) not listed on the MP label if the formulator, user group,
or grower has complied with U.S. EPA submission requirements
regarding support of such use(s)."
(b) , "This product may be used to formulate products for any
additional use(s) not listed on the MP label if the formulator,
user group, or grower has complied with U.S. EPA submission
requirements regarding support of such use(s)."
End-Use Products
Additional Product-Specific Data Requirements
Section 4(g)(2)(B) of FIFRA calls for the Agency to obtain any
needed product-specific data regarding the pesticide after a determination of
eligibility has been made. The product specific data requirements are listed
in Appendix D, the Product Specific Data Call-in Notice.
Registrants must review previous data submissions to ensure that they
meet current EPA acceptance criteria and if not, commit to conduct new
studies. If a registrant believes that previously submitted data meet current
testing standards, then study MRID numbers should be cited according to
the instructions in the Requirement Status and Registrants Response Form
provided for each product.
Labeling Requirements for End-Use Products
Engineering Control Requirements for Pesticide Handlers
For sole-active-ingredient end-use products that contain amitrole, the
product labeling must be revised to adopt the handler personal protective
equipment/engineering control requirements set forth in this section. Any
conflicting PPE requirements on the current labeling must be removed.
For multiple-active-ingredient end-use products that contain amitrole, the
handler personal protective equipment/engineering control requirements set
forth in this section must be compared to the requirements on the current
labeling and the more protective must be retained. For guidance on which
requirements are considered more protective, see PR Notice 93-7.
Products Intended Primarily for Occupational Use '
(WPS and nonWPS)
Minimum (Baseline) PPE/Engineering Control Requirements
The Agency is establishing minimum (baseline) engineering controls
for occupational uses of amitrole end-use products.
For the wettable powder packaged in water soluble packages (non
WPS), the Agency is requiring that mixers/loaders and persons cleaning
10
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equipment wear: long sleeve shirt and long pants, chemical resistant gloves,
chemical resistant apron, and shoes plus socks.
For the wettable powder packaged in water soluble packages (non
WPS), the Agency is requiring that applicators wear: long sleeve shirt and
long pants, and shoes plus socks. '
Determining PPE Requirements for End-use Product Labels
The PPE that would be established on the basis of the acute toxicity
category of the end-use product must be compared to the active-ingredient-
based minimum (baseline) personal protective equipment specified above.
The more protective PPE must be placed on the product labeling. For
guidance on which PPE is considered more protective, see PR Notice 93-7.
Placement in Labeling
The personal protective equipment requirements must be placed on
the end-use product labeling in the location specified in PR Notice 93-7,
and the format and language of the PPE requirements must be the same as
is specified in PR Notice 93-7.
Entry Restrictions
For sole-active-ingredient end-use products that contain amitrole the
product labeling must be revised to adopt the entry restrictions set forth in
this section. Any conflicting entry restrictions on the current labeling must
be removed.
For multiple-active-ingredient end-use products that contain amitrole
the entry restrictions set forth in this section must be compared to the entry
restrictions on the current labeling and the more protective must be
retained. A specific time period in hours or days is considered more
protective than "sprays have dried" or "dusts have settled."
Products Intended Primarily for Occupational Use - WPS uses
Since the registrant's voluntary cancellation of in-scope (nursery-
stock, the only WPS use) use has been received by the Agency, an REI is
not being presented ;
NonWPS use - Entry restrictions '
The Agency is establishing the following entry restrictions for
nonWPS occupational uses of amitrole end-use products:
"Do not enter or allow other employees to enter the treated area until
sprays have dried." ;
Placement in labeling: _....'
Place the appropriate nonWPS entry restrictions in the Directions for
Use, under the heading: "Entry Restrictions."
11
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Labeling Requirements
Products Intended Primarily for Occupational Use
The Agency is requiring the following labeling statements to be
located on all end-use products containing amitrole that are intended
primarily for occupational use.
Application Restrictions
"Do not apply this product in a way that will contact workers or
other persons, either directly or through drift. Only protected
handlers may be in the area during application."
User Safety Requirements
a. (Registrant: place this on the labeling if coveralls are required
for pesticide handlers on the end-use product label:)
Discard clothing or other absorbent materials that have been
drenched or heavily contaminated with this product's
concentrate. Do not reuse them.
b. (Registrant: place this on the labeling always:)
Follow manufacturer's instructions for
cleaning/maintaining PPfi. If no such instructions for
washables, use detergent and hot water. Keep and wash
PPE separately from other laundry.
User Safety Recommendations
"Users should wash hands before eating, drinking, chewing
gum, using tobacco, or using the toilet."
"Users should remove clothing immediately if
pesticide gets inside. Then wash thoroughly and put
on clean clothing."
"Users should remove PPE immediately after
handling this product. Wash the outside of gloves
before removing. As soon as possible, wash
thoroughly and change into clean clothing."
Environmental Hazard Statment
The following labeling statement must be added to the
"Environmental Hazards" section on all amitrole end-use products:
Ground water label advisory.
"This chemical demonstrates the properties and characteristics
associated with cl; micals detected in ground water. The use of this
chemical in areas <, -(ere soils are permeable, particularly where the
water table is shar.. -ปy, may result in ground-water contamination."
add list of end use product labeling requirements here, summarizing every
labeling change included in chapter V. of the RED.
12
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Regulatory The use of currentlyregistered products containing amitrolein
Conclusion accordance with approved labeling will not pose unreasonable risks or
adverse effects to humans or the environment. Therefore, all uses of these
products (not including the uses permitted with the liquid formulation in no-
glug container and the ornamental plant nursery use) are eligible for
reregistration.
Amitrole products will be reregistered once the required product-
specific data, revised Confidential Statements of Formula, and revised
labeling are received and accepted by EPA.
EPA is requesting public comments on the Reregistration Eligibility
Decision (RED) document for amitrole during a 60-day time period, as
announced in a Notice of Availability published in the Federal
Register. To obtain a copy of the RED document or to submit written
comments, please contact the Pesticide Docket, Public Response and
Program Resources Branch, Field Operations Division (7506C), Office of
Pesticide Programs (OPP), US EPA, Washington, DC 20460, telephone '
703-305-5805.
> Electronic copies of the RED and this fact sheet can be downloaded
from the Pesticide Special Review and Reregistration Information System
at 703-308-7224. They also are available on the Internet on EPA's gopher
server, GOPHER.EPA.GOV, or using ftp on FTP.EPA.GOV, or using
; WWW (World Wide Web) on WWW.EPA.GOV.
Printed copies of the RED and fact sheet can be obtained from EPA's
National Center for Environmental Publications and Information
(EPA/NCEPI), PO Box 42419, Cincinnati, OH 45242-0419, telephone
513-489-8190, fax 513-489-8695.
Following the comment period, the Amitrole RED document also will
be available from the National Technical Information Service (NTIS), 5285
Port Royal Road, Springfield, VA 22161, telephone 703-487-4650.
For more information about EPA's pesticide reregistration program,
the amitrole RED, or reregistration of individual products containing
amitrole, please contact the Special Review and Reregistration Division
(7508W), OPP, US EPA- Washington, DC 20460, telephone
703-308-8000.
For information about the health effects of pesticides, or for assistance
in recognizing and managing pesticide poisoning symptoms, please contact
V the National Pesticides Telecommunications Network (NPTN). Call toll-
free 1-800-858-7378, between 9:30 am and 7:30 pm Eastern Standard
Time, Monday through Friday.
13
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REREGISTRATION ELIGIBILITY DECISION
AMTTROLE
LIST A
CASE 0095
ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF PESTICIDE PROGRAMS
SPECIAL REVIEW AND REREGISTRATION DIVISION
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TABLE OF CONTENTS
AMITROLE REREGISTRATION ELIGIBILITY DECISION TEAM . i
EXECUTIVE SUMMARY .;.;..'.j"............... .':'.: ,..V/.'.'./.-. /..'.'.... .'-.'V. .v
I. INTRODUCTION .......... ^! ......... r ./.......... 1
'H..,'. CASE OVERVIEW ......'.-.....; ,v.,'.... ..,...,.'......... '....;.............. 2
A. Chemical Overview .........................;......2
B. Use Profile .....;......./...,..... ....... >.\...: ...2
C. Estimated Usage of Pesticide ....................................... .3
D. Regulatory History/Data Requirements 4
m. SCIENCE ASSESSMENT ...........;...,,......:...:, ...........:...... 5
A. Physical Chemistry Assessment ; 5
B. HumanHealth Assessment 6
1. Haizard Assessment ...;...............................,. .6
a. Acute Toxicity ,......... 6
b. Dermal Absorption ''. 8
c. Reference Dose .1,,, 8-
d. Toxicological Endpoints of Concern ................... 9
e. Carcinogen Classification 9
f. SubchrpnicToxicity ................ ............ 10
g. Combined Chronic Toxicity and Carcinogenicity ........ 12
h. Developmental Toxicity .....15
i. Reproductive Toxicity .17
j. Mutagenicity .-. 18
ki Metabolism ..19
2. Exposure Assessment 22
a^ Dietary Exposure .......:... >......................22
b. Occupational Exposure 22
3. Risk Assessment....................................'.,"'..': .26
a. Dietary.. ......:.... ^.........26
b. Occupational .26
C. Environmental Assessment .................. ^. ^........ ^....... 31
i. Ecological Toxicity Data ........31
a. Toxicity to Terrestrial Animals ..:.................... 31
b. Toxicity to Aquatic Animals '.:...'................ 33
c. Toxicity to Plants :'".."'..- 37
2. Environmental Fate and Transport Data .................... 38
.a. Environmental Fate Assessment ..;...,...... .....38
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b. Environmental Fate and Transport Data 39
c. Water Resources 43
3. Ecological Exposure and Risk Assessment 45
a. Ecological Exposure and Risk Characterization 45
b. Exposure and Risk to Nontarget Terrestrial Animals .... 46
c. Exposure and Risk to Nontarget Aquatic Animals 49
d. Exposure and Risk to Nontarget Plants 52
e. Endangered Species 54
4. Environmental Risk Characterization 54
a. Environmental Fate and Transport Assessment ......... 54
b. Risk to Nontarget Animals 55
c. Risk to Nontarget Plants .58
d. Risk to Endangered Species .... 58
IV. RISK MANAGEMENT AND REREGISTRATTON DECISION 59
A. Determination of Eligibility , 59
B. Determination of Eligibility Decision .... ; .59
1. Eligibility Decision .. ....... 59
2. Eligible and Ineligible Uses 60
C. Regulatory Position - Summary of Risk Management Decisions ........ 60
1. Tolerance Reassessment 60
2. Cancer Risk Assessment 60
3. Restricted Use Classification (RU) 60
4. Endangered Species Statement .......... 61
5. Human Health ... 62
6. Environmental 63
7. Labeling Rationale !. 65
8. Spray Drift Advisory .68
V. ACTIONS REQUIRED OF REGISTRANTS .69
A. Manufacturing-Use Products .;.. 69
1. Additional Generic Data Requirements 69
2. Labeling Requirements for Manufacturing-Use Products ...... 69
B. End-Use Products 70
1. Additional Product-Specific Data Requirements 70
2. Labeling Requirements for End-Use Products 70
a. Worker Protection Safety ... ..... 70
b. Environmental Hazard Statement 73
C. Existing Stocks 73
VI. APPENDICES .......;................., 75
APPENDIX A. Table of Use Patterns Subject to Reregistration .77
APPENDIX B. Table of the Generic Data Requirements and Studies Used to
Make the Reregistration Decision 80
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APPENDIX C. Citations Considered to be Part of the Data Base Supporting
the Reregistration of Amitrole ............. ......... . 87
APPENDIX D. Combined Generic and Product Specific Data Call-in 99
Attachment 1. Chemical Status Sheets 119
Attachment 2. Combined Generic and Product Specific Data Call-In
Response Forms (Form A inserts) Plus
Instructions ..>....... 121
Attachment 3. Generic and Product Specific Requirement Status and
Registrant's Response Forms (Form B inserts) and
Instructions 125
Attachment 4. EPA Batching of End-Use Products for Meeting Data
Requirements for Reregistration 132
Attachment 5. List of All Registrants Sent This Data Call-In (insert)
-,". Notice:....,......,.,.;.........,..::...... 133
Attachment 6, Cost Share, Data Compensation Forms, Confidential
Statement of Formula Form and Instructions .... 134
APPENDIX E. List of Available Related Documents . .........,..... 141
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AMITROLE REREGISTRATION ELIGIBILITY DECISION TEAM
Office of Pesticide Programs:
Biological and Economic Assessment
Gabe Patrick
Jim Saulmon
Arthur Grube
Biological Analysis Branch
Biological Analysis Branch
Economic Analysis Branch
Environmental Fate and Effects Assessment
William Effland
Andrew Bryceland
David Wells
Health Effects Assessment
Tom Myers
Pamela Hurley
Jeff Evans
Felicia Fort
Registration Support
i
Robert Taylor
Larry Fried
Risk Management
Sherry Sterling
Linda Propst ' ' "."
Mario Fiol
Walter Waldrop
Philip Poli
Environmental Risk Characterization Branch
Environmental Risk Characterization Branch
Environmental Risk Characterization Branch
Risk Characterization and Analysis Branch
Toxicology Branch I
Occupational and Residential Exposure Branch
Chemistry Branch Reregistration Support
Fungicide-Herbicide Branch
Registration Support Branch
Reregistration Branch
Reregistration Branch
Reregistration Branch
Reregistration Branch
Special Review Branch
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GLOSSARY OF TERMS AND ABBREVIATIONS
. . , . . ..
ADI Acceptable Daily Intake. A now defunct term for reference dose (RfD).
AE Acid Equivalent ' " .
a.i. Active Ingredient , . . .
ARC Anticipated Residue Contribution . ., v ,
CAS Chemical Abstracts Service
CI Cation
CNS Central Nervous System
CSF Confidential Statement of Formula - ;
DFR Dislodgeable Foliar Residue .
ORES Dietary Risk Evaluation System
D WEL . Drinking Water Equivalent Level (DWEL) The D WEL represents a medium specific (i.e. drinking
water) lifetime exposure at which adverse, non carcinogenic health effects are not anticipated to
occur. ,
EEC - Estimated Environmental Concentration. The estimated pesticideconcentration in an environment,
. such as a terrestrial ecosystem. ' ' ,
EP End-Use Product , ,
EPA U.S. Environmental Protection Agency
FAO/WHO Food and Agriculture Organization/World Health Organization
FDA Food and Drug Administration
FIFRA Federal Insecticide, Fungicide, and Rodenticide Act
FFDCA Federal Food, Drug, and Cosmetic Act
FOB Functional Observation Battery
GLC Gas Liquid Chromatography
GM Geometric Mean . . '
GRAS , Generally Recognized as Safe as Designated by FDA .
HA Health Advisory (HA). The HA values are used as informal guidance to municipalities and other
' organizations when emergency spills or contamination situations occur.
HOT Highest Dose Tested ,
LC,o Median Lethal Concentration. A statistically derived concentration of a substance that can be
expected to cause death in 50% of test animals. It is usually expressed as the weight of substance
per weight or volume of water, air or feed, e.g., mg/1, mg/kg or ppm,
Median Lethal Dose. A statistically derived single dose that can be expected to cause death in 50%
of the test animals when administered by the route indicated (oral, dermal, inhalation). It is
expressed as a weight of substance per unit weight of animal, e.g., mg/kg.
LDlo Lethal Dose-low. Lowest Dose at which lethality occurs.
LEL , Lowest Effect Level ,
LOG Level of Concern ,
LOD Limit of Detection ..'...
LOEL Lowest Observed Effect Level
MATC Maximum Acceptable Toxicant Concentration
MCLG Maximum Contaminant Level Goal (MCLG) The MCLG is used by the Agency to regulate
contaminants in drinking waterBunder the Safe Drinking Water Act.
ug/g Micrograms Per Gram - v ;
mg/L Milligrams Per Liter ..."*- . ,
MOE Margin of Exposure , , '
MP Manufacturing-Use Product .
MPI Maximum Permissible Intake , .
MRID Master Record Identification (number). EPA's system of recording and tracking studies submitted.
N/A Not Applicable ,
NOfiC No effect concentration . ,
LD
'30
HI
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GLOSSARY OF TERMS AND ABBREVIATIONS
NPDES National Pollutant Discharge Elimination System .
NOEL No Observed Effect Level
NOAEL No Observed Adverse Effect Level... .
OP Organophosphate
OPP Office of Pesticide Programs
PADI Provisional Accept!-:;e Daily Intake
PAG Pesticide Assessment Guideline
PAM Pesticide Analytical Method
PHED Pesticide Handler's Exposure Data
PHI Preharvest Interval
ppb Parts Per Billion
PPE Personal Protective Equipment ,
ppm Parts Per Million
PRN Pesticide Registration Notice
Q*, The Carcinogenic Potential of a Compound, Quantified by the EPA's Cancer Risk Model
RBC RedBloodCell -
RED Reregistration Eligibility Decision
REI Restricted Entry Interval
RfD ReferenceDose
RS Registration Standard
RUP Restricted Use Pesticide , '
SLN Special Local Need (Registrations Under Section 24 (c) of FIFRA)
TC Toxic Concentration. The concentration at which a substance produces a toxic effect.
TD Toxic Dose. The dose at which a substance produces a toxic effect.
TEP Typical End-Use Product '
TGAI Technical Grade Active Ingredient '
TLC Thin Layer Chromatography
TMRC Theoretical Maximum Residue Contribution
torr A unit of pressure needed to support a column of mercury 1 mm high under standard conditions.
ug/L Micrograms per liter .
WP Wettable Powder , , s
WPS Worker Protection Standard
IV
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EXECUTIVE SUMMARY
The Environmental Protection Agency has completed its reregistration eligibility decision
regarding the pesticide amitrole, (3-amino-l,2,4-triazole). This decision includes a
comprehensive reassessment of the required target data base supporting the use patterns of
currently registered products. Amitrole is a non-food use herbicide used primarily in industrial
areas (outdoors), non-agricultural rigtits-of-way, fencerows, hedgerows, non-agricultural
uncultivated areas, soils, ornamental and/or shade trees, and ornamental shrubs and vines,
Amitrole was classified for restricted use (RU) through the Registration Standard issued
March 1984. In May 1984, a Special Review of Amitrole was initiated based on carcinogenic
risk. In 1992, at the conclusion of the Special Review of Amitrole the Agency reinforced the RU
classification of amitrole because of positive carcinogenicity findings.
During the preparation of this Reregistration Eligibility Decision (RED) document, Hie
registrant, CFPI, requested that the Agency rescind the RU classification as part of the
reregistration evaluation of amitrole.
After reviewing all the submitted data and comparing other pesticidal chemicals also
classified as "restricted use," the Agency has determined that the restricted use classification 'is
no longer appropriate, Amitrole is classified as a B2-probable human carcinogen. Two thirds
of the Agency's calculated cancer risk of 10"5 to mixers/loaders (assuming handlers wear long
sleeve shirts, long pants, shoes and socks) is from inhalation exposure. The Agency believes that
the likelihood of inhalation exposure is almost non-existent since the amitrole is packaged in
water soluble bags. Focusing only on cancer risk from dermal exposure, the estimated cancer
risk approaches W6. Thus, with the low dermal absorption factor (0.5%), continued packaging
in water soluble bags, additional protection (although minimal because of the low dermal
absorption) afforded by chemical resistant gloves and chemical resistant apron, the Agency
concluded mat the Restricted Use classification could be rescinded if the registrant agreed to the
following conditions: voluntarily cancel their liquid formulation product; retain the cancer
warning label; retain the boom sprayer as the only application mode; retain the same use profile
as a non-food use pesticide, and provide the Agency with handler exposure studies for
mixers/loaders of water soluble packages to confirm the Agency's risk assessment and
conclusions. In addition, the registrant understands that any proposed future expansions of their
market will require that a separate risk assessment be performed for any new use/application
method. Furthermore, amitrole labels must carry a ground water advisory and the registrant must
submit additional ecological studies to complete the Agency's risk assessment. >
The registrant has requested voluntary cancellation for ornamental plant nursery uses and
has agreed to the Agency's conditions cited above. Therefore, the Agency through this document
will delete the restricted use classification from the wettable powder formulation (the only
remaining product). The Agency has determined that all registered uses for the wettable powder
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formulation packaged in water soluble bags are eligible for reregistration if labeled and used as
specified in this RED document .-.'"
The generic data base supporting the reregistration of amitrole has been reviewed and
determined to be substantially complete for all eligible uses. However, the following studies to
be conducted on the generic active ingredient are required to complete the Agency's risk
assessment: Guideline 71-4(a) and (b) Avian Reproduction studies (quail and duck) and
Guideline 72-4(b) Aquatic Invertebrate Life Cycle with Daphnia magna. In addition, the
following confirmatory studies are also required: Guideline 123-l(a) Seedling Emergence;
Guideline 123-2 Aquatic Plant Growth (five species); and Guidelines 231 and 232 handler
exposure studies to provide dermal and inhalation data on mixers and loaders during the use of.
water-soluble packages.
.*
Before reregistering products containing amitrole, the Agency is requiring that product
specific data, a revised Confidential Statement of Formula (CSF) and revised labeling be
submitted within eight months of the issuance of this document. These data include product
chemistry and acute toxicity testing. After reviewing these data and any revised labels and
finding them acceptable and in accordance with section 3 (c)(5) of FIFRA, the Agency will
reregister the product
VI
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I. INTRODUCTION
In 1988, the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) was amended
to accelerate the reregistration of products with active ingredients registered prior to November
1,1984. The amended Act provides a schedule for the reregistration process to be completed in
nine years. There are five phases to the reregistration process. The first four phases of the process
focus on identification of data requirements to support the reregistration of an active ingredient
and the generation and submission of data to fulfill the requirements. The fifth phase is a review
by the U.S. Environmental Protection Agency (referred to as "the Agency") of all data submitted
to support reregistration.
FIFRA Section 4(g)(2)(A) states that in Phase 5 "the Administrator shall determine
whether pesticides containing such active ingredient are eligible for reregistration" before calling
in data on products and either reregistering pro'ducts or taking "other appropriate regulatory
action." Thus, reregistration involves a thorough review of the scientific data base underlying a
pesticide's registration. The purpose of the Agency's review is to reassess the potential hazards
arising from the currently registered uses of the pesticide; to determine the need for additional
data on health and environmental effects; and to determine whether the pesticide meets the "no
unreasonable adverse effects" criterion of FIFRA.
* ".'.'.' "" ^
This document presents the Agency's decision regarding the reregistration eligibility of
the registered uses of amitrole. The document consists of six sections. Section I is the
introduction^ Section n describes amitrole, its uses, data requirements and regulatory history.
Section m discusses the human health and environmental assessment based on the data available
to the Agency. Section IV presents the reregistration decision for amitrole. Section V discusses
the reregistration requirements for amitrole. Finally, Section VI is the Appendices which support
this Reregistration Eligibility Decision. Additional details concerning the Agency's review of
applicable data are available on request.
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H. CASE OVERVIEW
A. Chemical Overview
The following active ingredient is covered by this Reregistration Eligibility
Decision:
Common Name:
Chemical Name:
Chemical Family:
CAS Registry Number:
OFF Chemical Code:
Empirical Formula:
Trade and Other Names:
Basic Manufacturer:
Amitrole
Amitrole (3 -amino- 1 ,2,4-triazole)
Triazole
61-82-5
004401
Amizol, Amitrol 'T, AT Liquid, AT-90,
Amino Triazole Weedkiller 90, Azaplant,
Azaplant Kombi, Azolan, Azole, etc.
CFPI of France.
B. Use Profile
The following information is on the currently registered uses of amitrole with an overview
of use sites and application methods. A detailed table of amitrole uses can be found in Appendix
A.
Type of Chemical: Herbicide
Mechanism of Action:
Use Groups and Sites:
Inhibits carotenoid synthesis, chlorophyll formation, and
limited regrowth of buds.
TERRESTRIAL NON-FOOD CROP
Industrial areas (outdoor), non-agricultural rights-of-way/fence-
rows/hedgerows, non-agricultural uncultivated areas/soils, ornamental
and/or shade trees, ornamental shrubs and vines
Pests: Broadl eaves: alfalfa, ash, bigleaf maple, blackberry, Canada thistle,
chrysanthemum, dewberry, dock, hemp, honeysuckle, kochia, kudzu,
locust, marijuana, pigweed, poison ivy, poison oak, salmonberry,
sowthistle, sumac, sunflower, western horsenettle, whitetop, wild cherry
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I t --',_ . - ' .
Grasses: annual bluegrass, barnyardgrass, bermudagrass, cheat,
couchgrass, foxtail, quackgrass, reed canarygrass, ripgut bronie, ryegrass,
wild barley, witchgrass
Other plants: horsetail, nutgrass
Formulation Types:
Single Active Ingredient (AT) Products
Solid/dust - 90% (Technical) -,.-.',
,...- Wettable powder - 90% (Water soluble bags)
Emulsifiable concentrate1" 21.6% (No-glug container)
(*The registrant has requested cancellation of
; this product's registration)
v. -'.,- . ^ '- -, --.',. -',... , -. .
Methods and Rates of Application:
->. , , ''.",'' ' ' ""
Wettable powder: For industrial areas (outdoor), nonagricultural rights-of-
way/fence-rows/hedgerows, nonagricultural uncultivated areas/soils, ornamental
and/or shade trees, ornamental woody shrubs and vines, spray when needed by
fixed-boom sprayers attached to tractors, trucks or railway wagons (ground
equipment) at 3.6 Ib Al/acre.
Emulsifiable concentrate:* , For nonagricultural rights-of-way/fence-
rows/hedgerows, nonagricultural uncultivated areas/soils, ornamental and/or shade
trees, when needed, spray at foliar or at nurserystock stage,'by fixed-boom
sprayers attached to tractors, trucks or railway wagons (ground equipment) at 8 Ib
". ' Al/acre. '. \ - '. ' '," ' -'': "-.'.-' "'".'.' '
Use Limitation:
Do not feed or graze animals on treated areas.
Do not apply directly to water or wetlands.
, C. Estimated Usage of Pesticide
? ' ' v ' - ^ " * '' '
The Agency estimates that annual usage of amitrole during 1984 was between 500,000
and 800,000 pounds of active ingredient but, by 1989, had decreased to between 50,000 and
100,000 pounds of active ingredient. Total annual usage of amitrole declined even further in
1990 to between 40,000 and 60,000 pounds of the active ingredient. It is probable that amitrole
usage since 1990 is at this level or below.
Primary areas of use are in combination with residual herbicides on highway guard rails,
bridge abutments, shoulders and median strips to reduce or eliminate mowing and improve
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visibility at intersections, of traffic signs under guard rails, and around other structures, and in
railroad yards, around signal equipment, leading areas to keep vegetation free for maximum
visibility, safety and prevent growth of potentially combustible weeds.
Additionally, public areas around industrial sites such as power substations, electric transmission
towers, fence lines, petroleum tank farms, lumber yards and other areas which need to be kept
vegetation free are also other major market areas of amitrole for the same reasons; that is, for
improved visibility, personal safety, and fire prevention.
D. Regulatory History/Data Requirements
Amitrole was first registered in 1948 for use on non-crop sites including rights-of-way,
marshes and drainage ditches, ornamentals and around commercial, industrial, agricultural,
domestic, and recreational premises. In 1958 amitrole was registered for use on cranberries on
a no-residue basis for post-harvest application only. In 1971 all amitrole food uses were canceled
by the Agency because experimental animal data demonstrated an oncogenic potential by the
dietary route. There are no tolerances for any food crop or water which will be used for
irrigation, drinking, or other domestic purposes, and to date no new registrations or establishment
of tolerances for amitrole have been requested. '
A Registration Standard for amitrole was issued on March 30, 1984 (NTIS Pub. No.
PB87-104766). The Registration Standard required the submission of product chemistry,
environmental and ecological effects data, and toxicology data. The Registration Standard also
informed registrants that even though amitrole was not used on food crops and there was no
dietary exposure to the chemical, the Agency had major concerns for dermal exposure, with
inhalation furnishing only a minor contribution to the total body burden. Human exposure, in
some circumstances, occurred at doses which resulted in antithyrpid effects in laboratory animals,
and that amitrole's use patterns and application techniques met the oncogenicity risk criterion for
Special Review. The Agency determined that it was not going to reregister any current product
and it was not going to register any new product containing amitrole until all pivotal data were
reviewed and a decision on the continued reregistrability of products containing amitrole was
made. All use patterns and applications techniques, except homeowner uses, were to be
classified as restricted, with labeling and protective clothing requirements to reduce exposure and
minimize risk during the period of data development.
On May 15,1984, the Agency issued a Notice of Special Review (Position Document-1)
of pesticide products containing amitrole. The Agency's Special Review was initiated to address
the use of amitrole on non-crop sites (highway rights-of-way primarily) and by homeowners, and
examined the carcinogenic risk to mixers, loaders and applicators. The data indicated that
amitrole induced thyroid, pituitary and liver tumors in laboratory animals. The registrant
voluntarily acted on a number of measures that reduced worker exposure to amitrole. Among
these were the deletion of the high exposure application methods such as knapsack sprayers, the
adoption of- a "no-glug" container design for the liquid formulation to reduce splashing while
pouring, the addition of protective clothing requirements to labels, and packaging of the wettable.
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powder formulation in water soluble packets. Lastly, the registrant voluntarily canceled all
homeowner products.
During the Special Review phase, two Data Call-ins (DCIs) were issued by the Agency.
A DCI was issued on February 22, 1990 requesting efficacy, usage and worker exposure
monitoring data for both liquid and powder formulations of amitrple. A second DCI was issued
on August 16,1991, requesting product chemistry, ecological and environmental fate studies and
toxicology studies. ' ,
Based on a risk and benefit assessment, the Agency concluded that the benefits provided
from the use of amitrole (taking into considerations the measures previously discussed) outweigh
the risks. Thus, the Agency on October 8, 1992, issued a Notice of Final Determination (57 FR
46448) of the Amitrole Special Review. The Agency continued to require: restricted use (RU)
classification, a cancer warning statement on the label, application methods remain limited to
boom sprayers, and protective clothing requirements remain on the label The Notice was
published in the Federal Register and comments were invited for 30 days. No;comments were
received. .''-. ; "-; '; ' - " ' --.._..., -. .,' ' , ., ,-..."! .' ' -
During the preparation of this Reregistration Eligibility Decision (RED) document, the
registrant requested reconsideration of the previous Registration Standard Decision (affirmed by
the Special Review decision) that all amitrole products bear a restricted use classification.! The
Agency, after review of the submitted data and comparing other pesticidal chemicals also
classified as "restricted use," determined that the restricted use requirement could be dropped if
the registrant were to. meet certain conditions. The registrant has agreed to voluntarily request
cancellation of the liquid formulation product in a "no-glug" container (a product posing higher
risks to handlers); retain the cancer warning label; retain boom sprayer as the application mode;
retain the same use profile as a non-food pesticide (non-cropland use only); and provide the
Agency with additional studies; specifically, handler exposure studies to mixers and loaders of
water soluble packages to confirm or complete the Agency's risk assessment and conclusions.
Additionally, any proposed future expansion of their market (i.e., liome-owner use), will require
a separate risk assessment.
SCIENCE ASSESSMENT
- - ,, V , - . '- ' ' . .
A". Physical Chemistry Assessment
The following active ingredient is covered by this Reregistration Eligibility Decision:
Common Name: Amitrole
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Chemical Name:
Amitrole (3-amino-l,2,4-triazole)
H
N.
N-
Empirical Formula:
Molecular Weight:
CAS Registry No.:
OPP Chemical Code:
84.08
61-82-5
004401
Amitrole technical is a transparent to off-white crystalline powder with a melting point
of 159ฐC. Amitrole is soluble in water (28 g/100 ml at 20ฐC) and ethanol (26 g/100 ml at 75 ฐC);
only slightly soluble in chloroform, acetonitrile, and ethyl acetate; and insoluble in acetone, ether,
and hydrocarbons. Amitrole has a vapor pressure 4.4 x 10E-7 mmHg, and the Octanol/Water
Partition Coefficient of log K^ = -0.15. Amitrole is stable under typical storage conditions.
B. Human Health Assessment
1.
Hazard Assessment
The toxicology data base for amitrole is adequate and will support a reregistration
eligibility determination for the currently registered non-food uses of amitrole.
a. Acute Toxicity
s
Results of the acute toxiciiy studies conducted with technical amitrole are summarized
below:
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Table 1. Acute Toxicity Values of Technical Amitrole.
Route
Oral
Oral
Dermal
Dermal
Inhalation
Eye Irritation1
Skin Irritation'
Dermal Sensitization*
' Species
Rat
Rat
Rabbit
Rat
Rat
Rabbit
Rabbit
Guinea Pig
, Results
LD50:
Males 24.6 g/kg
LD,0: 4.08 g/kg
LD50: >10 g/kg
LD50: >2.5 g/kg
Waived
Mild Irritant
No Irritation
Non sensitizer . - . -
Toxicity Category
IV
m
IV
ra
N/A
in
IV
N/A
* Not required for TGAI, however, presented hers for informational purposes.
The first acute oral study was tested only in the male rat and demonstrated an LD50 of
24.6 g/kg (MRID 00063601). In a second acute oral study both males and females were dosed
and demonstrated a LDso of 4.08 g/kg (Gaines et al. 1973; no MRID). Although, the second
study is based on a literature review and does not provide all the details required ,in the
guidelines, the results are consistent with the first study. It is unlikely that a new study will
indicate that amitrole is more acutely toxic via the oral route than a Toxicity Category ffl. The
two studies together are acceptable for regulatory purposes.
The first acute dermal study was tested in rabbits and demonstrated a LD50 of greater than
10 g/kg (MRID 00063599). In a second acute dermal study in the rat there were no clinical signs
noted at the highest dose tested of 2.5 g/kg (Gaines et al. 1973; no MRID). Both dermal studies
had incompletely reported data with little or no details on the Conduct of the study. Although
neither of the studies are totally acceptable, a new study will not be required due to the
consistency of the results of these two studies and due to the low dermal absorption value for this
chemical. , - <'
The requirement for an acute inhalation study was waived because a 2-year rat inhalation
study is available. This study indicates that the acute LC50 for inhalation is probably at least
greater than 0.5 mg/1. However, the 2-year study was not useful for carcinogenicity risk
assessment because of problems associated with the accuracy of the concentrations generated
throughout the study. It appears that the target concentrations were grossly exceeded due to
technical problems. The highest target concentration that was to be tested was 0.5 mg/1. The
animals probably received much more, including possible oral ingestion. Survival was a
problem, but not immediately. Therefore, it is likely that the acute inhalation toxicity of the
chemical is at least Toxicity Category m (MRID 00127930).
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Amitrole is a Toxicity Category Hi primary eye, irritant in rabbits. The study resulted in
cornea damage which cleared within 72 hours and conjunctival redness which cleared within 7
days (MRID 00127930).
* '
Amitrole is a Toxicity Category IV primary dermal irritant in rabbits
(MRID 00160450) and amitrole is not a skin sensitizer in guinea pigs (MRID 00160449).
Human Data
Oral Exposure
IARC Monographs. 1974: 39-yr old woman showed no signs of intoxication following
the ingestion of a commercial preparation containing 30% amitrole and 56% diuron. It
was reported that 50% of the estimated dose was eliminated in urine within a "few hours"
of exposure. Unchanged amitrole was found in the urine; no metabolites were identified.
Dermal Exposure
Dvnamac. 1982: Five male "spraymen" were exposed to amitrole for 10 working days
(5-days/week, 8-hour work days) and five males not exposed to the amitrole spraying
were considered to be controls. The medical monitoring reportedly found "no remarkable
findings based on palpating the thyroids of the control or exposed subjects." The results
of the thyroid function tests showed slightly higher TSH levels, slightly lower T4 levels
with basically no change in T3 levels through the two week follow up period. The authors
reported that all the thyroid function values "were within normal limits."
b. Dermal Absorption .
Amitrole (96.8% pure) and 14-C-amitrole (4.03mCi/nmol (millicuries/nanomole), 94.1%
pure) were tested in a dermal absorption study in Crl:CDฎ(SD)BR male rats. Groups of 20 rats
were tested with 0.10,1 or 10 mg amitrole/rat. Appropriate urine, feces, blood, skin and whole
carcass samples were analyzed. Four rats/test group were sacrificed at 0.5,1,2,4 or 10 hours
after dosing. The dermal penetration study indicated that IMe or no MC-Amitrole was absorbed
over a period of up to 10 hours at dose levels up to 10.0 mg/rat. Only 5/60 animals showed a
level of 0.1% or more of the dose in the urine (a range of 0.1 - 0.5%). No animals showed 0.1%
or more of the dose in the feces or carcass. However, significantly high percentages of the dose
remained in or on the washed skin and may be available for absorption over a longer period of
time. This study is acceptable for regulatory purposes (MRID 00151651).
c. Reference Dose
Since there is no food use pattern for amitrole, and since chronic or lifetime exposure is
an unlikely scenario for a-. :e, an RfD was not established. The Office of Pesticide Programs
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Reference Dose (RfD)/Peer Review Committee stated that the dosing regimens used in the
chronic studies for amitrole do not provide precise enough information to establish a
NOEL/LOEL for use in a chronic risk assessment: The Committee further stated that for nonfood
uses a margin of exposure (MOE) approach would be more appropriate and recommended that
an acceptable MOE of at least 100 be used for the purposes of risk assessment.
-' d. ToxicologicalEndpoints of Concern
The Office of Pesticide Program's Health Effects Division Less Than Lifetime Committee
(document datedJuly 25,1995) concluded the following for amitrole:
For acute dietary exposure. There are no food uses for amitrole, therefore, there are no
dietary exposure issues. ,
For short term occupational exposure (1 to 7 days) a risk assessment for inhalation
exposure is appropriate. The maternal and developmental NOEL of 4.0 mg/kg/day from
the oral developmental toxicity study in the rabbit is to be used for a risk assessment for
inhalation (MRID 00159997).
" ' ''""" ! . ' ' - , '
For intermediate term occupational exposure (1 week to several months) a risk assessment
for inhalation exposure is appropriate. The NOEL of 0.90 mg/kg/day from the
2-geheration reproduction study in the rat is to be used for a risk assessment for inhalation
(MRID 44016201).
For dermal short and intermediate term exposure, the maternal and developmental NOEL
of 1,500 mg/kg/day from the dermal developmental toxicity study is so high that a risk
assessment is not required for dermal exposure (MRIDs 40567701 and 40963701)
e. Carcinogen Classification
Amitrole has been classified as a Group B2-probable human carcinogen by the Office of
Pesticide Programs Carcinogenicity Peer Review Committee (document dated August 30,1991).
This classification is based on the thyroid tumors seen in the rat (both sexes, multiple strains), and
mouse (both sexes, two strains) and on liver tumors seen in the mouse (both sexes, multiple
strains) as described in the above studies. The Agency calculated a Ql* of 0.68 from the thyroid
tumor effects as seen in the first long term lexicological study (MRID 00132445), described
above. . - . '
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f. Subchronic Toxicity
The requirement for the 00-day dermal study was waived. The Less-than-Lifetime
Committee of the Agency's Office of Pesticide Programs determined (document dated
July 20, 1995) that results from a dermal absorption study and from the oral and dermal rabbit
developmental studies indicate that dermal absorption is very low (only up to 1-2%). Therefore,
it is unlikely that a 90-day dermal study conducted with amitrole will provide any additional
useful data. A 90-day feeding study will not be required in place of the 90-day dermal study
because sufficient data are available to indicate that a 90-day oral study will not provide any
additional Useful data for thejmrposes of risk assessment. The primary target organ is the
thyroid. Data from short term studies and chronic studies indicate that effects will appear in the
thyroid at lower dose levels than any other target organ.
Eleven short term studies were conducted with amitrole in order to study the effects of
amitrole on the thyroid. Although none of the studies can be categorized as being acceptable for
a subchronic feeding study, the data can still be used for making regulatory decisions. The
studies are summarized in Table 2. Some of the data were summarized from a review of the
literature and some of the studies were reports from laboratory studies. Where available, the
MRID numbers are provided. The subchronic data needed for risk assessment purposes is
extracted from the limited chronic data and from the studies listed in the table.
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g. Combined Chronic Toxicity and Carcinogenicity
Six long-term studies have been conducted on rats and mice with amitrole. When
assessed separately, each of the studies is unacceptable according to the Agency testing
guidelines. For chronic toxicity, the first two studies summarized below have been selected as
containing the most relevant data for regulatory purposes and when taken together, the two
studies are acceptable for regulatory purposes. For carcinogenicity, when all six studies are taken
together, the studies are acceptable for regulatory purposes because they adequately characterize
the potential chronic toxicity, and were considered by the Office of Pesticide Program's (OPP)
Carcinogenicity Peer Review Committee to contribute to the weight of the evidence for
carcinogenicity. The first study was used for carcinogenicity risk assessment.
In the first study, technical amitrole (94.59%) was tested in a chronic feeding study in
male and female Fischer 344 rats. The chemical was administered as a pulse dose for either 115
weeks for males or 119 weeks for females. Group A, control animals received no test compound,
Group B rats were fed amitrole in their diet at a constant level of 5 ppm during weeks 1-39 and
100 ppm during weeks 40-115 for males or 40-119 for females. Rats in Group C, D, E received
amitrole in their diet at pulsed levels (alternate 4 weeks periods) of 1, 3, and 10 ppm,
respectively, during weeks 1-39 and 20,60, and 200 ppm, respectively, during weeks 40^115 for
males or 40-119 for females. On alternate months, Groups C, D, and E were fed basal diets
without amitrole. The average dose levels are calculated to be: 0.0 (A), 0,35 (C), 1.04 (D),
3.4 (B) or 3.5 mg/kg/day (E) for 115 - 119 weeks. This study had body weight, food
consumption, hematology, clinical chemistry, urinalysis, gross necropsy and organ weight data
that were close to what is requested in the testing guidelines. However, an incomplete list of
organs was examined microscopically. At 0.35 mg/kg/day and above, there was an increase in
thyroid follicular cell hyperplasia in both sexes (p < 0.01; 0/60,12/57,29/55, 38/58 and 25/60
for males and 0/52,7/54,25/50,40/56 and 31/56 for females for increasing doses, respectively).
At 1.04 mg/kg/day and above, larger thyroids were observed; and at 3.4 mg/kg/day and above,
an increase in thyroid weight was observed (p < 0.05). Nothing else was observed in the study.
Amitrole induced a statistically significant increase in thyroid follicular cell adenomas in both
sexes at 1.04 mg/kg/day and above (p < 0.01 except for 1.04 mg/kg/day females in which
p < 0.05). There was also an increasing trend in both sexes (p < 0.01). There was an increasing
trend for thyroid follicular cell carcinomas in both sexes (p < 0.01 for males,p < 0.05 for
females). For combined follicular cell adenomas and carcinomas, there was a statistically
significant increase in both sexes at dose levels of 1.04 mg/kg/day and above (p < 0.01 for males;
p < 0.05 at 1.04 mg/kg/day and p < 0.01 at the two higher dose levels for females). There was
an increasing trend in both sexes (p < 0.01). Under the conditions of the study, the NOEL for
chronic toxicity was less than 0.35 mg/kg/day based on an increase in thyroid follicular cell
hyperplasia, larger thyroids and an increase in thyroid weight. This study is classified as Core
Supplementary for a chronic feeding study in the rat and is determined to be unacceptable for a
carcinogenicity study in the rat. However, for chronic toxicity, when combined with the
following study, the study may be used for regulatory purposes. For carcinogenicity, when
considered as part of the overall weight of the evidence with the results of the other
12
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carcinogen!city studies conducted with amitrole and under the conditions of this study, amitrole
is considered .to be carcinogenic to the rat In this particular study, inducing increases in thyroid
follicular cell adenomas, combined thyroid follicular adenomas/carcinomas and an increasing
trend in thyroid follicular cell adenomas, carcinomas and combined adenomas/carcinomas.
(MRID 00132445).
In the second study, technical amitrole (96.4-97.0%) was tested in a lifetime study in male
and female Wistar rats at the following dose levels in the diet: 0, 1, 10 or 100 ppm
(0, 0.05, 0.5 or 5.0 mg/kg/day). The maximum number of days the animals received the test
chemical was 1,021 days. No food consumption, hematology, clinical chemistry, urinalysis,
organ weight or gross necropsy data were provided. However, a fairly complete microscopic
examination was provided for most of the organs suggested by the Agency. There was a
reduction in survival time at 5.0 mg/kg/day for both sexes combined (p ฃ 0.007; mean survival
times of 980, 971, 973 and 940 days for controls, low, mid- and high dose groups respectively;
statistical analysis conducted on combined sexes at the high dose versus combined sexes and
dose levels for all other groups, including controls). In addition, there was an increase in thyroid
"cysts" at 5 mg/kg/day in both sexes as well (1/73 in controls versus 43/74 in males and 1/75 in
controls versus 27/74 in females; p<0.01). There was an increase in the incidence of thyroid
tumors (unspecified) in both sexes at the high dose when compared to controls (p < 001). There
was also an increase in trend in both sexes (p < 0.01). In addition, there was an increase in the
incidence of pituitary tumors (unspecified) in both sexes at the high dose (p < 0.05 for males and
< 0.01 for females). There was an increase in trend in females (p < 0.01). Under the conditions
of the study, the systemic NOEL is 0.5 mg/kg/day and the systemic LOEL is 5.0 mg/kg/day based
on slight reduction in survival and an increase in thyroid "cysts". The study is classified as Core
Supplementary for a chronic .feeding study in the rat. However, for chronic toxicity, when
Combined with the preceding study, the study may be used for regulatory purposes. This study
is unacceptable for a carcinogenicity study in the rat. Howeyer, when considered as part of the
overall weight of the evidence with the results of the other carcinogenicity studies conducted with
amitrole and under the conditions of this study, amitrole is considered to be carcinogenic to the
rat; in this particular study inducing increases in thyroid and pituitary tumors in both sexes and
an increasing trend in both thyroid and pituitary tumors in this particular study.
(MRID 00061351), . ' ',
Irt the third study, amitrole (grade and purity unspecified) was tested in a feeding study
in male and female rats (Charworth Farms) at dietary levels of 0,10, 50, and 100 ppm (equivalent
to 0, 0.5;, 2.5, and 5.0 mg/kg/day) for two years; another group, 500 ppm (equivalent to 25
mg/kg/day) was treated for 19 weeks and then placed on a controlled diet due to poor weight
gain; the weight loss was reversible, no pathology was reported for this group. This study suffers
from serious conduct problems, particularly in the area of the histological examination and
presentation of the data. Not all animals were examined, many were autolyzed and those which
were examined were not well reported by the pathologist and the reproduction of; the hard copy
from microfiche was extremely poor. Entire sections were either totally missing or totally
unreadable. Interim reports for the 13, 26 and 52 week sacrifices were also missing. Statistical
13
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analysis of the data by the Exact Trend Test (conducted in the knowledge that interpretation is
extremely limited) indicated that there were statistically significant dose-related positive trends
in the incidence of thyroid gland tumors. There were also non-statistically significant numerical
increases in the incidences of thyroid adenomas in the mid- and high dose groups and combined
thyroid adenomas/carcinomas in the high dose group in both sexes at the terminal sacrifice. This
study is unacceptable for a carcinogenicity study in the rat. However, when considered as part
of the overall weight of the evidence with the results of the other carcinogenicity studies
conducted with amitrole and under the conditions of this study, amitrole is considered to be
carcinogenic to the rat; in this particular study inducing a significant dose-related increasing trend
in the incidence of thyroid tumors (MRID 00082176).
In the fourth study, SPF-NMRI mice were fed 0, 1, 10 or 100 ppm (equivalent to
0, 0.15, 1.50 or 15.0 mg/kg/day) amitrole (96.4 - 97.0%) for 18 months. The authors reported
that survival, body weights and food consumption were similar for all treatment and control
groups throughout the study (no individual animal or group mean data were presented in the
report). Increased thyroid weights were observed in the 10 ppm male treatment group when
compared to controls at final sacrifice only. The high dose (100 ppm) male and female thyroid
weights were reportedly increased throughout the study. A slight non-significant increase in
incidence of hepatocellular neoplasia was observed for high dose females (100 ppm) when
compared to controls. There were also statistically significant positive trends for hepatocellular
carcinoma (p = 0.019) and combined adenoma/carcinoma (p = 0.019) in females. This study is
unacceptable for a carcinogenicity study in the mouse. However, when considered as part of the
overall weight of the evidence with the results of the other carcinogenicity studies conducted with
amitrole and under the conditions of this study, amitrole is considered to be carcinogenic to the
mouse; in this particular study inducing art increase in trend for liver tumors (MRBDs 00061348,
41317901, and 41462501).
In the fifth study, amitrole was used as a positive control in the screening of 120
compounds for tumorigenicity. C57BL/6 x C3H/Anf and C57BL/6 x AKR mice we
administered by stomach tube 1000 mg/kg (6700 ppm) amitrole from day 7 to day 28 of ag-
followed by 2192 ppm (equivalent to 329 mg/kg) in the diet for 18 months. All amitrole treated
animals either died or were sacrificed in extremis between 53 and 60 weeks on test of a designed
126 week study. The early deaths of all the amitrole treated animals in this study indicate that
the doses selected exceeded the Maximum Tolerated Dose (MTD) for these strains of mice. The
authors reported that "hepatomas" were observed in 67 (of 72) mice treated with amitrole. In one
of the article's footnotes, the authors also reported that "carcinoma of the thyroid were found in
64 [of 72] mice" treated with amitrole. This study is unacceptable for a carcinogenicity study in
the mouse. However, when considered as part of the overall weight of the evidence with the
results of the other carcinogenicity studies conducted with amitrole and under the conditions of
this study, amitrole is considered to be carcinogenic to the mouse; in this particular study
inducing increases in liver and thyroid tumors when used as a positive control in a screening
study for tumorgenicity (MRID 00043595).
14
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In the sixth study, B6C3F1 mice were fed 500 ppm amitrole (grade and purity unspecified,
equivalent to 75 mg/kg/day) ad libitum as follows: Group 1 - "pregnant females from the 12th
day of gestation to delivery" (mice exposed placentally in utero); Group 2- "mothers with litters
from delivery to weaning" (mice exposed preweaning through the mother's milk; Group 3 -
"offspring from weaning through 90 weeks" (mice exposed postweaning through the diet). Non-
treated controls were sacrificed at 52,90 or 142 weeks. Since it is unclear as to which of the non-
treated control groups (those sacrificed at 52, 90 or 142 weeks) were used to assess the
carcinogenic activity of amitrole in groups 1 and 2,, the study could not be evaluated for these 2
groups. However, adult males [Group 3] could be evaluated using the control group sacrificed
at 90 weeks. This group responded to protracted amitrol treatment with development of benign
and malignant liver tumors. The adult females [Group 3] showed only a marginal neoplastic
response. This study, when considered as part of the overall weight of the evidence with the
results of the other carcinogenichy studies conducted with amitrole and under the conditions of
this study, amitrole is considered to be carcinogenic to the mouse; in this particular study,
possibly inducing increases in liver tumors in both sexes (Vesselinovitch, 1983; ho MRID
number).
, h. Developmental Toxicity
For developmental toxicity, four studies are available to the Agency. They consist of an
oral developmental toxichy study in the rat, two oral developmental toxicity studies in the rabbit
and a dermal developmental toxicity study in the rabbit All studies are acceptable for regulatory
purposes.
In the first study, technical amitrole (91.83%) was tested in a developmental toxicity study
in CDฎ-Crl: COBSฎ CDฎ(SD)BR outbred albino rats. Amitrole was administered by gavage
in a dosage volume of 10 ml/kg deipnized water from gestational days 6 through 15 at the
following levels: 0, 100, 500 or 1000 mg/kg/day. Thirty-eight females were selected for each
dose group: 24 were sacrificed at gestation ,day, 21 and 14 were held to postnatal day 21. At
500 mg/kg/day and above, there were slight but statistically significant increases in mean absolute
and relative thyroid weights at both gestation day 21 and at postnatal day 21 (p value ranging
from < 0.05 to p < 6.001). There was also a slight, but statistically significant decrease in mean
bodyweight gajn for high dose dams during gestation days 6-18 (90.9% of controls, p < 0.05).
The NOEL for maternal toxicity is considered to be 100 mg/kg/day and the LOEL is considered
to be 500 mg/kg/day based on increased mean absolute and relative thyroid weights and
decreased maternal body weight gain. Statistically significant increases in the number of litters
with unossified cervical centra # 6 and proximal phalanges; bi-lobed cervical centra #'s 1, 2, 3
and/of 4; enlarged biparietal suture; poorly ossified proximal phalanges and maxillary and dark
thyroids were observed in the high dose group when compared to the control group. In addition,
the high dose group had a statistically significant lower mean bodyweight than the control group
Therefore, the NOEL for developmental toxicity is 500 mg/kg/day arid the LOEL is
1000 mg/kg/day (HDT) based on skeletal variations, decreased mean fetal body weights and dark
thyroids (MRID 00160448). ,
15
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In the secontf study, technical amitrole (91.83%) was tested in a developmental toxicity
study in rabbits. Timed-pregnant New Zealand White rabbits were administered amitrole by
gavage in a volume of 2.0 ml/kg deionized water during gestation days 6-18 at the following dose
levels: 0,4.0, 40.0 or 400.0 mg/kg/day. No.maternal effects were observed at 4.0 mg/kg/day.
At 40.0 mg/kg/day and above there was a statistically significant decrease in body weight gain
during the dosing period (121 grams in controls versus -219 and -436 grams in the mid- and high
dose groups, respectively). At 400.0 mg/kg/day, there was a statistically significant increase in
abortions (5 versus 0 in controls). The NOEL for maternal toxicity is 4.0 mg/kg/day and the
LOEL is 40.0 mg/kg/day based on decreases in body weight gain during the dosing period and
an increase in abortions. At 40.0 mg/kg/day and above, there were statistically significant
increases in the number of litters with a variety of malformations and variations in external,
visceral and skeletal examinations (p < 0.05 and p < 0.01). At 400.0 mg/kg/day, there were
statistically significant decreases in fetal body weight (70% of controls) and in percent live
fetuses/litter (62 versus 84%) and a statistically significant increase in postimplantation loss/litter
(290% of controls). The NOEL for developmental toxicity is 4.0 mg/kg/day and the LOEL is
40.0 mg/kg/day based on increases in the number of litters with a variety of malformations and
variations and decreases in fetal body weight and percent live fetuses/litter (MRID 00159997).
In the third study, technical amitrole (97.5%) was tested in a developmental toxicity study
in rabbits. Naturally inseminated rabbits were administered the test chemical by gavage in water
on gestation days 6-18, inclusive. The following dose levels were given: 0, 5,20 or 80 mg/kg
bodyweight/day. At 80 mg/kg/day, there were slight decreases in mean body weight of the does
from days 69 of the gestation period (bodyweight gain i'/om days 6-18 was 69% of controls, not
statistically significant). There were also decreases in food consumption (p < 0.001 on days 6-10
and p < 0.01 on days 14-19). Therefore, the NOEL for maternal toxicity is 20 mg/kg/day and the
LOEL is 80 mg/kg/day. The LOEL is a borderline NOEL because the effects were so slight and
they were supported by thyroid follicular cell hypertrophy on a parallel maternal toxicity range-
finding study. At 80 mg/kg/day, the only treatment-related developmental effect was a
statistically significant (p < 0.05) decrease in male fetal bodyweight (9i% of controls). This
effect is considered to be minimal. Therefore, the NOEL for developmental toxicity is
20 mg/kg/day and the LOEL is 80 mg/kg/day. The LOEL is considered to be a borderline LOEL
because the effect was so minimal (MRIDs 43643601 and 43643602).
In the fourth study, amitrole (93.9% pure) was tested in a dermal developmental toxicity
study in Hra:(NZW) SPF rabbits at the following dose levels: 0, 1.0, 1.5 or 2.0 g/kg/day in a
volume of 0.5 mg/g during gestation days 7-19. At 2.0 g/kg, there was an increase in does that
were thin and anorexic and a statistically significant decrease in body weight gain during the
latter days of the dosing period as well (days 14-20). By day 20, high dose females weighed 12%
less than the controls (p < 0.05). Food consumption was also significantly decreased on days
10-20. There appeared to be an increase in the number of resorptions/doe, although a statistical
analysis was not conducted and the mean number of live fetuses/doe was not significantly
affected at this dose level. The NOEL for maternal toxicity is 1.5 g/kg/day and the LOEL is
2.0 g/kg/day based on decreases in body weight and body weight gain during the dosing period.
16
-------
At 2.0 g/kg, a statistically significant decrease in mean fetal bodyweights for both sexes was
observed. Increases in skeletal anomalies were also observed at this dose level, however, these
increases were only seen in the number of fetuses affected and not in the number of litters
affected. Therefore, the NOEL for developmental toxicity is 1.5 g/kg/day and the LOEL is
2.0 g/kg/day based on decreases in. mean feta]-body weights for both sexes (MRIDs 40567701,
40963701). -
, i. Reproductive Toxicity
A reproduction study conducted in the rat is available to/ the Agency. The study is
acceptable for regulatory purposes.
. In a 2-generation reproduction study, Amitrole (97-98% a.i.) was administered to
30-31 Sprague-Dawley rats/sex/dose in the diet at dose levels of 0.5, 2,15 or 112.5* ppm. The
mean achieved dose levels were 0,0.03, 0.12, 0.90 or 5.88 mg/kg/day (males) and 0, 0.04, 0.16,
1.23 or 7.83 mg/kg/day (females) in the F0 generation and 0, 0.04, 0.16, 1.24 or 12.02 mg/kg/day
(males) and 0, 0.05, 0.21, 1.64 and 15.64 mg/kg/day (females) in the Ft generation. No
toxicologically significant effects were observed at dose levels of 0.5, 2 or 15 ppm. At 112.5
ppm, the following effects were observed in parental animals: clinical signs (hypoactivity,
piloerection, dyspnea, hypothermia), death, a decrease in mean body weight and body weight
gain during the premating and gestation periods (mostly, p < 0.001), a decrease in mean food
consumption and food efficiency, decreases in several absolute and relative organ weights and
an increase in absolute and relative thyroid weight (p < 0.01), increases in thyroid activity (small
follicles and decreased colloid content), thyroid follicular cell hypertrophy and hyperplasia,
thyroid nodular hyperplasia and/or adenoma, uni- or bilateral atrophy of the adrenal cortex, a
higher incidence of ceroid pigment accumulation in the adrenal cortical cells, hepatocellular
hypertrophy, hepatic cell degeneration/necrosis and higher incidence and/or severity of
perilobular steatosis, decrease in the number of acidophil cells in the pituitary, higher intensity
of vacuolated cells in the pituitary, a high incidence of pseudqpregnancy, a high incidence and/or
severity of acinar and/or ductular epithelial cell vacuolation in the mammary gland,
mineralization of .urothelium and/or urinary gravel in the renal pelvis, retardation of renal
maturity and a lower incidence of mononuclear cell aggregation, tubular basophilia and
accumulation of acidophilic globules in the cortical tubular epithelium. Also at 112.5 ppm the
following reproductive effects were observed: decreases in mating and fertility indices (not
statistically significant, partly explained by high death rate and decrease in implantation sites),
decreases in implantation sites/litter (p< 0.001), a slightly higher gestation interval (F^ p < 0.001)
and a decrease in the mean pup male/female ratio in the FI generation. The LOEL is 112.5 ppm
{lowest of F0 and Fx generations of 5,88 mg/kg/day in males, 7.83 mg/kg/day in females), based
on clinical signs, death, decreases in mean body weight, body weight gain, food consumption,
food efficiency and selected absolute and relative organ weights, an increase in thyroid weight
and activity, follicular cell hypertrophy and hyperplasia and nodular hyperplasia and/or adenoma,
hepatocellular hypertrophy and other microscopic changes in the adrenals, liver, pituitary,
mammary gland and kidney, a high incidence of pseudopregnancy, decreases in mating and
17
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fertility indices, implantation sites/litter and mean pup male/female ratio and a slightly higher
gestation interval. The NOEL is 15 ppm (0.90 mg/kg/day in males, 1.23 mg/kg/day in females;
(MRID 44016201).
j. Mutagenicity
Amitrole has been tested in many mutagenicity studies, most of which are in the literature.
Four submitted studies are summarized in this document. All four of the studies are acceptable
for regulatory purposes. In addition to the summaries of the 4 submitted studies, a summary
paragraph of the published mutagenicity literature on amitrble is given to provide a more
complete picture for this chemical.
In the first study, amitrole was tested in a Salmonella tvphimurium/mammalian
microsome mutagenicity assay at doses ranging from 20 to 12,500 ng/plate. Under the
conditions of the assay, amitrole was not mutagenic in S. tvphimurium strains TA1 S3 5T TA1537,
TA98 or TA100. Concentrations *2500 ug/plate with and without S9 were cytotoxic. Although',
the results were clearly negative, the rationale for the performance of the study with 30% S9 was
not provided, and a direct acting positive control was not included in the study. Nevertheless,
the study is acceptable and satisfies the guideline requirements for testing for gene mutation
(MRID 42214601).
In the second study, amitrole (99.4%) was tested for mutagenic activity in Saccharomyces
cerevisiae. strain D4 and in Salmonella tvphimurium. strains TA-1535, TA-1537 and TA 1538
in a series of microbial plate tests. It was tested both with and without metabolic activation
(enzymatic preparations from the liver, lungs or kidneys from the mouse, rat and monkey), The
following positive controls were also tested: ethyl methanesulfonate, 2-nitrofluorene and
quinacrine mustard (nonactivation) and dimethylnitrosamine, 2-acetylaminofluorene and
7,12-dimethylbenzanthracene (with activation). Amitrole was moderately toxic at 500 ug/plate
and a concentration of 100 ug/plate was selected for the screen. Amitrole tested negatively both
with and without metabolic activation. The positive controls induced a significant number of
revertants/plate. It appears that the mouse, rat and monkey livers were best suited for metabolic
activation, the monkey being the least suitable. The lung and kidney did not activate the positive
control chemicals. This study is acceptable (MRID 00052646).
In the third study, amitrole was tested in an in vivo micronucleus assay in the mouse using
a single oral gavage dose of 10,000 mg/kg. Amitrole did not induce overt toxicity in either males
or females at this dose level. In addition, the test chemical did not induce cytotoxiciry in the
target organ, or cause a significant increase in the frequency of micronucleated polychromatic
erythrocytes (MPEs) in bone marrow cells harvested 24,48 or 72 hours posttreatment. Based on
these findings, amitrole is not considered to be clastogenic in the mouse micronucleus assay. The
study is acceptable and satisfies the guideline requirement for testing for structural chromosomal
aberrations (MRID 42214602).
18
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In the fourth study, amitrole was evaluated for its ability to induce cellular transformation
in BALB/3 T3 cells in vitro. The parental clone had been selected for its low spontaneous
transformation rate and its high response to known carcinogens. For the first trial, a treatment
range of 1- 1000 ug/ml was used. For trials 2 and 3, the dose levels were separated by two-fold
serial dilutions between 0.6 and 5 mg/ml in an attempt to cluster the doses at the more active end
of the dosage range. Toxicity was observed in all plates at the 5 mg/ml level and in 2 of the 10
plates setup at the 2.5 mg/ml level. The mitotic indices of these cells were not determined, but
the treated cultures reached confluency at the same time as the untreated cultures; thus, the rates
of division did not appear to be impaired by the test chemical. A positive response was observed
at the 1 mg/ml and 0.01 mg/ml levels of the first trial, but not at any of the dose levels of the
second or third trials. Amitrole induced cellular transformation in cells of one of three trials, and
was interpreted as having a weak cellular transforming capacity in these cells. The study is
acceptable (MRID 00052648).
A summary of the genotoxicity data base for amitrole was written in the published article
by Richard N. Hill et al in Fundamental and Applied Toxicology 12: 629-697 (1989).
Although the published literature shows that amitrole does not induce positive results in a
majority of mutagenicity assays, there does appear to be some evidence that amitrole may have
some genotqxic activity. Most bacterial gene mutation assays are negative as well as the
Drosophila sex-linked recessive lethal assay and the mouse lymphoma assay. Assays for
chromosomal effects are generally negative, but there are in actuality very few test results (in
human lymphocytes and a mouse dominant lethal). Two sister chromatid exchange assays were
reported positive, there were some positive and some negative results for DNA damage and
unscheduled DNA synthesis and all in vitro cell transformation assays were positive.
k.
Metabolism
Metabolism studies are required only if the Agency determines that additional information
on the metabolism of the chemical is necessary to clarify unusual effects observed in chronic or
reproduction studies or to clarify issues concerning structure activity relationships. For amitrole,
no issues that need further clarification are identified that warrant the need for metabolism data.
Metabolism data were reviewed from the literature and from submitted studies. None of these
studies, either singly or combined, provide a complete picture of the absorption, distribution,
metabolism and excretion of amitrole. Nevertheless, as stated before, because the Agency does
not have any issues that need to be further clarified, no additional studies are required. The
available studies do provide useful information and are summarized here. When available, MRID
numbers are provided. All studies are referenced in the bibliography (Appendix C).
19
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Studies Conducted With Rats
Oral Exposure ~ ': ]
Fang. 1964: Wistar rats were fed 1 mg CM-amitrole (per rat) via stomach tube. The
expired air, urine, feces and tissues were analyzed for radioactivity during a three day
period following dosing. During the first 24 hours, 70-95.5% of the radioactivity was
found in the urine; a small variable amount of activity was found in the feces. After
absorption, amitrole was distributed throughout most body tissues. The maximum
radioactivity was found in liver and kidney. Within three to four hours of dosing, the
tissue levels began decreasing. Paper chromatography revealed both unchanged amitrole
and one unidentified metabolite in rat liver slices taken at various times following dosing.
Franco and Municio. 1975: Male Wistar (number unspecified) rats "were treated with
amitrole [unspecified amount] during 8 days by the method described elsewhere." The
authors reported that "unaltered amitrole and three metabolites are present in the urine of
treated animals." The metabolites were not identified or quantified.
Inhalation Exposure
MacDonald. Hazleton. 1976. fMRID 00052644V Rats (5/sex; Charles River Ltd.) were
exposed by inhalation to an estimated dose of 25.8 ug/L for "whole body" or 49.2 ug/L
for "head only" radiolabelled amitrole for one hour. Blood samples were taken at
specified intervals and urine, feces and carcasses were examined for radioactivity. The
results were reported as follows:
"Head Only": the blood plasma half life was estimated to be 20 hours;
approximately 75% of the radioactivity was found in urine; the level of
radioactivity is "substantially lower in females" and no appreciable quantities of
radioactivity were found in the carcasses.
"Whole Body": the blood plasma half life was estimated to be 23 hours; the major
route of excretion was the urine and no appreciable quantities of radioactivity were
found in the feces and carcasses.
Turner. Hazelton. 1976. (MRID 00052645V As a supplement to the "whole body" and
"head only" inhalation metabolism study (discussed above), metabolites in the urine and
feces were identified by using chromatography. The results were reported as follows:
Urine: 60% of the dose was presumed to be unchanged amitrole; 15-20% was
retained at the origin and 5-8% were unidentified. '
20
-------
Feces: 56% was of the dose was presumed to be unchanged amitrole and 25% was
. retained at the origin. ^
Studies Conducted With Rabbits
Dermal Exposure
Shah. 1977: This preliminary study in female New Zealand white rabbits
(3 animals/pesticide) was designed to obtain a comparative rate of dermal penetration of
5 radiolabelled pesticides, including amitrole. The pesticides were "applied in 0.1 ml of
acetone containing 1 mg of non-radioactive pesticide per kilogram body weight." Blood
samples were taken at specified intervals up to 24 hours following treatment. Urine and
feces were collected and "various organs" removed and assayed for radioactivity. After
24 hours, the site of application was swabbed with cotton arid acetone. The authors
reported that "after 15 minutes, the order of penetration into blood was aminotriazole >
carbaryl = parathion > malathibn > DDT > dieldrin." Although the percent of dose was
not reported, "appreciable quantities of aminotriazole was found in the urine, feces and
gallbladder." The amount of amitrole remaining at the site of application was estimated
to be "fifty percent or more."
Studies Conducted With Mice
Oral and/or Intravenous Exposure
Tialve. 1975. MRID 00052659: Male and female mice (7/sex; "C57/B1" strain) were
either intravenously injected or administered by gavage 5 uGi (microCuries) of C14
amitrole and sacrificed from 5 minutes to 5 days following treatment. Whole body
radiography showed a "high accumulation of radioactivity in tissues with'-rapid cell
turnover such as the bone marrow, the spleen, the thymus, the lymph nodes and the
gastrointestinal mucosa." The results appeared to be similar for both routes of exposure.
The authors reported the following for liver and thyroid:
Liver: "The radioactivity in the liver is irregularly distributed, being highest in the
peripheral parts of the liver lobules around the portal spaces;" "radioactivity was
also present in the mitochondrial and microsomal fractions."
Thyroid: "A moderate accumulation of radioactivity was found in the thyroid."
21
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2. Exposure Assessment
a. Dietary Exposure
.... t ._
There are no food uses for amitrole. Therefore, there are no known dietary exposures to
amitrole and a dietary exposure assessment is not required.
b. Occupational Exposure
An occupational and/or residential exposure assessment is required for an active
ingredient if (1) certain toxicological criteria are triggered and (2) there is potential exposure to
handlers (mixers, loaders, applicators, etc.) during use or to persons entering sites after
application is complete.
Although the Agency has identified inhalation as an appropriate route of exposure on
which to conduct short term and intermediate term risk assessment, the Agency also believes that
in reality there is little likelihood of actual inhalation exposure from mixing/ loading/ applying
of amitrole. The inhalation exposure estimates arr sry conservative because (1) amitrole is not
volatile, (2) amitrole is only packaged in water K;, ^ble bags (which greatly reduces the chance
for incidental inhalation exposure), (3) the inhalation exposure values presented in Table 3 reflect
data from the Agency's Pesticide Handlers Exposure Database (PHED VI.1), which for the water
soluble packaging data set includes some instances where detections were not found but a value
of half the limit of detection, was assumed, and (4) the Agency assumed 100% adsorption of
inhalation exposure from both the oral developmental toxicity study and the reproduction study.
The assumption of half the limit of detection is a common Agency practice in establishing
exposure/residue values. .
As previously discussed, the registrant voluntarily restricted the use patterns of amitrole
to reduce the exposure of amitrole to handlers. The wettable powder and liquid concentrate
formulations were voluntarily restricted by the registrant to water soluble packets and "no-glug"
containers, respectively. The only current application method is for fixed-boom sprayers attached
to ground equipment such as tractors, trucks or railroad wagons. The registrant has recently
requested the voluntary cancellation of the liquid formulation (in no-glug container) and has also
requested the use deletion of the only use currently within the scope of the Worker Protection
Standard, ornamental plant nurseries.
Occu national-use products
All products containing amitrole are for occupational use. There are no homeowner use
products containing amitrole.
22
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Handler (Mixers. Loaders. Applicators) Exposures
, '-. ,_ , and Assumptions
" ^ * " ' (
The three exposure scenarios identified for amitrole are:
(1) Mixing/loading the liquid concentrate formulation (packaged in no-glug
containers) to support ground application. As noted previously, the registrant has
requested voluntary cancellation of this product. The Agency has included the
mixer/loader, exposure/risk estimates for this formulation since the voluntary
cancellation is still in process.
(2) Mixing/loading the wettable powder formulation (packaged in water soluble bags)
to support ground application, and
(3) Applying as a spray with fixed-boom ground equipment. (Exposure data for
groundboom equipment is used as a surrogate for the fixed-boom ground
equipment).
~ Table 3 presents the short-term (1 - 7 days) and intermediate-term (1 week to several
months) dermal and inhalation exposure scenarios, while Table 4 summarizes the caveats and
parameters specific to each exposure scenario.
Post-Application Exposures and Assumptions
Post-application reentry and residue dissipation data have not been submitted to the
Agency in support of the amitrole reregistration, based on the agreements reached in the Special
Review. The potential for post-application exposure to amitrole residues is low because of the
use patterns for this chemical (i.e., herbicide used in areas where reentry exposure is not expected
to be problematic such as rights-of-way). .
23
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3.
Risk Assessment
a. Dietary
Based on
-------
With regard to cancer risk, the Agency included both dermal and inhalation exposure.
The lack of significant systemic effects from the dermal developmental toxicity study would not
bear on the cancer risk assessment. The following equation is used for determining the
carcinogenic risk:
Risk = LADD (mg/kg/day) x Qj* (mg/kg/day^1
where: .. ' ' ' . , ...-./. 7 .' . : "' ' '- ..''.,,' .' ' :' :.
LADD (mg/kg/day) = [Daily Total Dose (mg/kg/day)] x [(10 Work Days Per
Yr)/(365 Days Per Year)] x [(40 working Yrs/75 lifetime Yrs)]
LADD = Lifetime Average Daily Dermal and Inhalation Dose
' Risk From Handler Exposures:
Risks from Short-Term and Intermediate-Term
Exposures
The Agency conducted an assessment of the inhalation risks associated with amitrole
following short-term and intermediate-term exposures to occupational handlers. The Agency has
determined that a risk assessment is not required for short-term and intermediate-term dermal
exposures. Margins of exposure (MOE) for occupational inhalation exposures were calculated
for handlers using the NOELs of 4 mg/kg/day for short-term and 0.9 mg/kg/day for intermediate-
.term exposure. The calculated MOEs are presented in Table 5. Amitrole is not marketed to
homeowners (only application method is fixed-boom sprayer), therefore the sole exposure
concern is for occupational handlers. The calculations indicate that with the exception of one
scenario, all of the MOEs for short- and intermediate-term inhalation exposures at baseline
protection (i.e., no respirator) exceed 100 indicating acceptable risk. The exception is the
intermediate-term inhalation exposure of Scenario 1 (mixing/loading the liquid concentrate,
which has aii MOE of 82). However, the registrant is voluntarily cancelling this formulation.
; . - ' : '._ . v. - ' -'.,' . .. . - . , . ,. ,
Carcinogenic Risks
The Agency conducted an assessment of the carcinogenic risks associated with amitrole
following exposures tp occupational handlers (Table 6) including all currently registered uses,
which includes the liquid concentrate formulation (packaged in a no-glug container) for which
the registrant has recently requested a voluntary cancellation. . \
The calculations indicate that the risks at baseline protection (i.e., long-sleeve shirt, long
pants, shoes, and socks) are in the 10"s range for mixing/loading wettable powders (contained in
water-soluble packaging) and application using open-cab groundboom sprayers, the surrogate
for fixed-boom ground sprayers.. The calculations indicate that the risks at baseline protection
11
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arc greater than 10"* for mixing/loading liquid formulations. These calculations do not reflect the
exposure reduction expected to be realized from the mandatory use of "no-glug" containers for
liquid formulations. However, the registrant has recently requested voluntary cancellation for
this formulation. . ,
The risk assessment indicates that the risks at baseline protection are approximately 10'5
for mixing/loading the wettable powder formulation packaged in water soluble bags. Since the
risk assessment was conducted using this assumption, the Agency is requiring that the wettable
powder formulation continue to be marketed only in water-soluble packaging. In addition, since
the Agency has low confidence in the data used to assess exposure to mixers and loaders using
water-soluble packaging and amitrole is a relatively potent carcinogen, additional risk reduction
measures for mixers and loaders are being required. The following risk mitigation measures for
mixers and loaders handling the wettable powder amitrole formulations, should adequately
mitigate risk to these workers:
mandatory use of water-soluble packaging for wettable powder amitrole
formulations, and
requiring mixers and loaders to wear a chemical-resistant apron, long-sleeve shirt,
long pants, shoes, socks and chemical-resistant gloves.
28
_
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liable 5. Short-Tcrm and Intermediate-Term Inhalation MOEs for Workers Ex;
- ' ' Exposure Scenario
Baseline
Inhalation Dose*
(mg/kg/day)
Daily
:. Inhalation .
MOE"
CShnTf-Ti-rfn^
osed to Amitrole
. Daily Inhalation
MOEC
(intermediate Term)
, Mixer/Loader Exposure
*i ' -,-,.
Scenario (1)
Mixing' Liquid Groundboom Treatment
' Application
Scenario (2) , ' . . -
Mixing Wettable Powder (water soluble . ,
* packets) for Groundboom Treatment
Application
0.013
0.001
308
4,000
-, , 82
1125
* ' ' ,
-.'-....' Applicator Exposure ; . - .
1-
- 0^0075
'
533
141
* Daily inhalation dose = (maximum daily inhalation exposure)/(60 kg)
b Short term inhalation MOE = NOEL (4.0 mg/kg/day))/daily inhalation dose (mg/kg/day).
c Intermediate term inhalation MOE = NOEL (0.9 mg/kg/day) daily inhalation dose (mg/kg/day).
29
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Risk From Post-Application Exposures ' <
There are no amitrole-specific post-application exposure data available. For many
amitrole use scenarios, the Agency believes that the risks from post-application exposures will
not pose an unacceptable risk to persons entering treated areas because, in general, amitrole is
used in areas, such as rights-of-way, industrial areas, permanent landscape plantings, and other
non-crop areas, where frequent or routine prolonged contact with treated surfaces is unlikely.
Therefore, the Agency has determined that post-application exposures do not appear to pose an
unreasonable risk to persons entering treated areas, as long as entry is not permitted until sprays
have dried.
C. Environmental Assessment
The environmental assessment consists of the following sections: Ecological Toxicity
Date; Environmental Fate and Transport Date; Ecological Exposure and Risk Assessment; and,
Environmental Risk Characterization, The first two sections describe the ecological effects and
environmental fate and transport date from appropriate field and laboratory studies, analyzes the
impact to water resources, and details the environmental fate assessment; and the third and fourth
sections estimate ecological and environmental exposures and assess the effects to non-target
terrestrial and aquatic organisms, plants and endangered species. The section on environmental
risk characterization integrates the exposure and effects assessments to determine the extent and
potential for risk to the environment.
1. Ecological Toxicity Data .
a. Toxicity to Terrestrial Animals .
Although there are several unfulfilled data requirements, the Agency can partially
determine the hazard of amitrole to nontarget terrestrial and aquatic organisms.
(1) Birds, Acute and Subacute
In order to establish the toxicity of amitrole to birds, the following tests are required using
the technical grade material: one avian single-dose oral (LD50) study on one species (preferably
mallard or bobwhite quail); two subacute dietary studies (LCJO) on one species of waterfowl
(preferably the mallard duck) and one species of upland game bird (preferably bobwhite quail).
' Avian Acute Oral Toxicity Findings '
Species
Northern Bobwhite
%A.L
91.83
LDH ing/kg 1
>2150
MRTONo.
Author/Year
00160451
Fletcher/1985
Toxicity
Category
practically
non-toxic
Fulfills Guideline
Requirement
Yes
-------
Avian Subacute Dietary Toxiclty Findings
Species
Northern Bobwhite
Mallard
Mallard
Pheasant
/.A.I.
91.83
91.83
Technical
Technical
LCHppm
>5000
>5000
>5000
>5000
MRID No.
Antfaor/Year
00160452
Fletcher/1985
00160476
Fletcher/1985
00022923
Hill/1982
00022923
Hill/1982
Toxldty
Category
practically
. non-toxic
practically
non-toxic
practically
non-toxic
practically
non-toxic
Fulfills Guideline
Requirement
Yes
Yes
Yes
Yes
These results indicate that amitrole is practically non-toxic to avian species on an acute
oral and subacute dietary basis. The guideline requirements are fulfilled. (GLN 71-1,
MRID 00160451; GLN 71-2, MRIDs 00160452, 00160476)
(2) Birds, Chronic
Avian reproduction studies are required when birds may be exposed to amitrole repeatedly
or continuously through persistence, bioaccumulation, or multiple applications, or if mammalian
reproduction tests indicate reproductive hazard. Amitrole has a half-life exceeding four days, can
be applied in multiple applications, and has chronic effects on mammals at relatively low levels.
Based on these conditions, avian reproduction studies are required, with the bobwhite quail and
mallard duck. Guideline 71-4 will be fulfilled when adequate avian reproductive studies with
both species of birds are submitted, reviewed and found acceptable.
1 '..'*>
(3) Mammals ,
Wild mammal testing is required on a case-by-case basis, depending on the results of the
lower tier studies such as acute and subacute testing, intended use pattern, and pertinent
environmental fate characteristics. In most cases, however, an acute oral LDjo (reported below)
from the Office of Pesticide Program's Health Effects Division is used to determine toxiciry to
mammals.
Mammalian Acute Oral Toxicity Findings
Species
Rat (small mammal surrogate; males only)
Rat (small mammal surrogate; male and female)
LDMs/ke
24.6 g/kg
4.08 g/kg
Mnn>#
00063601
Oainesetal., 1973
(no MRID)
Toxiclty Category
practically non-toxic
practically non-toxic
1. Datafrom HED RED chapter.
32
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The available mammalian data indicate amitrole is practically non-toxic to small mammals
on an acute oral basis.
In an acceptable two-generation rat reproduction study (MRJDD 44016201), the LOEL is-
112.5 ppm (lowest of FO and Fx generations of 5.88 mg/kg/day in males and 7.83 mg/kg/day in
females) and the NOEL is 15 ppm (0.90 mg/kg/day for males, 1.23 mg/kg/day for females).
Additionally, a developmental study with New Zealand white rabbits also gives pertinent
mammalian toxicity data because the study reported developmental effects (MRID 00159997).
The pregnant rabbits were administered amitrole by gavage for 12 days during gestation. The
NOEL for developmental toxicity is 4.0 mg/kg/day and the LOEL is 40 mg/kg/day based on
increases in the number of litters with a variety of malformations and variations in external,
visceral, and skeletal examinations, and decreases in fetal body weight, and percent live
fetuses/liter.
' . '-, \ ' , - ,
(4) Insects
\ ' , . - ' -
A honey bee acute contact LD50 study is required since the use patterns for amitrole
(terrestrial nonfood and outdoor residential sites) are expected to result in exposure to honeybees.
Nontarget Insect Acute Contact ToricKy, Findings .
Species
Honey Bee
/ AI
Technical
LDwpga.L/bee ,
> 12.09
S
MRID No.
Author/Year
00036935
Atkins/1975
Toxicity
Category
relatively non-
toxic
Fulfills Guideline
Requirement
Yes
There is sufficient information to characterize amitrole as relatively non-toxic to bees.
The guideline requirement is fulfilled. (GLN 141-1; MRID 00036935) '
b. Toxicity to Aquatic Animals
(1) Freshwater Fish
o Acute
To establish the toxicity of a pesticide to freshwaterfish, the minimum data required on
the technical grade of the active ingredient are two freshwater fish toxicity studies. One study
should use a coldwater species (preferably the rainbow trout), and the other should use a
warmwater species (preferably the bluegill sunfish).
33
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Sปecks
Bluegill suofiih
Rainbow Trout
Bluegill lunfish
Fathead minnow
Channel catfish
Rainbow trout
Rainbow trout
/.A.L
96.3
96.5
90
90
90
90
formulated
product
(Fenavar)
Freshwater Fis
LCuppma.i.
>IOOO
>1000 '
>180
>100,
>160
>180
65 ppiQ
h Acute Toxicity Findings
MRIDNo.
Author/Year
00160453"
McAllister/1985
00160454
McAllister/1985
43923702
McCann/1976(USEPA
lab)
40094602
Johnson/1980
40094602
Johnson/1980
43923701
McCann/1976
00024959
McCann/1972
.
Toxiclty
Category
practically non-
toxic
practically non-
toxic
practically non-
toxic
practically non-
toxic
practically non-
toxic
practically non-
toxic
slightly toxic
Fulfill* Guideline
Rcfl nircmmt
Yes
Yes
Yes ,
Yes
Yes
Yes
No (supplemental)
The results of the 96-hour acute toxicity studies indicate that amitrole is practically non-
toxic to fish. The guideline requirements are fulfilled. (GLN 72-1, MRIDs 00160453 and
00160454)
o Chronic
Data from fish early life-stage tests or life-cycle tests with aquatic invertebrates (on
whichever sped- = is most sensitive to the pesticide as determined from the results of the acute
toxicity tests) are required if the product is applied directly to water or expected to be transported
to water from the intended use site, and if any one or more of the following conditions apply:
if the pesticide is intended for use such that its presence in water is likely to be
continuous or recurrent regardless of toxicity; or
if any acute LCj
jo is greater than 1 mg/1; or
if the EEC in water is equal to or greater than 0.01 of any acute EC50 or LCj0
value; or,
if the actual or estimated environmental concentration in water resulting from use
is less than 0.01 of any acute ECso or LQ0 value and any of the following
conditions exist:
34
.
-------
- studiies of other organisms indicate the reproductive physiology offish and/or
invertebrates may be affected; or
- physicochemical properties indicate cumulative effects; or the pesticide has a
half-life of greater than 4 days in water.
Amitroie exceeds a half-life of four days (aerobic soil metabolism half-life of
ซ22-26 days; terrestrial field dissipation half-lives of 17-21 days) and multiple applications are
listed on the label. Based on these conditions, either a fish early life-stage (72-4(a)) study or
aquatic invertebrate life-cycle (72-4(b)) study is required. Using the acute toxicity data for
aquatic species (refer to the Estuarine and Marine Animals section), the most sensitive aquatic
species is the marine/estuarine invertebrate Daphnia magnet. Therefore, to complete the chronic
hazard assessment for amitrole, an aquatic invertebrate life-cycle (Guideline 72-4(b)) with
Daphnia magna study is required.
The fish life-cycle test is required when an end-use product is intended to be applied
directly to water or is expected to transport to water from the intended use site, when any of the
following conditions apply: the EEC is equal to or greater than one-tenth of the NOEL in the fish
early life-stage or invertebrate life-cycle test; or if studies of other organisms indicate the
reproductive physiology of fish may be affected.
The Agency is reserving the requirement for a fish life-cycle test study (Guideline 72-5).
The requirement of a fish life-cy^cle study will depend on the results from an acceptable aquatic
invertebrate life-cycle study.
The risk to aquatic species (on a chronic basis) will be determined once the registrant
submits the fish early life-stage (Guideline 72-4(a)) or aquatic invertebrate life-cycle studies.
Exposure to aquatic enviornments may occur by runoff or spray drift. The aquatic invertebrate
life-cycle study with Dapnia magna is being required.
(2) Freshwater invertebrates
The minimum testing required to assess the hazard of a pesticide to freshwater
invertebrates is a freshwater aquatic invertebrate toxicity test, preferably using first instar
Daphnia magna or early instar amphipods, stoneflies, mayflies, or midges.
35
-------
Freshwater Invertebrate Toiletry Findings
Specks
Daphnia magna
Daphnla magna
Daphnia magna
%AA
91.8
technical
Amhrol-T
(fonnulated
product)
ECM(ppm)
18
23 (26hr)
30
MRIDNO.
Author/Year
00160455
Forbis/1985
00017800 ,
Crosby/1966
05001497
Sanders/1970
Toridty
Category
slightly
toxic
slightly
toxic
slightly
toxic
Fulfills Gnldellne
Requirement
Yes
No (supplemental)
No (supplemental)
There is sufficient information to characterize amitrole, on an acute basis, as slightly toxic
to aquatic invertebrates. The guideline requirement is fulfilled. (GLN72-2; MRID 00160455)
(3) Estuarine and Marine Animals
Acute toxicity testing with estuarine and marine organisms is required when an end-use
product is intended for direct application to the marine/estuarine environment or is expected to
reach this environment in significant concentrations. The terrestrial non-food use of amitrole may
result in exposure to the estuarine environment since roadsides and rights-of-way could occur
close to estuaries.
The requirements under this category include a 96-hour LC50 for an estuarine fish, a
96-hour LCso for shrimp, and either a 48-hour embryo-larvae study or a 96-hour shell deposition
study with oysters.
Estnaiine/Marine Acute Toxicity Flndln
Sfeck*
Eastern oyster shell deposition
(C. virginlca)
Mytidopstt bahla
Sheepthead minnow
(C, variegates)
/.A.L
98.22
98.22
98.22
LCMorEQ,
(ppm)
110
2.8
>1000
MRTONo.
Author/Year
42837401
Dionne/1993
42818201
Collins/1993
42817801
' Collins/1993
s '
Toxicity Category
practically non-toxic
moderately toxic
practically non-toxic
Fulfills Guideline
Requirement
Yes
Yes
Yes
There is sufficient information to characterize amitrole as moderately toxic to
marine/estuarine crustaceans, and practically non-toxic to marine/estuarine finfish and bivalves
on an acute basis. The guideline requirement is fulfilled. (GLN 72-3; MRIDs 42837401,
42818201,42817801)
36
-------
c. Toxicity to Plants
(1) Terrestrial Plants
Currently, terrestrial plant testing (seedling emergence and vegetative vigor) is required
by the Agency for herbicides which have terrestrial non-residential outdoor use patterns and
appear to move off site of application through volatilization (vapor pressure >1.0 x 10'5mni Hg
at 25ฐC) or drift (aerial or irrigation); and/or which may have endangered or threatened plant
species associated with the site of application. The above testing requirements apply for amitrole
because it has terrestrial non-food crop use, and the sites of application may have endangered
species present.
Limited Tier n toxicity data on the technical/TEP material for the most sensitive species
are listed below (Note - the seed germination and vegetative vigor data were submitted in a single
study report under one MKED number)
Species
Mono
M-
Wheat
._
Com
Leek
._
Dicot
Cucumber
.._
Pepper
- ,
_
Sunflower
Lettuce
i
MRID
No.
42813702
nd indicates values were not determined.
Nontarget Terrestrial Plant Toxicity Findings '
Fulfills
Guideline
Requirements
Nofor .
GLN.123-l(a) '
(supplemental for
seed germination/
seedling
emergence tests);
Yesfor
GLN 123-l(b)
(acceptable for
vegetative vigor
tests)
%.A-I-
98.22
Seed,
Germination
EC,,
(Ibsai/A)
>8
>8
>8
>8
nd
>8
0.28
Vegetative Vigor EQj , ,
(Ibs ai/A for each parameter)
Dry Weight
nd1
0.005
0.008
nd
1.613
0.347
0.269
Leaf Length
nd
nd
nd
6.445
7.742
3.444
0.425
Shoot Height
0.740
nd
nd
nd
nd
nd
nd
The results indicate amitrole adversely affects the vegetative vigor of both monocots
(wheat) and dicots (pepper). The guideline requirements for the vegetative vigor tests
(GLN 123-l(b)) are fulfilled. However, the guideline requirement Guideline 123-l(a) is not
fulfilled since the study was classified as supplemental and does not fulfill the guideline
requirement.
(2) Aquatic Plants
f - ~ '" ' - ' \ ' ' ' ' .
Currently, aquatic plant testing is required for any herbicide which has outdoor non-
residential terrestrial uses that may move off-site of application by runoff (solubility
>10 ppm in water), by drift (aerial or irrigation), or is applied directly to aquatic use sites (except
residential). Amitrole meets the runoff condition for aquatic plant testing. The following species
37
-------
should be tested. Selenastrum capricornutum, Lemna gibba, Skeletonema costatum, Anabaena
flos-aquaeฑ?and a freshwater diatom. s
Tier II to:cicity data on the technical material are listed below:
Nontarget Aquatic Plant Toxicity Findings
Species
Selenastrum capricornutum
% A.I.
98.22
MRIDNo.
Author/Yea
r
42813701
Cross/1993
Fulfills
Guideline
Requirements
No
(supplemental)
ECSO
>5.7 mg/1
The five listed aquatic plant studies are required to complete the aquatic plant risk
assessment. Only the study on Selenastrum capricornutum was submitted; therefore, the
guideline requirements are not fulfilled (GLN 123-2).
2. Environmental Fate and Transport Data
a. Environmental Fate Assessment
Acceptable and supplemental information from environmental fate studies with respect
to the persistence and mobility of amitrole under laboratory and field conditions has been
reviewed. Persistence classes discussed in the following sections were based, on the groupings
(ranging from non-persistent to persistent) published in Goring et al., (1975) and McEwen and
Stephenson (1979). The environmental fate data base for amitrole with terrestrial nonfood crop
use is essentially complete.
The following information is derived from acceptable environmental fate studies reviewed
by the Agency. The studies determining laboratory persistence (degradation and metabolism
processes) indicate amitrole is slightly to moderately persistent [aerobic soil half-life (t1/2) ป22-26
days; aerobic aquatic half-life of ซ57 days] with degradation primarily through biotic processes
such as microbial-mediated metabolism. Abiotic hydrolysis is not a significant degradation
process. Amitrole was reportedly stable to photodegradation in water and was shown to
photodegrade slowly on soil with a tw of >30 days. Results of the anaerobic aquatic metabolism
study demonstrate that amitrole is persistent with a t1/2 of >1 year. In an aerobic aquatic
metabolism study, amitrole was moderately persistent with an experimentally-determined t1/2 of
*57 days for a flooded sandy loam sediment. Results of terrestrial field dissipation studies in
Washington and Oregon show amitrole dissipating fairly rapidly under field conditions with
DTMs ranging from ป17-21 days.
The mobility of amitrole wa;> evaluated with batch equilibrium studies and amitrole was
determined to be mobile in silty cla sandy loam, sand, and silt soils (Kds ranged
38
-------
from 0.152-0.922 ml/g). The reported vapor pressure of amitrole is 4.4 x 10"7 mm Hg . - . .'
(5.9 x 10"? Pa) and the estimated Henry's Law Constant of 1.6 x"*fO attrf-m /mol are low;
therefore, volatilization and subsequent photodegradation in air are hot considered probable
routes of dissipation. .; .
The bioaecumulation in fish study was not submitted; however, the high solubility
(280 g/1) and low octanol/water partition coefficient (log K^, = -0.15) indicate limited potential
for bioaccumulation in fish.
Amitrole is mobile, somewhat persistent and may have the potential to contaminate
ground water. This assessment is based on the acceptable environmental fate studies which
indicate amitrole has a significant number of characteristics in common with pesticides that are
known to leach to ground water. Amitrole is stable to hydrolysis, and aerobic soil and anaerobic
aquatic metabolism and field dissipation data indicate that it is somewhat persistent. Amitrole
is classified as mobile becaiise the low Kd and K,,,. values indicate it will not strongly absorb to
soil. Pesticides with similar properties have been found in ground water.
i , s - . ' *', - - '-,--'- '
Amitrole may contaminate surface water from runoff or spray drift associated with ground
spray application. Amitrole is stable to degradation from abiotic hydrolysis and aqueous
photolysis, and is slightly to moderately persistent (aerobic soil metabolism t1/2 ซ22-26 days;
aerobic aquatic metabolism t^ ป57 days) in aerobic environments. Amitrole does not adsorb
significantly to soil particles and may be transported in the dissolved phase by runoff to surface
water bodies. Amitrole's primary route of dissipation is microbial-mediated metabolism;
however, amitrole is stable in anaerobic environments.
b. Environmental Fate and Transport Data
: ' ,' ~~- ' - " = ' '',./-
(1) Degradation
(a) Abiotic Hydrolysis
" - ' '" . ~ f. ' ' '_ - - .- --''. ' '' ' .' ' '. >
Amitrole does not degrade by abiotic hydrolysis and was stable in the sterile test solutions.
Amitrole did not degrade in filter-sterilized aqueous buffer solutions (pH 5, 7, and 9) during 30
days of incubation in the dark at approximately 25ฐ C. Amitrole comprised 100% of the
recovered radioactivity at all sampling intervals. The half-life was not calculated because
hydrolytic degradation was not observed. ;In another study, amitrole was stable to hydrolysis in
aqueous buffered pH 5, 7, and 9 solutions that were incubated m the dark for 34 days at
25 ฑ 1 ฐC (Accession #153181). The guideline requirement is fulfilled. (GLN161-1;
MRID 42843801)
39
-------
(2) Photodegradation in Water
Amitrole is considered stable to degradation by aqueous photolysis. Amitfole tlid not
substantially photodegrade in filter-sterilized aqueous buffer solutions (pH 5, 7, and 9) during
30 days of artificial light exposure (UV glass-filtered xenon arc lamp) at approximately
25ฐ C. For the pH 5 test solutions, amitrole comprised 100% of the recovered radioactivity at all
sampling intervals; therefore, the half-life at pH 5 was not determined. In the pH 7 and 9 test
solutions after 30 days irradiation, amitrole was measured at 96.77% and 97.83% of the initial
concentrations, respectively. The half-lives for the pH 7 and pH 9 test conditions were calculated
to be 204 and 761 days, respectively; however, the accuracy of these estimated half-lives is
uncertain because the data were extrapolated beyond the 30-day study duration. In another study,
amitrole did not photodegrade in sterile pH 7 buffer solutions irradiated for 31 days (Accession
#153182). The guideline requirement is fulfilled. (GLN 161-2; MRID 42943201)
(3) Photodegradation on Soil
- s
Based on acceptable study results, amitrole is considered moderately resistant to
Photodegradation on soil. Amitrole photodegraded with an observed half-life of >30 days on
sandy loam soil that was irradiated on a 12-hour photoperiod with artificial light (xenon arc lamp)
for 30 days at 25ฐ C. In contrast, amitrole did not degrade on sandy loam soil incubated for 30
days at 25ฐ C in darkness. The only degradate identified in the samples was 1,2,4-triazole
(maximum concentration of 9.9% at 30 days). The photolysis half-life on soil for amitrole was
estimated to be 73 days; however, the accuracy of this estimated half-life is uncertain because the
data were extrapolated beyond the 30-day study duration. In another study, amitrole applied to
a sandy loam soil irradiated with sunlight degraded with a registrant-calculated half-life of ป22
hours (Accession #153183). The guideline requirement is fulfilled. (GLN 161-3; MRID
42676601)
(4) Photodegradation in Air
No studies were required. The reported vapor pressure of amitrole at 20ฐ C is
4.4 x 10"7mm Hg (5.9 x 10-s Pa) and estimated Henry's Law Constant of 1.6 x 10'15 atm-mVmol
are low; therefore, volatilization and subsequent photolysis in the atmosphere are not considered
probable routes of dissipation.
(5) Aerobic Soil Metabolism
\ '
Amitrole is slightly persistent (t1/2 ป22-26 days) to metabolism in soil under aerobic
conditions when incubated at 20-24 ฐC. Amitrole is metabolized more slowly at lower
temperatures (registrant-calculated half-life of ซ64-69 days for soil incubated at 7ฐ C). Triazole
ring-labeled [3-14C]amitrole (lH-l,2,4-triazol-3-ylamine; radiochemical purity >98%), at
0.8 //g/g, degraded fairly rapidly (t^ ซ22-26 days) in loamy sand soil that was continually aerated
in the dark at 21-24 ฐC for up to 52 weeks. Microbial-mediated metabolism of amitrole to carbon
40
-------
dioxide is ah important biotransformation process because 14CO2 totaled >50% after 26 weeks.
Two unidentified [l4C]degradates, isolated at <4% of the applied radioactivity, were minor
constituents in the degradation pathway of amitrole under aerobic conditions. Unextracted
[MC]residues reached a maximum of 43.11% at 13 weeks and decreased slightly to 38.31% at 52
weeks which suggests substantial amounts of amitrole are incorporated as "bound residues" in
soil. In another study, amitrole degraded rapidly (observed half-lives of ซ1-7 days, dependent
on sampling intervals) in German sandy soil (standard soil 2.2) and English loam soil (Study
# 153487). The guideline requirement is fulfilled. (GLN 162-1; MRID 43457801) ,
(6) Anerobic Soil Metabolism
- ... ' ' - '-''''. i '-
No studies were required. Information on degradation of amitrole under anaerobic
conditions is discussed in the anaerobic aquatic metabolism study.
'-'' i .. . -. ' -. " -'.."-'".-''
(7) Anerobic Aquatic Metabolism
Based on acceptable study results, amitrole is considered stable to metabolic
transformations under the anaerobic aquatic conditions of this study. Tfiazole ring-labeled
[3-14C]amitrole(lH-l,2,4-Mazol-3-ylamine;radiochemical purity 98.20%), at 1.27 mg/container,
degraded very slowly in flooded sandy loam sediment (150 g water:24 g soil) that was incubated
under anaerobic conditions in the dark at 5-9 ฐC and 21-24 ฐC for up to 52 weeks. Two unknown
[14C]degradates were isolated at <10% of the applied (maximum concentration of "Unknown A"
was ป7% at39 weeks, decreasing to ซ1% by 52 \yeeks; "UnknownB" was ซ2% at26 weeks
only). In another study, amitrole at 1.25 mg/1 degraded with an observed half-life of *56 days
in non-sterile sandy soil that was incubated anaerobically in the dark at 25 ฑ 1 ฐC. In the present
studyj the study authors concluded "the half-life is greater than one year." The guideline
requirement is fulfilled. (GLN 162-3; MRID 43570301)
(8) Aerobic Aquatic Metabolism
Amitrole is considered moderately persistent (ty2 ซ57-74 days) to metabolism under
aerobic aquatic test conditions. Triazole ring-labeled [3-14C]amitrole (lH-l,2,4-triazol-3-
ylamine), at 8.4-8.5 /zg/mL, degraded slowly in flooded sandy loam sediment that was
continually aerated in the dark at 21-24 ฐC for up to 30 days. Two [14C]degradates were isolated
at <5% of the applied, but were not identified. Using HPLC data from the first 21 days of the
study, the registrant-calculated half-life was 57 days (r2 = 0.97, n = 8). The half-life was
estimated to be ซ74 days (r2 = 0.91, n = 9) using TLC analyses and data through 30 days post-
treatment. The guideline requirement is fulfilled. (GLN 162-4; MRID 43099801)
-------
(9) Mobility
* * " ' , *
(a) Adsorption/Desorption
Based on batch equilibrium experiments, amitrole (in 1% sodium azide solutions) was
determined to be mobile in silty clay, sandy loam, sand, and silt soils, with Freuhdlich Kads values
of 0,152-0.922 ml/g. Freundlich Klds values were 0.714 (1/n = 0.7671) for the silty clay soil,
0.223 (1/n ซ 0.8549) for the sandy loam soil, 0.152 (1/n = 0.8722) for the sand soil, and 0.922
(1/n = 0.8590) for the silt soil; corresponding K,,,. values were 11.6, 29.7, 20.2, and 51.2.
Amitrole was mobile in these same soils when the soils were acidified to approximately pH 4.5;
Freundlich K^ values ranged from 0.575-2.28. In another batch equilibrium study, amitrole was
determined to be mobile to slightly mobile in Plainsfield sand (Kadg = 0.685,1/n = 0.7975), CA
sandy loam (&& = 3.52,1/n = 0.6487), Kewaunee silty clay loam (ฃ,*= 1.57, 1/n = 0.8563), and
Piano silt loam (Kadf = 3.79, 1/n = 0.7739) soils (Study #153186). No discernible correlation
between adsorption and either organic carbon content or CEC of the soils was observed. The
guideline requirement is fulfilled. (GLN 163-1; MRID 42676602)
(b) Soil Thin Layer Chromatography
In a previously-reviewed study using soil TLC methods, uncharacterized [14C]amitrole
residues aged for 5 days were determined to be of low mobility (Rf= 0.1; mobility class 2) in a
sandy loam soil treated with residues of [3,5-14C]amitrole (radiochemical purity >85%) at
3.37 mg/kg. (GLN 163-1; Study #153185)
(c) Volatility - Laboratory and Field
No studies were required. The reported vapor pressure of amitrole is
4.4 xlO'7 mm Hg (5.9 xlO'5 Pa) and estimated Henry's Law Constant of
1.6 x 10'15 atm-m3/mol are low; therefore, volatilization is not considered a probable route of
dissipation. ;
(10) Field Dissipation - Terrestrial
Based on acceptable study results, the terrestrial field dissipation studies indicate amitrole
is slightly persistent (DTjoS of 17-21 days) for the tested sites. Amitrole (lH-l,2,4-triazol-3-
ylamine; AMIZOLฎ') dissipated with a registrant-calculated DT50 and DTW of 17 and 55 days,
respectively, from the upper 15 cm of a bare-ground test plot of loam soil in Hillsboro, OR after
application of amitrole at approximately 9.170 kg ai/ha(ซ8.2 Ib ai/A). In Moses Lake, WA,
amitrole applied at approximately 8.212 kg ai/ha (ซ7.3 Ib ai/A) dissipated with registrant-
calculated DTjo and DTjo of 21 and 70 days, respectively, from the upper 15 cm of a bare-ground
test plot of loam soil. Amitrole was detected in several samples to a maximum, depth of
15-30 cm. The degradate, cyanamide was detected at both study locations (maximum
concentration of 0.020 mg/kg); however, cyanamide concentrations dissipated rapidly (within
42
-------
3 days after application) and were below the limits of quantification (0.010 and 0.025 mg/kg for
OR and WA, respectively). The guideline requirement is fulfilled. (GLN 164-1;
MRID 43646801)
In two previously-reviewed terrestrial field dissipation studies, amitrole, applied at
12 Ib ai/A, dissipated with an observed half-life of ซ23 days from the 0-15 cm depth in plots of
Common Bermuda grass on a Norfolk sandy loam soil in North Carolina, For a silt loam soil at
an Iowa test location, amitrole applied at a nominal application rate of 12 ib ai/A, dissipated with
an observed half-life of <3 days from the 0-15 cm soil depth in soybean plots (MRID 40595901).
(11) Bioaccumulation in Fish
The reported solubility of amitrole in water is 2.80 x 108 mg/L at 20ฐ C and the log K
of -0.15 support the assumption of limited biqacummulation in fish.
(12) Spray Drift
No amitrole-specific studies were reviewed. Droplet size spectrum (GLN 201-1) and drift
field evaluation (GLN 202-1) studies may be required for amitrole, since the different
formulations may be applied by ground boom spray equipment and it is estimated that there will
be detrimental effects to non-target organisms due to drift. However, to satisfy these
requirements the registrant in conjunction with other registrants of other pesticide active
ingredients formed the Spray Drift Task Force (SDTF). The SDTF has completed and submitted
to the Agency its series of studies which are intended to characterize spray droplet drift potential
due to various factors, including application methods, application equipment, meteorological
conditions, crop geometry, and droplet characteristics. During 1996 the Agency plans to
evaluate these studies. In the interim and for this assessment of amitrole, the Agency is relying
on previously submitted spray drift data and the open literature for off-target drift rates; The
estimated drift rates at 100 feet downwind of the treated sites are 1% at the applied spray volume
from ground applications and 5% from aerial applications. After review of the new studies the
Agency will determine whether a reassessment is warranted of the potential risks of the
application of amitrole products to outdoor industrial areas, nonagricultural right-of-
ways/fencerows/hedgerows, nonagricultural uncultivated areas/soils, and ornamental and/or
shade trees.
c. Water Resources
(1) Ground Water
. ' .' ' I >;'.' " -
Amitrole is mobile, somewhat persistent and may have the potential to contaminate
ground water. This assessment is based on the acceptable environmental fate studies which
indicate amitrole has a significant number of characteristics in common with pesticides that are
known to leach to ground water. Amitrole is stable to hydrolysis and anaerobic aquatic
43
-------
metabolism, and aerobic soil metabolism and field dissipation data indicate that it is somewhat
persistent.-The low Kd and Iv. values indicate that amitrole will not strongly bind to soil;
therefore amitrole is mobile. Because pesticides with similar properties have been found in
ground water, the Agency is requiring a ground water label advisory to be placed on all amitrole
labels.
(2) Surface Water
' r -' . .
Amitrole may contaminate surface water from spray drift associated with ground
application or in the dissolved phase during surface runoff. Transport of amitrole in the dissolved
phase during surface runoff events which occur soon after application could be considerable
because of amitrole's slight-to-moderate persistence (aerobic soil metabolism half-life of ซ22-26
days; aerobic aquatic metabolism half-life of 57 days), low soil/water partitioning coefficient
(K,jS <1), and, less importantly, it's high solubility (280 g/L). Amitrole is less persistent in aerobic
(i.e., well-drained) soil environments due to microbial-mediated metabolism (aerobic soil
metabolism half-lives of ซ22-26 days; terrestrial field dissipation half-lives of 17-21 days) and
incorporation into soil-bound residues. In anaerobic environments such as very poorly drained
soils, and sediments in stream and lake bottoms, amitrole is persistent (anaerobic aquatic
metabolism half-life >1 year). The low soil/water partitioning coefficients for amitrole (Kds of
0.152-0.922 ml/g) indicate amitrole in surface runoff would occur primarily dissolved in the
runoff water and would not be adsorbed onto eroding soil or entrained sediment.
In well-mixed, receiving surface water bodies, amitrole is predicted to be moderately
persistent (aerobic aquatic metabolism half-life of 57 days). Volatilization of amitrole from
surface waters is not considered an important route of dissipation based on the low vapor pre'ssure
(4.4 x 10'7 mm Hg) and low Henry's Law constant (1.6 x 10'1S atni-m3/mol, estimated). The high
solubility in water (280 g/L) and the low octanol/water partitioning coefficient flog Kw = -0.15)
indicate amitrole should not significantly bioaccumulate.
Although amitrole has the potential to contaminate surface water from runoff and spray
drift, several published surface water monitoring studies using multi-residue analytical methods
did not detect amitrole (Baker, 1988; Moyer and Cross, 1990; Goolsby et al., 1993; Jordan and
Stamer, 1991). In addition to these studies, amitrole detections for surface waters were not found
in a search of the Agency STORET database. Results of the monitoring studies suggest a low
potential for amitrole to contaminate surface water. Lastly, amitrole is not regulated under the
Safe Drinking Water Act (SDWA) and a Maximum Contaminant Level (MCL) has not been
established.
44
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3. Ecological Exposure and Risk Assessment
a. Ecological Exposure and Risk Characterization
The Levels of Concern are criteria used to indicate potential risk to nontarget organisms.
The criteria indicate that a chemical, when used as directed, has the potential to cause undesirable
effects on nontarget organisms. There are two general categories of LOG (acute and chronic) for
each of the four nontarget faunal groups and one category (acute) for each of two nontarget floral
groups. In order to determine if an LOG has been exceeded, a risk quotient must be derived and
compared to the LOCs A risk quotient is calculated by dividing an appropriate exposure
estimate, e.g. the estimated environmental concentration, (EEC) by an appropriate toxicity test
effect level, e.g. the LC50. The acute effect levels typically are:
- EC2j (terrestrial plants),
- EC50 (aquatic plants and invertebrates),
- LC50 (fish and birds), and
- LD50 (birds and mammals)
. ' i ' ! ' ,
The chronic test results are the:
NOEL (sometimes referred to as the NOEC) for avian and mammal reproduction
studies, and either the NOEL for chronic aquatic studies, or the Maximum
Allowable Toxicant Concentration (MATC), the geometric mean of the NOEL and
the LOEL (sometimes referred to as the LOEC) for chronic aquatic studies.
When the risk quotient exceeds the LOG for a particular category, risk to that particular
category is presumed to exist. Risk presumptions are presented along with the corresponding
LOCs:
45
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Levels of Concern (LOCs) and Associated Risk Presumption
Mammals, Birds
wrm LOG
acute RQ> 0.5
acute RQ> 0.2
acute RQ> 0.1
chronic RQ> 1
Fish, Aquatic invertebrates
PRESUMPTION
Acute risk
Risk that may be mitigated through restricted use
Endangered species may be affected acutely
Chronic risk, endangered species may be affected
chronically,
acute RQ>
acute RQ>
acute RQ> ,
chronic RQ>
Plants *
RQ>
RQ>
0.5
0.1
0.05
1
LOG
1
1
PRESUMPTION
Acute risk
Risk that may be mitigated through restricted use
Endangered species may be affected acutely
Chronic risk, endangered species may be affected
chronically
PRESUMPTION
Risk
Endangered plants may be affected
* Currently, no restricted use or reproductive effects criteria for plants have been
established.
b. Exposure and Risk to Nontarget Terrestrial Animals
(1) Birds
Pesticide residues found on avian dietary food items following application are compared
jo values to predict hazard for birds. The Agency estimates the day 0 residues on vegetation
based on the work of Hoerger and Kenaga (1972) as modified by Fletcher et al. (1994). For
amitrole, LCso values were not available; therefore, the LC50s were characterized as greater than
5000 ppm. The maximum concentration of residues of amitrole which may be expected to occur
on selected avian dietary food items following both single and multiple foliar applications
(2 appl. at 4 Ibs ai/acre) are reported in the table below along with the R.Qs calculated from LC50
values of 5,000 ppm (the maximum dose):
46
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Food items
Short Grasses
Long grasses
Broadleaf plants, leaves and leafy
crops, forage e.g. alfalfa
Fruit, Pods, and Seeds
3.6 Ibs ai/A
EEC (ppm)
864
396
486
54
RQ
<0.08
<0.09
<0.01
4.01bsai/A
EEC f
960
440
540
60
RO
<0.19
<0.08
-------
Acute Risk Quotients For Small Mammals Consuming Estimated Residues
Mammal Type and Diet
Small herbivore consuming
short grass
Small granivore consuming
seeds
Small insectivore consuming
insects
Maximum EEC (ppm)
at 8 Ibs ai/A
1920
120
1080
RQs
0.29
0.00
0.29
Maximum EEC (ppm)
at 4 Ibs ai/A
960
60
540
RQs
0.14
0.00
0.15
Maximum EEC (ppm)
at3.61bsai/A
864
54
486
RQs
0.13
0.00
0.13
At 8 Ibs ai/A, the RQs for small herbivores consuming short grass and small insectivores
consuming insects exceeded the LOCs for acute risk that may be mitigated through restricted use
(0.2). The RQs for small granivores consuming seeds do not exceed any LOCs (0.1-1).
For the 4.0 and 3.6 Ibs ai/A use rates, the RQs for both small herbivores and small
insectivores exceeded the LOG for acute effects on endangered species (0.1). The RQ for small
granivores did not exceed any LOCs (0.1-1).
The mammalian chronic risk assessment is based on the NOEL for the two-generation rat
reproduction study. The NOEL is 0.90 mg/kg/day which is the most sensitive toxicological
value. The following formula was used to estimate the NOEL and LOEL in ppm of diet. For the
LOEL calculated in the formula below, the rat reproduction study value of 5.88 mg/kg/day was
substituted for the NOEL.
NOEL (ppm of diet) = NOEL fmg/kg/dav)
% body wt consumed (expressed as a decimal)
48
-------
Estimated NOELs For Mammals Of Varied Sizes And Food Consumptions
Minimal Body Weight (g)
46 (meadow vole or herbivore)
35 (field mouse or granivore)
5 (least shrew or insectivore)
% Body Wt Consumed in ป Day
. ' 61% :.'
16%
' 110%
Estimated
NOEL (ppm)
1.48
5.63
0.82
Estimated
LOEL (ppm)
9.64
36.75
5.35
' Chronic Risk Quotients For Small Mammals Consuming Estimated Residues
Mammal Type and Diet
Small herbivore consuming
short grass
Small granivore consuming
seeds
Small insectivore consuming
insects
Maximum EEC (ppm)
at 8 Ibs ai/A
1920
120
1080
RQs
1297
21
1317
Maximum EEC (ppm)
at 4 Ibs ai/A
,960
60
540
RQs
649
11
649
Maximum EEC (ppm)
at3.61bsai/A
. 864
54
486 ,
RQs
584
10
593
The RQs for all use rates exceed the chronic LOG (1.0) for small herbivores, granivores
and insectivores. This assessment indicates use of amitrole at all application rates has the
potential for chronic risk to mammalian species, and may also chronically affect endangered
mammalian species.
(3) Insects
There is sufficient information to characterize amitrole as relatively non-toxic to bees.
, . *
c. Exposure and Risk to Nontarget Aquatic Animals
Aquatic Estimated Environmental Concentrations: The toxichy of amitrole to most
aquatic organisms tested to date ranges from practically non-toxic (freshwater finfish) to
moderately toxic (marine invertebrates). The Agency calculated generic EEC levels using the
GENEEC program. The GENEEC program considers the results of required environmental fate
studies and is applicable to the typical field runoff scenario. It assumes runoff for a 10 hectare
field into a 1 hectare pond two meters deep. The following environmental fate information was
used for the GENEEC simulations: Kx = 30 ml/g; solubility = 280,000 mg/L; and the aerobic
soil metabolism half-life = 26 days, For modeling, spray drift was assumed 1% from ground
spray applications and the application rates varied from 3.6 to 8 Ibs ai/A. In this assessment, the
screening model GENEEC was used to model runoff from non-agricultural use sites for amitrole.
The GENEEC model was based on an agricultural use scenario, and is a conservative estimate
of exposure from surface runoff because agricultural land uses are intensive and may cover large
areas.
49
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Generic Estimated Environmental Concentrations (GEECs) For Amitrole
Use Sites
Industrial areas
Nonagricultural rights-of
way/ fcncerows/hedgerows
Nonagricultural uncultivated
areas/soils
Ornamental and/or shade
Trees
Ornamental woody shrubs
and vines
Application
Method
Boom Sprayer
i
Application
Rate in Ibs
a.i7A
3.6
4.0
8.0
Initial
EEC
(ppm)
0.173
0.192
0.384
4-day
EEC
(ppm)
0.173
0.192
0.383
21-day
EEC
(ppm)
0.172
0.191
0.382
56-day
EEC
(ppm)
0.172
0.191
0.381
1. The GEN EEC model is a Tier 1 screening model and is not the refined EEC or Tier 2 evaluation.
The use rates for amitrole range from 3.6 to 8.0 Ibs. ai/A. The GENEEC program
calculated Generic Estimated Environmental Concentrations (GEECs) that ranged from 0.172 to
0.384 ppm for these use rates. The assumed method of application is ground treatment with a
boom sprayer. - , ' -
The results of the Tier 1 Aquatic EEC modeling with GENEEC are listed in Table the
table above. The range of aquatic EECs was 0.173 mg/L for the 3.6 Ib a.i. application rate and
0.384 mg/L for the 8.0 Ib a.i. application rate. The Initial or maximum EEC varied by a factor
of 0.048 mg/L for each pound increase in amitrole. Comparison of the Initial EEC estimates and
the 4-day, 21-day, and 56-day EECs indicate limited degradation of amitrole occurs in aquatic
environments. This conclusion is consistent with the moderate persistence noted in the surface
water assessment.
(1) Freshwater Fish and Amphibians
The RQs for the 3.6 to 8.0 Ibs. ai/A use rates of amitrole do not exceed any levels of
concern for freshwater finfish (0.1-1).
Chronic risk to freshwater fish can not be assessed because the fish life-cycle data are not
available.
50
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, Risk Quotients (RQ) for Freshwater Fish and Amphibians ,
Use ";'-: ' . ' .
"^ ' , " --"''
Industrial areas
NonagricuKural rights-of way/fencerows/hedgerows
Nonagricultural uncuhivated areas/soils ,
Ornamental and/or shade Trees
Ornamental woody shrubs and vines
Application
Rate
3.6
4.0
8.0
Surrogate
Species
Bluegill
Rainbow trout
Bluegill.
Rainbo\V trout
Bluegill
Rainbow trout
EEC
(ppm)1
0.172
0.172
0.192
0.192
0.384
0.384
LCป
(ppm).
1000
1000
1000
1000
1000
iooo
Risk
Quotients
EEC/LQ,
0.000
0.000
0.000
0.000
0.000
0.000
1. Initial EEC value (immediately after runoff event).
(2) Freshwater Invertebrates
, Risk Quotients (RQ) -
for Freshwater Invertebrates '
Use '
Industrial areas
Nonagricultural rights-of , '
way/fencerows/hedgerows
Nonagricultural uncultivated areas/soils
Ornamental and/or shade Trees
Ornamental woody shrubs and vines
Application
Rate
3.6
4.0
8.0
Surrogate
Species
Daphnia ,
magna
Daphnia
tnagno
Daphnia
magna
EEC-
(ppm)1
0.172
0.192
/ ,0.384
EC,
(ppm)
18
18
18
Risk
Quotients
EEC/ECV
0.010
0.011
0.021
- 1. Initial EEC value (immediately after runoff event).
The RQs for the 3.6 to 8.0 Ibs. ai'/A use rates of amitrole do not exceed any LOGs for
freshwater invertebrates (0,1-1): However, the chronic risk to freshwater invertebrates will be
assessed once the invertebrate life cycle study is reviewed.
51
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(3) Estuarine and Marine Animals
Risk Quotients (RQ)
"N for Estuarine and Marine Species
Use
Industrial areas
Nonagricuttural righti-of
waytfencerows/hedgerows
NooagricuKural uncultivated areas/soils
Ornamental and/or shade Trees
Ornamental woody shrubs and vines
Application
Rate
3.6
4.0
8.0
, Surrogate
Species
.Sheepshead
Minnow
Eastern Oyster
Mysidopsis
bahia
Sheepshead
Minnow
Eastern Oyster
Mysidopsis
bahia
Sheepshead
Minnow
Eastern Oyster
Mysidopsis
bahia
EEC
(ppm)1
0.172
0.172
.0.172
0.192
0.192
0.192
0.384
0.384
0.384
1A,
(ppm)
1000
110
2.8
1000 ^
v
110
2.8
1000
110
2.8 ,
Risk
Quotients
EEC/LC,,
0.000
0.002
0.061
0.000
0.002
.0.069
0.000
0.004
0.137
1. Initial EEC value (immediately after runoff event).
The RQs for marine finfish (sheepshead minnow) and mollusks (eastern oyster) do not
exceed the LOCs for the three application rates. At the 8 Ib ai/A use rate for amitrole, the RQ for
marine/estuarine invertebrates (Mysidopsis bahia) exceeds the LOC for acute risk that may be
mitigated through restricted use (0.1). The shrimp (Mysidopsis bahia) species are the most
sensitive of the organisms tested. The RQs for 3.6 and 4.0 Ibs ai/A use rates of amitrole exceed
the LOCs for acute effects to endangered marine/estuarine crustaceans (0.05). There are
currently no endangered marine or estuarine crustacean species. These exceedances represent
relatively low acute risk.
Chronic risk to estuarine/marine animals will be assessed once the aquatic invertebrate
life-cycle data is reviewed.
d. Exposure and Risk to Nontarget Plants
(1) Terrestrial and Semi-aquatic .
' Non-target terrestrial plants inhabit non-aquatic areas. Non-target "semi-aquatic" plants
are plants that usually inhabit low-lying wet areas that may or may not be dry in certain times of
the year. These plants are not obligatory aquatic plants in that they do not live in a continuously
52
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aquatic environment. The terrestrial and "semi-aquatic" plants are exposed to pesticides from
runoff, drift or volatilization. -
From the information currently available, amitrole affects the vegetative vigor of both
monocots and dicots at very low exposure levels (<0.01 Ibs ai/A). The risks to non-target plants
from sheet and channelized runoff was not determined with certainty because plant toxicity data
was limited (seedling emergence data are not available). Qualitatively, amitrole's broad spectrum
plant control due to its mode of action (i.e., inhibition of carotenoid synthesis) suggests exposure
of amitrole may impact non-target plants.
: Ground Spray Evaluation For Terrestrial And Semi-Aquatic Plant Species
Use Site
Industrial areas -
Nonagricuhural rights-of
way/fencerows/hedgerows
Nonagricuhural uncultivated
areas/soils
Ornamental and/or shade trees
Ornamental woody shrubs and
vin^c
Maximum Application
; Rate
(Ibs. ai/A)
3.6
4.0
8.0
- ,
Type of EEC
drift based on
ground spray
application
: f ''
t
EEC
(Ibs ai/A)
0.036
0.04
0.08
ECa1
(Ibs ai/A)
0.005 (pepper)
0.008 (wheat)
0.005 (pepper)
0.008 (wheat)
j.
0.005 (pepper) "
0.008 (wheat)
Risk Quotient
(EEC/EQu)
;
7.2
4.5
8.0
5.0
16.0
10.0
1. ECjj is based on dicot (pepper) and monocot (wheat) dry weights.
Drift from Ground Spray Application: Based on the 3.6 to 8.0 Ibs, ai/A use rates of
amitrole, risk quotients exceed the levels of concern for terrestrial and semi-aquatic plants (1.0).
Risk quotients are based on EC^s from the dry weight parameter for wheat (monocot) and pepper
(dicot) from the vegetative vigor study. The wheat and pepper plant EC25s were the most
.sensitive plants tested and the lowest levels for the available plant toxicity .data.
(2) Aquatic Plants
Exposure to non-target aquatic plants may occur through runoff and/or drift from
terrestrial applications. The risk assessment for aquatic plants is usually conducted for aquatic
vascular plants from the surrogate duckweed Lemna gibba. Assessing risk to algae and diatom
species is a useful indicator to determine potential impact to these food sources on aquatic
organisms because algae and diatom species are the base of the food chain in aquatic
environments. . .
53
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RQ and EF.C Values for Aqi'Kttr Plant Species
Use She
Industrial areas
Nonagricuftunl rights-of
way/fencerows/hedgerows
NonagricuKural uncultivated
areas/soils
Ornamental and/or shade Trees
(Ornamental woody shrubs and
vTnfMr
Maximum
Application Bate
(lbsai/A)
3.6 ,
4.0
8.0
Type of
Plant
algae1
algae
algae
Type of EEC!
runoff
runoff
runoff
EEC
(ppm)
0.172
0.192
0.384
Ety
(ppm)
5.7
5
5.7
5.7
Risk Quotient
(EEC/EC,)
0.03
0.03
0.07
1. Only the test wiihSelenastrum capricomutum was provided and EQ, was >5.7 mg/1.
For algae, none of RQs for the three application rates exceed the levels of concern (10).
However, this risk assessment is incomplete for vascular plants because only one of the five
required plant species has been tested. Bisk is unknown for the other species of aquatic plants.
e. Endangered Species
The risk assessment indicates that the use .of amitrole may effect endangered mammals
and plants. ,
4. Environmental Risk Characterization
a. Environmental Fate and Transport Assessment
Following review of acceptable and supplemental information in the environmental fate
data base, amitrole appears to be slightly to moderately persistent in aerobic soil environments
and persistent in anaerobic soil environments. Amitrole was mobile in four soils of widely-
varying textures ranging from sand to silly clay. Amitrole dissipates fairly rapidly in aerobic soil
environments (half-lives of 22-26 days) principally by micfobial degradation and incorporation
in soil-bound residues. In anaerobic soil environments, amitrole dissipates slowly (estimated
half-life of "greater than 1 year"). Abiotic processes such as hydrolysis, photolysis, and
volatilization are not important degradation mechanisms for amitrole. In terrestrial field studies
conducted in Oregon and Washington, amitrole was slightly persistent with DT^s of 17 and 21
days, respectively. The terrestrial field dissipation times (DTsos) show good agreement with the
laboratory-derived aerobic soil metabolism half-lives. The environmental fate assessment has
a high level of certainty because it is based oh acceptable laboratory and field studies which
report consistent dissipation times and half-lives.
54
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Based on the environmental fate information, amitrole is mobile, somewhat persistent and
has the potential to leach to ground water. There is ho evidence of groundwater contamination
from amitrole residues; however, data for groundwater sampling of amitrole is extremely limited.
Amitrole may also contaminate surface water both from spray drift associated with ground
spray applications and may be transported in the dissolved-phase by runoff to surface water
bodies. Amitrole is not regulated under the Safe Drinking Water Act; therefore, .an MCL has not
been established. The groundwater and surface water assessments have a medium level of
certainty because of very limited monitoring information.
b. Risk to Nontarget Animals
I _ ' - - !_? r ' ,,..'. - ,-.'. ,-..-''
The acute risk to nontarget animals (birds, insects, mammals, fish and aquatic
invertebrates) is predicted to be low. Chronic risk to mammals was identified; however, the
chronic risk to other nontarget animals (birds, fish and aquatic invertebrates) was not determined
because chronic ecological effect data were not available.
Acute Risk
The acute risk to nontarget avian species and insects from applications of amitrole is
expected to be low. For birds, it is important to note that the LC50 values used to calculate the
RQs were greater than the highest dose tested (5,000 ppm). At the 5,000 ppm dose, little or no
mortality was observed. Based on the Kenaga residue values, the maximum residues on avian
food items (1080 and 1920 ppm) do not approach the concentration (5,000 ppm) at which zero
or low mortality occurred. It is concluded that amitrole poses minimal acute risk to birds,
including endangered species.
The acute risk from applications of amitrole is expected to be low to freshwater and
marine/estuarine organisms. The risk quotients determined from application rates ranging from
3.6-8.0 Ibs ai/A are less than the levels of concern for the tested aquatic animals at all use rates,
except for marine/estuarine invertebrates. TheRQ formysid shrimp was 0.137 (8 Ibs ai/acre)
which exceeded the LOCs for endangered species (0.05) and restricted use (0.1) by a small
margin. In this assessment, the screening model (GENEEC was used to model runoff from non-
agricultural use sites for amitrole. The GENEEC model was based on an agricultural use scenario
and is a conservative estimate of exposure from surface runoff because agricultural land uses are
intensive and may cover large areas.
The conclusion of low acute risk to estuarine crustaceans is based not only on the fact that
the LOCs were exceeded by a small margin, but also because amitrole is used on non-agricultural
use sites (outdoor industrial areas, nonagricultural rights-of-way/ fencerows/ hedgerows,
nonagricultural uncultivated areas/soils, ornamental and/or shade trees, ornamental woody shrubs
and vines). In addition to marginal LOG exceedances and non-agricultural uses, the amount of
amitrole applied annually in the United States is relatively small., It is probable that total usage
55
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of amitrole is between 40,000 and 60,000 pounds of active ingredient on an annual basis.
Furthermore, endangered estuarine invertebrates are not currently listed by the USFWS.
The acute risk to nontarget mammals from applications of amitrole is also expected to be
low. The RQs for small herbivores and insectivores (0.13 to 0.29) exceeded the LOCs for
endangered species (0.1) and restricted use (0.2) by small margins. Some of the use areas (e.g.,
rights-of-ways), however, may be typical habitat for small mammals. .
Chronic Risk
Mammals
Amitrole may be hazardous to mammalian reproduction in localized areas. Using the
acceptable two-generation rat reproduction study, the risk assessment indicates use of amitrole
has the potential for chronic risk to mammalian species, and may also chronically affect
endangered mammalian species.
Assessment of the data from an acceptable toxicological developmental study
(MRID 44016201) also indicates amitrole causes small mammals to produce smaller litters and
deformed young. The developmental study, which was acceptable, used gavage to administer
amitrole directly to pregnant rabbits. Amitrole affected fetal development in rabbits at
40 mg/kg/day by causing malformations in external appearance, viscera and skeletons of fetuses,
and decreasing the percent of live fetuses per litter.. These effects occurred with only 12 days of
exposure during pregnancy. If these developmental effects occur in the environment, affected
mammals may not survive and reproduce. .
The estimated residues on mammalian food items exceed the NOEL of 4 mg/kg/day. For
two mammal groups (small herbivores and insectivores), the estimated residues also exceed the
LOEL (lowest observed effect level) of 40 mg/kg/day. Using the maximum EECs, the risk
quotients calculated using the LOEL would be as follows:
Risk Quotients For Small Mammals Using The LOEL
Mammal Type and Diet
Small herbivores consuming short grass
Small granivores consuming seeds
Smalt insectivores consuming insects
8LBS/A
29
<1
30
4LBS/A*
14
<1
15
3.6LBS/A
13
<1
3
* May be applied twice a year to a maximum of 8 Ibs ai/A
56
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From the LOEL risk quotient analyses, pregnant herbivores and insectiyores may consume
food items containing residues exceeding the level that, in the laboratory study, .caused deformed
fetuses and reduced litter sizes.
,- , '..'-. :, > " ,
This exposure analysis uses residue levels which represent the maximum estimated values,
and the residues are expected to be lower on most food items. Amitrole residues are predicted
to decline by microbial-mediated metabolism or physical removal by washoff from rain and other
routes of dissipation; however,.the rate of foliar dissipation is not available for amitrole. Willis
et al. (1980) reported foliar dissipation half-lives that were typically less than 10 days for several
classes of pesticides. Results of the terrestrial field dissipation studies for amitrole indicate
dissipation times (DTJ0s) of 17 to 21 days on soil. Furthermore, the amitrole residue levels on
insects and seeds in treated areas are not known because the food items may not be directly
exposed to amitrole. The food items (insects, seeds) may not contain amitrole residues because
the items were covered by vegetation during area treatment.
The extent of exposure depends, in part, on how many acres are treated, and the type of
habitat that is exposed. For amitrole, the extent of treated acreage is unknown and was estimated
to range from a minimum of approximately 5,000 acres to a maximum of 40,000 acres. The
treated,acreage estimate assumes 40,000 Ibs ai are applied in the U.S. annually and the label
application rates range from 1.0 to 8.0 Ibs ai/A. Many of the treated areas, such as non-
agricultural use sites, rights-of-way, fencerows, hedgerows and other may shelter a variety of
mammal species; "These areas may be prime habitat for small mammals including rabbits, voles,
shrews, and other mammals. The mammals do not necessarily leave the treated areas and may
feed on fopd items containing amitrole residues.
The risk to avian species on a chronic basis will be assessed once the avian reproductive
data are submitted. Avian reproductive studies (preferably with the bobwhite quail and mallard
duck) are required.
Aquatic Species
The risk to aquatic species (on a chronic basis) will be determined once the registrant
submits the fish early life-stage (72-4(a)) or aquatic invertebrate life-cycle studies. Exposure to
aquatic environments may occur by runoff or spray drift. The aquatic invertebrate life-cycle
study with Daphiamagna (water fleas) is being required.
57
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c. Risk to Nontarget Plants
Terrestrial and Semi-aquatic Plants
The risk to nontarget terrestrial and semi-aquatic plants from applications of amitrole is
expected to be moderate to high. Plant toxicity tests indicate amitrole affects vegetative vigor.
The vegetative vigor study evaluates effects to plants from foliar exposure. However, seedling
emergence data, which represent effects to seedlings from soil exposure, was not available.
Amitrole is considered to affect a wide variety of plant species. The mode of action (inhibition
of carotenoid synthesis and chlorophyll formation) results in non-selective weed control. The list
of target plants on the label that are controlled suggests that amitrole is a "broad spectrum"
herbicide.
The extent of impact beyond the treated sites is not known. While it is fairly certain that,
to some extent, amitrole will drift and transport with runoff, the degree to which this occurs is
uncertain. In addition to the uncertainly concerning extent of exposure, there is also uncertainty
whether the magnitude of risk is adequately characterized because seedling emergence data were
not available. The seedling emergence study provides data to assess risk to nontarget plants from
amitrole in soil.
Aquatic Plants
; . , '
Based on data for one species only, the LOG for aquatic plants has not been exceeded.
However, risk to aquatic plants may occur from exposure by runoff and spray drift. Aquatic plant
toxicity data for 5 species of plants, including a vascular species (Lemna gibba), are needed to
determine risk to nontarget plants. (
d. Risk to Endangered Species
Based on available mammalian data, amitrole may affect mammals (chronic effects), and
terrestrial and semi-aquatic endangered plants. No data are available, however, to determine risk
for endangered avian species and aquatic invertebrates (chronic effects), and aquatic plants.
When the Endangered Species Protection Program becomes final, limitations in the use
of amitrole may be required to protect endangered and threatened species. These limitations may
be formulation specific. The Agency anticipates that a consultation with the Fish and Wildlife
Service will be conducted in accordance with the species-based priority approach described in
the Program. After completion of consultation, registrants will be informed if any required label
modifications are necessary. Such modifications would most likely consist of the generic label
statement referring pesticide users to use limitations contained in county Bulletins.
58
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IV. WSK MANAGEMENT AND REREGISTRATION DECISION
- A. Determination of Eligibility
Section 4(g)(2)(A) of FIFRA calls for the Agency to determine, after submission of
relevant data concerning an active ingredient, whether products containing the active ingredients
are eligible for reregistration. The Agency has previously identified and required the submission
of the generic (r.e. active ingredient specific) data required to support reregistration of products
containing amitrole active ingredients. The Agency has completed its review of these generic
data, and has determined that the data are sufficient to support reregistration of all products
containing amitrole. Appendix B identifies the generic data requirements that the Agency
reviewed as part of its determination of reregistration eligibility of amitrole, and lists the
submitted studies that the Agency found acceptable.
The data identified in Appendix B were sufficient to allow the Agency to assess the
registered uses of amitrole and to determine that amitrole can be used without resulting in
unreasonable adverse effects to humans and the environment. The Agency, therefore finds that
all products containing amitrole as the active ingredient with the requirements and conditions
specified herein, are eligible for reregistration. The reregistration of particular products is
addressed in Section V of this document.^
The Agency made its reregistration eligibility determination based upon the target data
base required for reregistration, the current guidelines for conducting acceptable studies to
generate such data, published scientific literature, etc. and the data identified in Appendix B.
Although the Agency has found that all uses of amitrole (assuming the nursery stock use is
deleted) are eligible for reregistration, it should be understood that the Agency may take
appropriate regulatory action, and/or require the submission of additional data to support the
registration of products containing amitrole, if new information comes to the Agency's attention
or if the data requirements for registration (or the guidelines for generating such data) change.
B. Determination of Eligibility Decision
1. Eligibility Decision
Based on the reviews of the generic data for the active ingredient amitrole, the Agency,
has sufficient information on the health effects of amitrole and on its potential for causing adverse
effects in fish and wildlife and the environment. The generic data base supporting the
reregistration of amitrole is substantially complete for all uses. However, the Agency is requiring
the submission of two ecological studies and two handler exposure studies to be conducted with
the generic active ingredient to complete the Agency's risk assessment and two plant testing *
ecological studies to confirm the Agency's risk assessment. Nevertheless, the Agency has
determined that amitrole products not requested to be cancelled by the registrant prior to the
issuance of this Reregistration Eligibility Decision document, labeled and used as specified in this
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RED document, will not pose unreasonable risks or adverse effects to humans or the
environment Therefore, the Agency concludes that all uses of the wettable powder formulation
packaged in water soluble bags are eligible for reregistration. The ornamental nursery stock use
is being deleted. .
2. Eligible and Ineligible Uses
The Agency has determined that all currently registered uses of amitrole (not including
the uses associated with the liquid formulation which the registrant has requested voluntary
cancellation and the ornamental nursery stock use which is being deleted), labeled and used as
specified in this RED document as a terrestrial non-food crop herbicide are eligible for
reregistration.
C. Regulatory Position - Summary'of Risk Management Decisions
The following is a summary of the regulatory positions and rationales for amitrole. Where
labeling revisions are imposed, specific language is set forth in Section V of this document.
1.
Tolerance Reassessment
Because amitrole is only registered for nonfood uses, there are no tolerances for any food
crop or water which will be used for irrigation, drinking, or other domestic purposes.
2.
Cancer Risk Assessment
Amitrole has been classified as a Group B2 (probable human carcinogen) by. the Office
of Pesticide Programs Carcinogenicity Peer Review Committee (document dated August 30,
1991). This determination is based on the thyroid tumors seen in the rat (both sexes, multiple
strains), mouse (both sexes, two strains), and on liver tumors seen in the mouse (both sexes,
multiple strains) as described in the appropriate toxicology studies. The Agency calculated a Ql *
of 0.68 from the thyroid tumor effects as seen in the first long term toxicological study.
3. Restricted Use Classification (RU)
Amitrole'was classified for Restricted Use through the Registration Standard, issued
March 1984. In May 1984, a Special Review of Amitrole was initiated based on carcinogenic
risk. In 1982, the Special Review of Amitrole was concluded with the following determination:
"...because of the positive carcinogenicity studies, the Agency will continue to require that
Amitrole remain a restricted use pesticide, that the cancer warning statement remain in place, that
the current application method remain limited to boom sprayers and that the preset protective
clothing requirements remain on labeling."
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The registrant, CFPI requested that the Agency rescind the restricted use classification as
part of me reregistration evaluation of amitrole.
After reviewing all the submitted data and comparing other pesticidal chemicals also
classified as "restricted use," the Agency has determined that the restricted use classification
could be rescinded for the following reasons and under the following conditions. Although the
Agency's calculated cancer risk to mixers/loaders from amitrole packaged in water; soluble bags
is approximately 10~s, (assuming handlers wear long sleeve shirts, long pants, shoes and socks)
two thirds (2/3) of the estimated exposure/cancer risk is from inhalation exposure. As explained
in this document, .in the exposure assessment section, the Agency believes that actual inhalation
exposure is likely to be practically non-existent. Focusing only on cancer risk from dermal
exposure, the estimated cancer risk approaches 10"* (1/3 X 8.2 X 10's from Table 6). Thus, with
the low dermal absorption factor (0.5%), continued packaging in water soluble bags, the
additional protection (although minimal because of the low dermal absorption) afforded by
chemical resistant gloves and chemical resistant apron, and the conditions specified in the
paragraph below, the Agency believes that a Restricted Use classification is no longer warranted.
In addition, the following conditions must be met: voluntary cancellation of the liquid
formulation product (in process within the Agency), retention of the cancer warning label,
limiting the sole application method to fixed-boom ground sprayers, retention of the same use
profile as a non-food pesticide (non-cropland use only), and a commitment to provide .the Agency
with handler exposure studies to mixers/loaders of water soluble packages to confirm the
Agency's risk assessment and conclusions. In addition, any proposed future expansion of their
market will require that a separate risk assessment be performed for any new use/application
method.
4. Endangered Species Statement
Currently, the Agency is developing a program ("The Endangered Species Protection
Program") to identify all pesticides whose use may cause adverse impacts on endangered and
threatened species and to implement mitigation measures that will eliminate the adverse impacts.
The program would require use restrictions to protect endangered and threatened species at the
county level. Consultations with the Fish and Wildlife Service may be necessary to assess risks
to newly listed species or from proposed new uses. In the future, the Agency plans to publish a
description of the Endangered Species Program in the Federal Register and have available
voluntary county-specific bulletins. Because the Agency is taking this approach for protecting
endangered and threatened species, it is not imposing label modifications at this time through this
RED document. Rather, any requirements for product use modifications will occur in the future
under the Endangered Species Protection Program. .
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5. Human Health
(a) Dietary
There are no food uses for amitrole. Therefore, there are no dietary exposures to amitrole
and a dietary exposure assessment is not required.
(b) Worker (Mixer/Loader/Applicator)
Acute (Short TernO and Intermediate Term
The Agency conducted an assessment of the inhalation risks associated with amitrole
following short-term and intermediate-term exposures to occupational handlers. The Agency has
determined that a risk assessment is not required for short-term and intermediate-term dermal
exposures. Margins of exposure (MOE) for occupational inhalation exposures were calculated
for handlers using the NOEL for short-term exposure (4 mg/kg/day) and the NOEL for
intermediate-term exposure (0.9 mg/kg/day). The calculated MOE's are presented in Table 5 of
Section m(B)(b). Amitrole is not marketed to homeowners (the only application method is
fixed-boom sprayer), and because of the nature of the use pattern, the sole exposure of concern
is for occupational handlers. The calculations indicate that the MOEs for short- and intermediate-
term inhalation exposures at baseline protection (i.e., no respirator) exceed 100 with the
exception of Scenario I (mixing liquid to support groundboom application) which has a
calculated MOE of 82. As previously stated, the registrant has requested voluntary cancellation
of this product.
Amitrole is classified as a B2-probable human carcinogen. The Agency will continue to
require a cancer warning statement on all amitrole labels, continue packaging in water soluble
bags, retain boom sprayers as the only application mode, require mixers and loaders to wear a
chemical resistant apron and gloves, long sleeve shirts, long pants, shoes and socks.
Additionally, the registrant has requested voluntary cancellation of the liquid formulation.
The restricted use classification is being rescinded since the Agency has determined that
actual inhalation exposure is likely to be practically non-existent. Considering the low dermal
adsorption factor, continued packaging in water soluble bags and the additional protection
afforded by chemical resistant gloves and apron, the cancer risk from dermal exposure
approaches 10-6.
Post-Application
There are no amitrole-specific post-application exposure data available. For many
amitrole use-scenarios, the Agency believes that the risks from post-application exposures will
not pose an unacceptable risk to persons entering treated areas because, in general, amitrole
used in areas, such as rights-of-way, industrial areas, permanent landscape plantings, and other
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non-crop areas, where frequent or routine prolonged entry by persons who contact treated
surfaces is unlikely. Therefore, the Agency has determined that such post-application exposures
do not appear to pose an unreasonable risk to persons entering treated areas, as long as entry is
not permitted until sprays have dried.
6.
Environmental
x The acute risk to npntarget animals (birds, insects, mammals, fish and aquatic
invertebrates) is predicted to be low. Chronic risk to mammals was identified; however, the
chronic risk to other nontarget animals (birds, fish and aquatic invertebrates) was not determined
because chronic ecological effect data were not available.
(a) Avian
, / , ". , ' , " "'.'.- ." i .'",., .
, Acute/Chronic
Studies indicate that amitrole is practically non-toxic to avian species on an acute oral and
subacute basis. For birds, it is important to note that the LCSO values used to calculate the RQs
were greater that the highest dose tested (5,000 ppm). The Agency considers amitrole to
represent low acute risk to birds. At this time chronic risk to birds cannot be assessed, because
avian reproduction data are not available.
- i (b) Mammals ; ...,
Acute/Chronic
Amitrole is practically non-toxic to small mammals on an acute oral basis. The RQs for
small herbivores and insectivores (0.13 to 0.29) exceeded by small margins the LOCs fpr
endangered species (0.1) and restricted use (0.2), Amitrole however, may be hazardous to
mammalian reproduction in localized areas. Using the acceptable two-generation rat
reproduction study, the risk assessment indicates use of amitrole has the potential for chronic risk
to mammalian species and may also chronically affect endangered mammalian species. The
mammalian exposure asssessments use residue levels which represent the maximum estimated
values, and the resiudes are expected to be lower on most food items. Amitrole residues are
predicted to decline by microbial-mediated metabolism, physical removal by washoff and other
dissipation pathways. The amitrole residue levels on food items in treated areas are" not known
because the treated areas are limited to nonagricultural use sites (rights-of way, fencerows,
hedgerows, etc.) and the extent of exposure may be limited.
, (c) Insects ,
There is sufficient information to characterize amitrole as relatively non-toxic to bees.
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(d) Freshwater Fish and Amphibians
The toxicity of amitrole to most aquatic organisms tested to date range from practically
non-toxic (freshwater fmfish) to moderately toxic (marine invertebrates). Chronic risk to
freshwater fish can not be assessed because the fish life-cycle data are not available at this time.
, (e) Aquatic Invertebrates .
There is sufficient information to characterize amitrole as slightly toxic to aquatic
invertebrates. However, the chronic risk to freshwater invertebrates will be assessed once the
invertebrate life cycle study is reviewed. '
(f) Estuarine and Marine Organisms
The acute risk from applications of amitrole is expected to be low to freshwater and
marine/estuarine organisms. The risk quotients determined from application rates ranging from
3.6-8.0 Ibs ai/A are less than the levels of concern for the tested aquatic animals at all use rates,
except for marine/estuarine invertebrates. The RQ for mysid shrimp was 0.137 (8 Ibs ai/acre)
which exceeded the LOCs for endangered species (0.05) and restricted use (0.1) by a small
margin. In this assessment, the screening model GENEEC was used to model runoff from non-
agricultural use sites for amitrole. The GENEEC model was based on an agricultural use scenario
and is a conservative estimate of exposure from surface runoff because agricultural land uses are
intensive and may cover large areas.
The conclusion of low acute risk to estuarine crustaceans is based not only oh the fact that
the LOCs were exceeded by a small margin, but also because amitrole is used on non-agricultural
use sites. In addition to marginal LOC exceedances and non-agricultural uses, the amount of
amitrole applied annually in the United States is relatively small. Usage information for amitrole
in the U.S. provided by the registrant is between 40,000 and 60,000 pounds of active ingredient
on an annual basis. Furthermore, endangered estuarine invertebrates are not currently listed by
the United States Fish Wildlife Service (USFWS).
(g) Nontarget Plants (Terrestrial, Semi-Aquatic
and Aquatic)
From the available information, amitrole affects the vegetative vigor of bom monocots
and dicots at very low levels (O.01 Ibs ai/A). The risks to non-target plants from sheet and
channelized runoff was not determined with certainty because plant toxicity data was limited
(seedling emergence data are not available). Qualitatively, amitrole's broad spectrum plant
control due to its mode of action (i.e., inhibition of carotenoid synthesis) suggests exposure of
amitrole may impact non-target plants. Based on the 3.6 to 8.0 Ibs. ai/A use rates of amitrole, rc.k
quotients exceed the levels of concern for terrestrial and semi-aquatic plants (1.0). Risk quotients
are based on ECjjS from the dry weight parameter for wheat (monocot) and pepper (dicot) from
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the vegetative vigor study. The wheat and pepper plant EC25s were the most sensitive plants
tested and the lowest levels for the available plant toxicity data.
Because the risk assessment is incomplete for non-target terrestrial and aquatic plants,
terrestrial (seedling emergence) and aquatic plant (all five species) testing is being required to
confirm and complete the Agency's risk assessment and conclusions.
(h) Surface Water
Even though amitrole exhibits some of the characteristics associated with chemicals that
contaminate surface water from runoff or spray drift from with ground spray application, the
Agency is not requiring surface water monitoring studies nor a surface water advisory because
several published surface water monitoring studies using multi-residue analytical methods did
vnot detect amitrole. In addition to these studies, amitrole detections for surface waters were not
found in a search of the Agency's STORET database. Results of the monitoring studies suggest
a low potential for amitrole to contaminate surface water. Lastly, amitrole is not regulated under
the SafeDrinking Water Act (SDWA) and a Maximum Contaminant Level (MCL) has notbeeh
established.
; , ''.",' ' ',.'-' ''- - - ..... ,_^ ... - -
(i) Ground Water
Amitrole is mobile, somewhat persistent and may have the potential to contaminate
ground water. This assessment is based on the acceptable environmental fate studies which
indicate amitrole has a significant number of characteristics in common with pesticides that are
known to leach to ground water. Amitroleis stable to hydrolysis, and aerobic soil and anaerobic
aquatic metabolism and field dissipation data indicate that it is somewhat persistent Amitrole
is classified as mobile because the low K^ and K^ values indicate it will not strongly absorb to
soil. Pesticides with similar properties have been found in ground water There is no evidence
of groundwater contamination from amitrole residues. Although the Agency is not requiring
additional studies, it is requiring a ground water advisory to be included in all labels.
7. Labeling Rationale
a. Occupational and Residential Labeling Rationale/
Risk Mitigation Measures
(1) Compliance with the Worker Protection
Standard (WPS)
(a) Uses of Amitrole and Scope of the WPS
The 1992 Worker Protection Standard for Agricultural Pesticides (WPS) established
certain worker-protection requirements (personal protective equipment, restricted-entry intervals,.
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etc.) to be specified on the label of all products that contain uses within the scope of the WPS.
Uses within the scope of the WPS include all commercial (non-homeowner) and research uses
on farms, forests, nurseries, and greenhouses to produce agricultural plants (including food, feed,
and fiber plants, trees, turf grass, flowers, shrubs, ornamentals, and seedlings). Uses within scope
include not only uses on plants, but also uses on the soil or planting medium the plants are (or
will be) grown in.
At this time some of the registered uses of amitrole (nursery stock) are within the scope
of the Worker Protection Standard for Agricultural Pesticides (WPS). However, the registrant
has indicated that they will voluntarily cancel the nursery stock use. Uses that are outside the
spope of the WPS include use:
On plants that are in ornamental gardens, parks, golf courses, and public or private
lawns and grounds and that are intended only for decorative or environmental,
benefit. (However, pesticides used on sod farms are covered by the WPS).
In a manner not directly related to the production of agricultural plants, including,.
for example, control of vegetation along rights-of-way and in other nondrop areas.
The only remaining uses of amitrole will be as an industrial herbicide for use on
"rights-of-way" and other similar uses not covered by the worker protection
standard, once the voluntary cancellation of the liquid formulation bearing uses
for nursery stock (as well as other uses) is formally requested and completed.
(b) Compliance With the WPS
The following discussion regarding compliance with worker prtoection standard is
included since the nursery stock use is still technically registered, pending the Agency's receipt
of the registrant's requestfor voluntary cancellation of nursery stockuses.
Any product whose labeling can be reasonably interpreted to permit use in the production
of an agricultural plant on any farm, forest, nursery, or greenhouse must comply with the labeling
requirements of PR Notice 93-7, "Labeling Revisions Required by the Worker Protection
Standard (WPS)," and PR Notice 93-11, "Supplemental Guidance for PR Notice 93-7," which
reflect the requirements of EPA's labeling regulations for worker protection statements (40 CFR
part 156, subpart K). These labeling revisions are necessary to implement the Worker Protection
Standard for Agricultural Pesticides (40 CFR part 170) and must be completed in accordance
with, and within the deadlines specified in, PR Notices 93-7 and 93-11. Unless otherwise
specifically directed in this RED, all statements required by PR Notices 93-7 and 93-11 are to be
on the product label exactly as instructed in those notices.
AfterApril21,1994, except as otherwise provided in PR Notices 93-7 and 93-11,
the labeling of all products within the scope of those notices must meet the
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requirements of the notices when the products are distributed or sold by the
primary registrant or any supplementally registered distributor.
After October 23, 1995, except as otherwise provided in PR Notices 93-7 and
93-11, the labeling of all products within the scope of those notices must meet the
requirements of the notices when the products are distributed or sold by any
person.
(c) Personal Protective Equipment/
Engineering Controls for Handlers
For each end-use product, PPE requirements for pesticide handlers are set during
reregistration in one of two ways:
1. If the Agency determines that no regulatory action must be taken as the result of
the acute effects or other adverse effects of an active ingredient, the PPE for
; " pesticide handlers will be based on the acute toxicity of the end-use product. For
occupational-use products, PPE must be established using the process described
in PR Notice 93-7 or more recent Agency guidelines.
2. If the Agency determines that regulatory action on an active ingredient must be
taken as the result of very high acute toxicity or to certain other adverse effects,
such as allergic effects or delayed effects (cancer, developmental toxicity,
reproductive effects, etc.):
In the RED for that active ingredient, the Agency may establish minimum
or "baseline" handler PPE requirements that pertain to all or most end-use
products containing that active ingredient
These minimum PPE requirements must be compared with the PPE that
would be designated on the basis of the acute toxicity of the end-use
product.
' The more stringent choice for each type of PPE (i.e., bodywear^ hand
protection, footwear, eyewear, etc.) must be placed on the'label of the end-
use product.
Personal protective equipment requirements usually are set by specifying one or more pre-
established PPE units . sets of items that are almost always required together. For example, if
chemical-resistant gloves are required, then long-sleeve shirts, long pants, socks, and shoes are
assumed and are also included in the required minimum attire. If the requirement is for two
layers of body protection (coveralls over a long- or short-sleeve shirt and long or short pants), the
minimum must also include (for all handlers) chemical-resistant footwear and chemical-resistant
67
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headgear for overhead exposures and (for mixers, loaders, and persons cleaning equipment)
chemical-resistant aprons.
(d) Occupational-WPS and Non-WPS Use Products
The Agency has determined that the establishment of active-ingredient-based minimum
PPE and engineering-control requirements for occupational handlers must be taken for amitrole,
because of the carcinogenic risk to mixers and loaders.
(e) Homeowner-Use Products
There are no homeowner uses of amitrole.
(f) Reentry Restrictions
WPS Uses
Uses covered by the Worker Protection Standard (i.C;, the nursery stock use) is going to
be, as noted above, voluntarily cancelled. Although the Agency has calculated risks for the
handlers of the liquid formulation it has not determined reentry intervals or PPE for early entry
for this use.
(g) Occupational-Use Products (NonWPS Uses)
Since the Agency has concerns about immediate post-application exposures to persons
after nonWPS occupational uses of amitrole, it is establishing entry restrictions for all nonWPS
occupational uses of amitrole end-use products. For specific requirements, refer to Section V of
this document ,.-.-.
(h) Additional Labeling Requirements
The Agency is also requiring other use and safety information to be placed on the labeling
of all end-use products containing amitrole. For the specific labeling statements, refer to Section
V of this document.
;
8. Spray Drift Advisory
The Agency has been working with the Spray Drift Task Force, EPA Regional Offices
and State Lead Agencies for pesticide regulation to develop the best spray drift management
practices. The Agency is now requiring interim measures that must be placed on product
labels/labeling as specified in Section V. Once the Spray Drift Task Force completes their
studies, submits data, and the Agency evaluation is completed, there may be further refinements
in spray drift management practices.
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V. ACTIONS REQUIRED OF REGISTRANTS
This section specifies the data requirements and responses necessary for the reregistration of
both manufacturing-use and end-use products.
A. Manufacturing-Use Products
1. Additional Generic Data Requirements
The generic data base supporting the reregistration of amitrole for the above eligible uses has
been reviewed and determined to be substantially complete for all uses. Nevertheless, the following
studies are required to be conducted on the generic active ingredient:
o Guideline 7 l-4(a) and (b)
p Guideline 72-4(b)
Avian Reproduction studies
Aquatic Invertebrate Life Cycle with Daphnia
Magna
The following confirmatory studies are required in order to complete the Agency's risk
assessment and conclusions:
Guideline 123-l(a)
Guideline 123-2
Guideline 231 and 232
JTerrestrial Plant Testing: Seedling Emergence
only
Aquatic Plant Testing: All five (5) species
Handler exposure study to provide dermal and
inhalation data on mixers and loaders during the
use of water-soluble packages.
2. Labeling Requirements for Manufacturing-Use Products
To remain in compliance with FIFRA, manufacturing use product (MP) labeling must be
revised to comply with all current Agency (EPA) regulations, PR Notices and applicable policies.
' , v .'.-'-'' . . '
An MP registrant may, at his/her discretion, add one of the following statements to an MP label
under "Directions for Use" to permit the reformulation of the product for a specific use or all
additional uses supported by a formulator or user group:
(a) "This product may be used to formulate products for specific use(s) not listed
on the MP label if the formulator, user group, or grower has complied with U.S.
EPA submission requirements regarding support of such use(s)."
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(b) "This product may be used to formulate products for any additional use(s) not
listed on the MP label if the formulator, user group, or grower has complied
with U.S. EPA submission requirements regarding support of such use(s)."
B. End-Use Products
1. Additional Product-Specific Data Requirements
Section 4(gX2)(B) of FIFRA calls for the Agency to obtain any needed product-specific data
regarding the pesticide after a determination of eligibility has been made. The product specific data
requirements are listed in Appendix D, the Product Specific Data Call-In Notice.
Registrants must review previous data submissions to ensure that they meet current EPA
acceptance criteria and if not, commit to conduct new studies. If a registrant believes that previously
submitted data meet current testing standards, then study MRID numbers should be cited according
to the instructions in the Requirement Status and Registrants Response Form provided for each
product
2. Labeling Requirements for End-Use Products
a. Worker Protection Safety
o PPE/Engineering Control Requirements for
Pesticide Handlers
For sole-active-ingredient end-use products that contain amitrole, the product labeling must
be revised to adopt the handler personal protective equipment/engineering control requirements set
forth in this section. Any conflicting PPE requirements on the current labeling must he removed.
For multiple-active-ingredient end-use products that contain amitrole, the handler personal
protective equipment/engineering control requirements set forth in this section must be compared to
the requirements on the current labeling and the more protective must be retained. For guidance on
which requirements are considered more protective, see PR Notice 93-7.
o Products Intended Primarily for Occupational Use (WPS
and nonWPS)
Minimum (Baseline^ PPE/Engineering
Control Requirements
The Agency is establishing minimum (baseline) engineering controls for occupational uses of
amitrole end-use products.
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For the wettable powder packaged in water soluble packages (non WPS), the Agency is
requiring that mixers/loaders and persons cleaning equipment wear:
long sleeve shirt and long pants,
chemical resistant gloves,
chemical resistant apron, and
..shoes plus socks
For the wettable powder packaged in water soluble packages (non WPS), the Agency is
requiring that applicators wear:
long sleeve shirt and long pants, and
shoes plus socks
o Determining PPE Requirements for End-use Product
Labels v
i , ' '
The PPE that would be established on the basis of the acute toxicity category of the end-use
product must be compared to the active-ingredient-based minimum (baseline) personal protective
equipment specified above. The more protective PPE must be placed on the product labeling. For
guidance on which PPE is considered more protective, see PR Notice 93-7.
Placement in Labeling
The personal protective equipment requirements must be placed on the end-use product
labeling in the location specified in PR Notice 93-7, and the format and language of the PPE
requirements must be the same as. is specified in PR Notice 93-7.
o Determining Entry Restrictions
For sole-active-ingredient end-use products that contain amitrole the product labeling must be
revised to adopt the entry restrictions set forth in this, section. Any conflicting entry restrictions on
the current labeling must be removed.
For multiple-active-ingredient end-use products that contain amitrole the entry restrictions set
forth in this section must be compared to the entry restrictions on the current labeling and the more
protective must be retained. A specific time period in hours or days is considered more protective than
"sprays have dried" or "dusts have settled."
-" . -' '';"' WPS uses :-'.".'-. .-./.
Since the registrant's voluntary cancellation of in-scope (nursery-stock, the only WPS use) use
has been received by the Agency, an REI is not being presented.
. "-'" ' V 71 -..'-. '"
-------
NonWPS uses
* 4 ' '
Hie Agency is establishing the following entry restrictions for nonWPS occupational uses of
amitrole end-use products: .
"Do not enter or allow other employees to enter the treated area until sprays have dried."
Placement in labeling
Place the appropriate nonWPS entry restrictions in the Directions for Use, under the heading:
"Entry Restrictions."
o Other Labeling Requirements
Products Intended Primarily for Occupational Use
The Agency is requiring the following labeling statements to be located on all end-use products
containing amitrole that are intended primarily for occupational use.
Application Restrictions
"Do not apply this product in a way that will contact workers or other persons, either
directly or through drift. Only protected handlers may be in the area during
application."
User Safety Requirements
a. (Registrant: place this on the labeling if coveralls are required for pesticide handlers on the
end-use product label:)
Discard clothing or other absorbent materials that have been drenched or heavily
contaminated with this product's concentrate. Do not reuse them.
b. {Registrant: place this on the labeling always:!
Follow manufacturer's instructions for cleaning/maintaining PPE. If no such
instructions for washables, use detergent and hot water. Keep and wash PPE
separately from other laundry.
User Safety Recommendations
"Users should wash hands before eating, drinking, chewing gum;
using tobacco, or using the toilet."
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b.
"Users should remove clothing immediately if pesticide gets
inside. Then wash thoroughly and put on clean clothing."
"Users should remove PPE immediately after handling this
product. Wash the outside of gloves before removing. As soon
as possible, wash thoroughly and change into clean clothing."
Environmental Hazard Statement
The following labeling statement must be added to the "Environmental Hazards" section on
all amitrole end-use products:
Ground water label advisory
"This chemical demonstrates the properties and characteristics
associated with chemicals detected in ground water. The use of this
chemical in areas where soils are permeable, particularly where the
water table is shallow, may result in ground-water contamination."
C.
Existing Stocks
Registrants may generally distribute and sell products bearing old labels/labeling for 26 months
from the date of the issuance of this Reregistration Eligibility Decision (RED). Persons other than the
registrant may generally distribute or sell such products for 50 months from the date of the issuance
of this RED document. However, existing stocks time frames will be established case-by-case,
depending on the number of products involved, the number of label changes, and other factors. Refer
to "Existing Stocks of Pesticide Products; Statement of Policy"; Federal Register. Volume 56 No
123, June 26, 1991. . . ซ:*,.-
The Agency has determined that registrants may distribute and sell amitrole products bearing
old labels/labeling for 26 months from the date of issuance of this RED document. Persons other than
the registrant may distribute or sell such products for 50 months from the date of the issuance of this
RED document Registrants and persons other than registrants remain obligated to meet pre-existing
Agency imposed label changes and existing stocks requirements applicable to products they sell or
distribute.
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VI. APPENDICES
-------
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I
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1
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s
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uated for
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ail I
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ill I
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GUIDE TO APPENDIX B
Appendix B contains listings of data requirements which support the reregistration for
active ingredients within the case amitrole covered by this Reregistration Eligibility Decision
Document It contains generic data requirements that apply to amitrole in all products, including
data requirements for which a "typical formulation" is the test substance.
^ .
The data table is organized in the following format:
1. Data Requirement (Column 1). The data requirements are listed in the order in which
they appear in 40 CFRPart 158. the reference numbers accompanying each test refer to the test
protocols set in the Pesticide Assessment Guidelines, which are available from the National
Technical Information Service, 5285 Port Royal Road, Springfield, VA 22161 (703) 487-4650.
2. Use Pattern (Column 2). This column indicates the use patterns for which the data
requirements apply. The following letter designations are used for the given use patterns:
A Terrestrial food
B Terrestrial feed
C Terrestrial non-food
D Aquatic food
E Aquatic non-food outdoor
F Aquatic non-food industrial
G Aquatic non-food residential
H Greenhouse food
I Greenhouse non-food
J Forestry
K Residential
L Indoor food
M Indoor non-food
N Indoor medical
O Indoor residential
3. Bibliographic citation (Column 3). If the Agency has acceptable data in its files, this
column lists the identifying number of each study. This normally is the Master Record
Identification (MRED) number, but may be a "GS" number if no MRID number has been
assigned. Refer to the Bibliography appendix for a complete citation of the study.
80
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GUIDE TO APPENDIX C
CONTENTS OF BIBLIOGRAPHY. This bibliography contains citations of all studies
considered relevant by EPA in arriving at the positions and conclusions stated '
elsewhere in the Reregistration Eligibility Document. Primary sources for studies in
this bibliography have been the body, of data submitted Ito EPA and its predecessor
agencies in support of past regulatory decisions. Selections from other sources _
including the published literature, in those instances where they have been considered,
are included. '
UNITS OF ENTRY. The unit of entry in this bibliography is called a "study". In the
case of published materials, this corresponds closely to an article. In the case of
unpublished materials submitted to the Agency, the Agency has sought to identify
documents at a level parallel to the published article from within the typically larger
volumes in which they were submitted. The resulting " studies" generally have a ,
distinct title (or at least a single subject), can stand alone for purposes of review and
can be described with a conventional bibliographic citation. The Agency has also
attempted to unite basic documents and commentaries upon them, treating them as a
single study. -..,'
IDENTIFICATION OF ENTRIES. The entries in this bibliography are sorted
numerically by Master Record Identifier, or "MRID number". This number is unique
to the citation, and should be used whenever a specific reference is required. It is not
related to the six-digit "Accession Number" which has been used to identify volumes of
submitted studies (see paragraph 4(d)(4) below for further explanation)., In a few
cases, entries added to the bibliography late in the review may be preceded by a nine
character temporary identifier. These entries are listed after all MRID entries. This '
temporary identifying number is also to be used whenever specific reference is needed.
FORM OF ENTRY. In addition to the Master Record Identifier (MRID), each entry .
consists of a citation containing standard elements followed, in the case of material
submitted to EPA, by a description of the earliest known submission. Bibliographic
conventions used reflect the standard of the American National Standards Institute
(ANS^, expanded to provide for certain special needs.
a Author. Whenever the author could confidently be identified, the Agency has
chosen to show a personal author. When no individual was identified, the
Agency has shown an identifiable laboratory or testing facility as the author.
When no author or laboratory could be identified, the Agency has shown the
first submitter as the author.
b. Document date. The date of the study is taken directly from the document.
When the date is followed by a question mark, the bibliographer has deduced
the date from the evidence contained in the document. When the date appears
as (19??), the Agency was unable to determine or estimate the date of the
document.
88
-------
Title. In some cases, it has been necessary for the Agency bibliographers to
create or enhance a document title. Any such editorial insertions are contained
between square brackets. ' ป .
Trailing parentheses. For studies f'lbmitted to the Agency in the past, the
trailing parentheses include (in add aon to any self-explanatory text) the
following elements describing the earliest known submission:
(1) Submission date. The date of the earliest known submission appears
immediately following the word "received."
(2) Administrative number. The next element immediately following the
word "under" is the registration number, experimental use permit
number, petition number, or other administrative number associated
with the earliest known submission.
(3) Submitter. The third element is the submitter. When authorship is
defaulted to the submitter, this element is omitted.
(4) Volume Identification (Accession Numbers). The final element in the
trailing parentheses identifies the EPA accession number of the volume
in which the original submission of the study appears. The six-digit
accession number follows the symbol "CDL," which stands for
"Company Data Library." This accession number is in turn followed by
an alphabetic suffix which shows the relative position of the study within
the volume.
89
-------
MRID
BIBLIOGRAPHY
CITATION
Alexander, N.M.; (1959) Antithyrioid Action of 3-Amino-l,2,4-triazole: J.
Biol. Chem. 243:148-150.
- Daston, D.; Krauss, R.; Eling, T.; Caspary, W. (1?86) Peroxidase-mediated
metabolic activation of amitrole. Environ Mutagen 8 (Suppl 6): 21-22.
Dynamac (1928) Medical Moniotring and Assessment of Exposure to Workers
Applying Amitrole to Utility Rights-ofWay. (Unpublished study prepared by
Dynamac Corp. submitted by Union Carbide).
Fang, S.C.,; George, M.; Yu, T.C. (1964) Metabolism of 3-amino-l,2,4-
triazole-5-C14by Rats. Agricultural Food Chemistry 12(3):219-223.
Franco, L.; Municio, A.M. (1975) Comparative Metabolism of 3-Amino-l,2,4-
Triazole: General Pharmacology 6:163-169.
Gaines, T.B.; Kimbrough, R.D.; Linder, R.E.; (1973) The Toxicity of Amitrole
in the Rat: Toxicol. Appl. Pharmacol. 26:118-129.
Heddle, J.; Kite, M.; Kikhart, B.; Mavournin, K.; Mac Gregor, J.; Newele.; G.
Salamone, M; (1983) The induction of micronuclei as a measure of
gneotocicity. A report of the U. SJ. Environmental Protection Agency Gene-Tox
program. Mutation Research 123:61-118.
Hill, R.; Erdreich, L.; Paynter, O.; Roberts, P.; Rosenthal, S.; Wilkinson, C.
(1989) Thyroid follicular cell carcinogenisis. Fund Appl Toxicol 12:629-697.
IARC Monographs (1974) the Evaluation of Carcinogenic Risk of Chemicals
to Man, Vol. 7, page 31, Lyori, France.
Innes, J.R.M. (1967) Summary Sheet: Project #16: Carcinogenisis Assay
Studies: PM No. 66/749. Unpublished study received May 8; 1967 under
unkown admin, no.; submitted by Union Carbide Agricultural Products Cois
Amber, Pa;; CDL: 107013-A.
Innes, J.R.M.; Ulland, B.M.; Valerio, V.; Petrucelli, L.; Hart, E.R.; Bates, R.R.;
Falk, H.L.; Gart, J.J.; Klein, M.; Mitchell, I..; Peters, J. (1969) Bioassay of
Pesticides aiid Industrial Chemicals for Tufnorigeniciry in Mice: A Preliminary
Note. Journal National Cancer Institute 42:1101-1114.
Jukes, T.H. and Shaffer, C.B. (1960) Antithyroid Effects of Aminotriazole.
Sience 132:296-297.
90
-------
BIBLIOGRAPHY
MRID
CITATION
Krause, R. and Eling, T. (1987) Macromolecular binding of the thyroid
carcinogen 3-amino-l,2,4-triazole (amitrole) catalyzed by postgandin H
synthase, lactoperoxidase and thyroid peroxidase. Carcinogenisis 8:659-664.
Shah, P.V. and Gutrie, F.E. (1977) Dermal Absorption, Distribution and the
Fate of Six Pesticides in the Rabbit. Pesticide Management and Insecticide
Resistance; Academic Press, NY, pgs. 547-
Steinhoff, D. Weber, H.; Mohr, U.; Boehme, K. (1983) Evaluation of Amitrole
(Aminotriazole) for Potential Carcinogenicity in Orally Dosed Rats, Mice, and
Golden Hamster. Toxicology and Applied Pharmacology 69:161-169.
Strum, J.M. Karnovsky, M.J. (1971) Aminotriazole Goiter Fine Structure and
Localization of Thyroid Peroxidase Activity. Laboratory Investigation 24:1-12.
Tsuda, H.; Hirose, M.; Fukushima, A.; Takahahi, M. (1974) changes in the
Thyroid Galnd of Rats Given 3-amino-l,2,4-Triazole. H Changes Following
Long Term Administration. Nippon Byorigakku Kaishi 63:186-492.
Tsusui, T.; Maizumi, H.; Barrett, J.C. (1984) Amitrole -induced cell
transformation and gene mutations in Syrian hamster embryo cells in culture.
Mutation Research 140:205-207.
Vesselinovitch (1983) Perinatal Hepatocarcinogenisis. Biological Research in
Pregnancy and Perinatology 4(l):22-25.
00024959
00028434
00043595
00052643
McCann, J.A. (1972) 0Fenayar: Toxicity to Rainbow Trout |: Test No. 478.
(U.S. Agricultural Research Service, Pesticides Regulation Div., Animal
Biology Laboratory, unpublished report.)
Keller, J.G. (1960) Final Report: 28-Day Dietary Feeding Study-Rats,
(Unpublished study received Aug 9,1960 under unknown admin, no.; prepared
by Hazleton Laboratories, Inc., submitted by Union Carbide Agricultural
Products Co., Ambler, Pa.; CDL: 106983-A)
Innes, J.R.M. (1967) Summary Sheet: Project # 16: Carcinogenesis Assay
Studies: P.M. No. 66/749. (Unpublished study received May 8,1967 under
unknown admin, no.; submitted by Union Carbide Agricultural Products Co.,
Ambler, Pa.; CDL:107013-A)
Babish, J.G. (1977) Triiodothyronine (TaeS-1) and Thyroxine (T-4ae) Levels in
Male Rats Consuming Amitrole (3-Amino, 1-2-4-triazole) in Their Diets for
Four Weeks Followed by a Four-Week Recovery Period: Laboratory No. 5539.
91
-------
BIBLIOGRAPHY
MRID
CITATION
(Unpublished study,received Sep 22, 1980 under 264-135; prepared by Food
and Drug Research Laboratories, Inc., submitted by Union Carbide Agricultural
Products Co., Ambler, Pa.; CDL:243310-A)
00052644
00052645
00052648
00052652
00052653
00052656
00052658
Macdonald, C.M.; Pullihger, D.H. (1976) A Pharmacokinetic Study To
Compare Head Only and Whole Body Inhalation Methods of -114aeC-Amitrole
Exposure: Project No. 291/1. (Unpublished study received Sep 22, 1980 under
264-135; prepared by Hazleton Laboratories Europe, Ltd., submitted by Union
Carbide Agricultural Products Co., Ambler, Pa.; CDL:243310-B)
Turner, D.M.; Gilbert, CM. (1976) Evidence of Metabolism of (-14aeC)
Amitrdle in the Rat after Inhalation Administration: ProjectNo. 291/la.
Supplementary rept, May 1976. (Unpublished study received Sep 22, 1980
under 264-135; prepared by Hazleton Laboratories Europe, Ltd., submitted by
Union Carbide Agricultural Products Co., Ambler, Pa.; CDL:243310-C)
Brusick, D.J. (1976) Mutagenicity Evaluation of 3-Amino-l,2,4-triaz6le: Final
Report-in vitro-Cellular Transformation in BALE/ 3T3 Cells: LBI Project No.
2549. (Unpublished study received Sep 22, 1980 under 264-135; prepared by
Litton Bionetics, Inc., submitted by Union Carbide Agricultural Products Co.,
Ambler, Pa.; CDL:243310-F)
World Health Organization (1974) Amitrole: Joint Meeting of the FAO
Working Party of Experts on Pesticide Residues and the WHO Expert
Committee on Pesticide Residues: Rome, 2-11 December 1974:
FAD/RES/74.4C. (Extracted from V. 7 1974, IARC monographs on the
evaluation of the carcinogenic risk of chemicals to man; English only,
unpublished study; CDL:243309-C)
Snelsbn, J.T. (1974) Amitrole: Joint FAO/WHO Meeting of Experts on
Pesticide Residues 1974: Document PB 227. (Draft monograph; Australia,
Dept. of Agriculture, unpublished study; CDL: 243309-D)
Napalkov, N.P. (1962) Tumor-Inducing Action of ATA. (Unpublished study
received Sep 22, 1980 under 264-135; prepared by U.S.S.R., Academy of
.Medical Science, Institute of Oncology, submitted by Union Carbide
Agricultural Products Co., Ambler, Pa.; CDL: 243309-G)
Fregly, M.J. (1968) Effect of Aminotriazole on thyroid function in the rat.
Toxicology and Applied Pharmacology 13:271-286. (Also -]~Iri~unpublished
submission received Sep 22,1980 under 264-135; submitted by Union Carbide
Agricultural Products Co., Ambler, Pal; CDL:243309-I)
92
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00061348 Steinhoff, D.; Boehme, K.; Lorke, D*.; et al. (1979) Aminotriazole (Amitrole):
Carcinogenesis Study with Oral Administration to Mice: Report No. 8490.
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00061349 Iwan, G.R. (1978) -^14aeC-Amitrole, Bluegill Sunfish-Lepomis
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00061351 Steinhoff, D.; Boehme, K. (1979) Aminotrazole (Amitrole) Cancerogenesis
Test with Oral Administration to Rats: Report No. 8450. (Translation;
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AG, W. Germany, submitted by Union Carbide Agricultural Products Co.,
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00063598 Fogleman, R.W. (1954) Final Report: Acute Oral Administration-Mice; Acute
Oral AdministrationDogs; Acute Intravenous AdministrationDogs;
PharmacodynamicsDogs; Subacute FeedingRats. (Unpublished study
received Feb 26,1957 under 241-37; prepared by Hazleton Laboratories,
submitted by American Cyanamid Co., Princeton, N.J.; CDL:222312-G)
00063599 Elsea, J.R. (1954) Acute Dermal Application; Acute Eye Application.
(Unpublished study received Feb 26,1957 under 241-37; prepared by Hazleton
Laboratories, submitted by American Cyanamid Co., Princeton, N.J.;
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00063601 Bagdon, R.E.; Shaffer, C.B.; Vidone, L.B. (1956) Aminotriazole: Acute and
Subacute Toxicity: Report No. 56-29. (Unpublished study received Feb 26,
1957 under 241-37; submitted by American Cyanamid Co., Princeton, N.J.;
CDL:222312-J) ,
00082174 Vidone, L.B.; Shsffer, C.B. (1958) Report on Aminotriazole: 32-day Repeated
Feeding to Rats: Comparison of Effects of 1000 ppm Fed on Alternative Days
with 500 ppm Fed on Consective Days: Report No. 58-4. (Unpublished study
received Dec 20,1958 under PP0210; submitted by American Cyanamid Co.,
New York, N.Y.; CDL; 090236-D)
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00082176 Keller, J.G. (1959) Final Report: Two-year Chronic Feeding-Rats.
(Unpublished study received Dee 20,1958 under PP0210; prepared by
Hazleton Laboratories, submitted by American Cyanamid Co New York,
N.Y.; CDL:090236-F)
00127930 Becci, P. (1983) Evaluation of the Chronic Inhalation Toxicity and
Carcinogenicity of Amitrole in Rats: FDRL Study No. 5821; (Unpublished
f study received Apr 27, 1983 under 264-221; prepared by Food & Drug"*
Research Laboratories, Inc., submitted by Union Carbide Agricultural Products
Co., Inc.- Research Triangle Park, NC; CDL:250048-A; 250049; 250050'
250051) ,
Johnson, W.; Becci, P.; Parent, R. (1981) Lifetime Feeding Study of Amitrole
in Fischer 344 Rats: Laboratory No. 5651. (Unpublished study received Aug 7,
,1981 .under 264-226; prepared by Food and Drug Research Laboratories, Inc.* '
submitted by Union Carbide Agricultural Products Co., Inc., Research Triangle
Park, NC;CDL:251644-A; 251045; 25 i646)
Puhl, R. (1985) Dermal Absorption of Carbon 14-Amitrole in Male Rats: Final
Report: Study No. 6158-105. Unpublished study prepared by Hazleton
Laboratories America, Lie. 49 p. ฐ
Union Carbide Agricultural Products Co., Inc. (1984) Product Chemistry Data
for Amitrole. Unpublished study. 14 p.
Union Carbide Agricultural, Products Co. (1985) Product Chemistry Data
Using Amitrole. Unpublished study. 45 p.
Tyl, R. (1986) Teratogenicity Evaluation of Aminotriazole Technical
Administered by Gavage to New Zealand White Rabbits: Project Report 49-66.
Unpublished study prepared by Union Carbide, Bushy Run Research Center.
444 p.
00160447 Helfant,L. (1986) Aminotriazole Stability Data: Project No. 862F10.
Unpublished study prepared by Union Carbide Agricultural Company, Inc.
20 p. :.
00160448 Tyl, R. (1986) Teratogenicity Evaluation of Aminotriazole Technical
Administered by Gavage to CD Rats: Project Report 49-45. Unpublished study
prepared by Bushy Run Research Center. 741 p.
00151651
00152463
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00159997
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OOlc. 449 "M-- .- s, R.; Christopher, S. (1986) Aminotriazole: Dermal Sensitization Study
in the Guinea Pig: Project Report 49-50 Revised. Unpublished study prepared
by Bushy Run Research Center. 20 p.
00160450 Myers, R. (1985) Aminotriazole: Dermal and Ocular Irritancy Study: Project
Report 48/130. Unpublished study prepared by Bushy Run Research Center.
lip.
00160451 Fletcher, D. (1985) Acute Oral Toxicity Study with Aminotriazole Technical in
Bobwhite Quail: Blal No. 85 QD 58. Unpublished study prepared by Bio-Life
Associates, Ltd. 28 p.
00160452 Fletcher, D. (1985) 8-Day Dietary LC50 Study with Aminotriazole Technical
in Bobwhite Quail: Blal No. 85 QC 57. Unpublished study prepared by
Bio-Life Associates, Inc. 29 p.
00160453 McAllister, W.; Bowman, J. (1985) Acute Toxicity of Aminotriazole to
Bluegill Sunfish (Lepomis macrochirus): Report #33716. Unpublished study
prepared by Analytical Bio-Chemistry Laboratories, Inc. 50 p.
00160454 McAllister, W.; Bowman, J. (1985) Acute Toxicity of Aminotriazole to
Rainbow Trout (Salmo gairdneri): Report #33717. Unpublished study prepared
by Analytical Bio-Chemistry Laboratories, Inc. 49 p.
00160455 Forbis, A.; Burgess, D. (1985) Acute Toxicity of Aminotriazole to Daphnia
magna: Report #33718. Unpublished study prepared by Analytical
Bio-Chemistry Laboratories, Inc. 38 p.
00160476 Fletcher, D. (1985) 8-Day Dietary LC50 Study with Aminotriazole Technical
in Mallard Ducklings: Blal No. 85 DC 59. Unpublished study prepared by
Bio-Life Associates, Ltd. 28 p.
40567701 Kenwood, S. (1988) Percutaneous Teratology Study with Amitrole Technical
in Rabbits: Study No. HLA 6224-107. Unpublished study prepared by
Hazleton Laboratories America, Inc. 185 p.
40595901 Nygren, R. (1988) Amitrol T Brand Aminotriazole Herbicide: Soil Dissipation:
ProjectNo. 862R10. Unpublished study prepared by Union Carbide
Agricultural Products Co., Inc. in cooperation with Chemonics Laboratories.
107 p.
95
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Kenwood, S, (1988) Supplemental Data for Percutaneous Teratology Study
with Amitrole Technical in Rabbits: Project ID: HLA 6224-107. Unpublished
study prepared by Hazleton Laboratories America, Inc. 4 p.
Bomhard, E.; Mohr, U. (1989) Aminotriazole Carcinogenesis Study with Oral
Administration to Mice: Addendum (Historical Control Data Compilation): Lab
Project Number: 0061348. Unpublished study prepared by Bayer Ag Institute
for Toxicolpgical and Chemical Industry. 65 p. /
Bomhard, E. (1990) Aminotriazole Carcinogenesis Study with Oral
Administration to Mice: Addendum for Historical Control Data Compilation:
Lab Project Number: 8490. Unpublished study prepared by Bayer AG Jhst for
Toxicological and Chemical Industry.
Herbold, B. (1980) Amitrole Salmonella/Microsome Test for Detection of
Point-Mutagenic Effects: Lab Project Number: 9339. Unpublished study
prepared by Bayer Ag Institute of Toxicplogy-Monheim. 1.9 p.
Herbold, B. (1982) Amitrole Micronucleus Test on the Mouse to Evaluate for
Mutagenic Effect: Lab Project Number: 11139. Unpublished study prepared by
Bayer Ag Institute of Toxicology. 21 p.
*l ' '
Das, Y. (1990) Photodegradation of (Triazple(3,5)-(carbon 14)Amitfole On Soil
under Artificial Sunlight: Lab Project Number: 89170: EC-89-084.
Unpublished study prepared by Innovative Scientific Services, Inc. 100 p.
Anderson, C. (1989) Adsorption/Desorption of Amitrole in Soils: Lab Project
Number: M 131 0309-7: PF-3218. Unpublished study prepared by Bayer AG,
Institute for Metabolism. 63 p.
Cross, J. (1993) Non-Target Phytotoxicity of Amitrole in Terrestrial Use:
Growth and Reproduction of Selenastrum capricornutum: Lab Project Number:
198S01PARTA. Unpublished study prepared by EPL Bio-Analytical
Services, Inc. 82 p.
Cross, J. (1993) Non-Target Phytotoxicity of Amitrole in Terrestrial Use: Seed
Germination and 'Vegetative Vigor: Lab Project Number: 198S01 PART B.
Unpublished study prepared by EPL Bio-Analytical Services, Inc. 306 p.
Collins, M. (1993) Amitrole Technical-Acute Toxicity to Sheepshead Minnow
(Cyprinodon variegatus) Under Static Renewal Conditions: Final Report: Lab
Project Number: 93-4-4721: 12983. 1292.6102.500. Unpublished study
prepared by Springborn Labs, Inc. 62 p. -.',.,"
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bahia) under Static Conditions: Final Report: Lab Project Number: 93-4-4736:
''"" 12983.1292.6101.510. Unpublished study prepared by Springborn Labs., Inc.
63 p. ' . .
42837401 Dionne, E. (1993) Amitrole TechnicalAcute Toxicity to the Eastern Oyster
(Crassostrea virginica) under Flow-Through Conditions: Final Report: Lab
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prepared by Springborn Labs, Inc. 63 p.
42843801 Bonhoff, A. (1993) Determination of Aqueous Hydrolysis Rate Constants and
Half-Lives: (carbon 14)-Amitrole: Final Report: Lab Project Number:
93/002/1002: 1002.0293.18102.1716. Unpublished study prepared by
Springborn Labs. (Europe) AG. 45 p.
42943201 Bonhoff, A. (1993) Carbon-14 Amitrole-Determination of Aqueous Photolysis
Rate Constants and Half-Lives: Lab Project Number: 93-003-1002:
1002.0293.18102.1720. Unpublished study prepared by Springborn Labs
(Europe) AG. 50 p.
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Amitrole in a Natural Water and its Associated Sediment over a 30 Day
Incubation Period: Interim Data Summary: Lab Project Number: 382801: 9992.
Unpublished study prepared by Inveresk Research Int. 81 p.
43457801 Hall, B. (1994) The Aerobic Degradation of Radiolabelled Amitrole in Soil:
Lab Project Number: 10526: 382754. Unpublished study prepared by Inveresk
Research International. 153 p.
43570301 McGowan, C.; Mackie, J.; Hall, B. (1995) The Anaerobic Degradation of
Radiolabelled Amitrole in a Natural Water and Its Associated Sediment:
Re-issue: Lab Project Number: 10496: 382817. Unpublished study prepared
by Inveresk Research International. 120 p.
43643601 Kolb, J. (1994) Supplementary Study on Maternal Toxicity in Pregnant Rabbits
After Oral Administration: Amitrole: Lab Project Number: T4055284: 23484.
Unpublished study prepared by Bayer Ag. 104 p.
43643602 Kolb, J. (1994) Developmental Toxicity Study in Rabbits After Oral
Administration; Amitrole: Lab Project Number: 75044250: 23486.
Unpublished study prepared by Bayer AG. 287 p. .
97
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Report: Lab Project Number: 93/10/4999: 12983/0393/6106/360:
Unpublished study prepared by Springborn Labs, Inc. and Collins Agricultural
Consultants, Inc. 193 p. "
McCann, J. (1976) Biological Report of Analysis: Static Jar Test: Amitrole:
Rainbow Trout: Lab Project Number: TSD 1.206: 1052: STATIC JAR TEST
1052. Unpublished study prepared by United States E.P.A. 2 p.
McCann, J. (1977) Biological Report of Analysis: Static Jar Test: Amitrol:
Bluegill: Lab Project Number: TSD 1.206: 1060: STATIC JAR TEST 1060.
Unpublished study prepared by United States E.P. A. 2 p.
Richard, J. (1995) Two-Generation Study by Oral Route (Dietary Admixture)
in Rats: Amitrole: Lab Project Number: 9521 RSR/T 5041262. Unpublished
study prepared by Centre International de Toxicologie (C.LT.). 3386 p.
98
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
OFFICE OF
PREVENTION, PESTICIDES
AND TOXIC SUBSTANCES
; NOV 2 2 '^,
GENERIC AND PRODUCT SPECIFIC
DATA CALL-IN NOTICE
CERTIFIED MAIL
Dear Sir or Madam: ,-''.
This Notice requires you and other registrants of pesticidei products containing the
active ingredient identified in Attachment A of this Notice, the Data Call-in Chemical Status
Sheet, to submit certain data as noted herein to the U.JS. Environmental Protection Agency
(EPA, .the Agency). These data are necessary to maintain the continued registration of your
, produces) containing this active ingredient. Within 90 days after you receive this Notice you
must respond as set form in Section HI below. Your response must state:
1. How you will comply with the requirements set forth hi this Notice and its
Attachments 1 through?; or
2. Why you believe you are exempt from the requirements listed in mis Notice and
in Attachment 3 (for both generic and product specific data), the Requirements
Status and Registrant's Response Form, (see section ffl-B); or
" . , .."''''. - '" ,' -
3. Why you believe EPA should not require your submission of data in the manner
. specified by this Notice (see section ffl-D).
>t" ''." , ; . -
If you do not respond to this Notice, or if you do not satisfy EPA that you will comply
with its requirements or should be exempt or excused from doing so, then the registration of
your produces) subject to this Notice wiU be subject to suspension. We have provided a list of
all of your products subject to this Notice in Attachment 2. All products are listed on both the
generic and product specific Data Call-In Response Forms. Also included is a list of all
registrants who were sent this Notice (Attachment 5).
, ' -- _ , , . \ ,---,
The authority for this Notice is section 3(c)(2)(B) of the Federal Insecticide, Fungicide
and Rodenticide Act as amended (FIFRA), 7 U.S.C. section 136a(c)(2)(B). CoUection of this
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information is authorized under the Paperwork Reduction Act by OMB Approval No.
2070-0107 and 2070-0057 (expiration date 3-31-96).
This Notice is divided into six sections and seven Attachments. The Notice itself
contains information and instructions applicable to all Data Call-In Notices. The Attachments
contain specific chemical information and instructions. The six sections of the Notice are:
Section I
Section n
Section m
Section IV
Section V
Section VI
Why You are Receiving this Notice
Data Required by this Notice
Compliance with Requirements of this Notice
Consequences of Failure to Comply with this Notice
Registrants' Obligation to Report Possible Unreasonable Adverse Effects
Inquiries and Responses to this Notice
The Attachments to this Notice are:
1 - Data Call-in Chemical Status Sheet
2- Generic Data Call-In and Product Specific Data Call-In Response Forms with
Instructions (Form A)
3. Generic Data Call-In and Product Specific Data Call-In Requirements Status
and Registrant's Response Forms with Instructions (Form B)
4. EPA Batching of End-Use Products for Meeting Acute Toxicology Data
Requirements for Reregistration
5 - List of Registrants Receiving This Notice
6- Cost Share, Data Compensation and Confidential Statement of Formula Forms
SECTION I. WHY YOU ARE RECEIVING THIS NOTICE
The Agency has reviewed existing data for this active ingredients) and reevaluated the
data needed to support continued registration of the subject active ingredients). This
reevaluation identified additional data necessary to assess the health and safety of the continued
use of products containing this active ingredients). You have been sent this Notice because
you have produces) containing the subject active ingredients.
SECTION H. DATA BEQU1RED BY THIS NOTICE
n-A. DATA REQUIRED '
The data required by this Notice are specified in the Requirements Status and
Registrant's Response Forms: Attachment 3 (for both generic and product specific data
requiremer. ). Depending on the results of the studies required in this Notice, additional
studies/tesung may be required. -
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P-B. SCHEDULE FOR SUBMISSION OF DATA
You are required to submit the data or otherwise satisfy the data requirements specified
in the Requirements Status and Registrant's Response Forms (Attachment 3) within the
timeframes provided.
-!'' , 'fr ' . ' . , ."'' .' ' , . . v --,, , ' -" ' . ' -- : '
n-C. TESTING PROTOCOL
All studies required under this Notice must be conducted in accordance with test
standards outlined in the Pesticide Assessment Guidelines for. those studies for which
guidelines have been established.
These EPA Guidelines are available from,the National Technical Information Service
(NTIS), Attn: Order Desk, 5285 Port Royal Road, Springfield, Va 22161 (Telephone number
703-487-4650).
Protocols approved by the Organization for Economic Cooperation and Development-
(QECD) are also acceptable if the OECD recommended test standards conform to'.those-
specified in the Pesticide Data Requirements regulation (40 CFR ง 158.70). When using the
OECD protocols, they should be modified as appropriate so that the data generated by the
study will satisfy the requirements of 40 CFR ง 158. Normally, the Agency will not extend
deadlines for complying with data requirements when the studies were not conducted in
accordance with acceptable standards, The OECD protocols are available from OECD, 2001 L
Street, N.W., Washington, D.C. 20036 (Telephone number 202-785-6323; Fax telephone
number 202-785-0350). " ,
;AU new studies and proposed protocols submitted in response to this Data Call-in
Notice must be in accordance with Good Laboratory Practices [40 CFR Part 160].
D-D. REGISTRANTS RECEIVING PREVIOUS SECTION 3(c)(2)(B) NOTICES ISSUED
BY THE AGENCY ~^~~ . < ' . . ~
Unless otherwise noted herein, this Data Call-in does not in any way supersede or
change the requirements of any previous Data Call-In(s), or any other agreements entered into
with the Agency pertaining to such prior Notice. Registrants must comply with the
requirements of all Notices to avoid issuance of a Notice of Intent to Suspend their affected
products.'- . ./; ''''. , ..;. - ''.'"' ; .-.-'' ' . '....-;.. '..'.''.'
SECTION m. COMPLIANCE WITH REQUIREMENTS OF THIS NOTICE
" ' . s ' ' ' , - - s - ' ' ,_ t. _
You must use the correct forms and instructions when completing your response to this
Notice. The type of Data Call-in you must comply with (Generic or Product Specific) is
specified in item number 3 on the four Data Call-In forms (Attachments 2 and 3),
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m-A. SCHEDULE FOR RESPONDING TO THE AGENCY
The appropriate responses initially required by this Notice for generic and product
specific data must be submitted to the Agency within 90 days after your receipt of this Notice.
Failure to adequately respond to this Notice within 90 days of your receipt will be a basis for
issuing a Notice of Intent to Suspend (NOIS) affecting your products. This and other bases for
issuance of NOIS due to failure to comply with this Notice are presented in Section IV-A and
IV-B.
m-B. OPTIONS FOR RESPONDING TO THE AGENCY
1. Generic Data Requirements
The options for responding to this Notice for generic data requirements are: (a)
voluntary cancellation, (b) delete use(s), (c) claim generic data exemption, (d) agree to satisfy
the generic data requirements imposed by this Notice or (e) request a data waiver(s).
A discussion of how to respond if you choose the Voluntary Cancellation option, the
Delete Use(s) option or the Generic Data Exemption option is presented below. A discussion
of the various options available for satisfying the generic data requirements of this Notice is
contained in Section m-C. A discussion of options relating to requests for data waivers is
contained in Section DI-D.
Two forms apply to generic data requirements, one or both of which must be used in
responding to the Agency, depending upon your response. These two forms are the
Data-Call-in Response Form, and the Requirements Status and Registrant's Response Form,
(contained in Attachments 2 and 3, respectively).
The Data Call-In Response Forms must be submitted as part of every response to this
Notice. The Requirements Status and Registrant's Response Forms also must be submitted if
you do not qualify for a Generic Data Exemption or are not requesting voluntary cancellation
of your registration(s). Please note that the company's authorized representative is required to
sign the first page of both Data Call-in Response Forms and the Requirements Status and
Registrant's Response Forms (if this form is required) and initial any subsequent pages. The
forms contain separate detailed instructions on the response options. Do not alter the printed-
material. If you have questions or need assistance in preparing your response, call or write the
contact person(s) identified in Attachment 1.
a. Voluntary Cancellation -
You may avoid the requirements of this Notice by requesting voluntary cancellation of
your produces) containing the active ingredient that is the subject of this Notice. If you wish
to voluntarily cancel your product, you must submit coniskted Generic and Product Specific
Data Call-in Response Forms (Attachment 2), indicating "6ur election of this option.
Voluntary cancellation is item number 5 on both Data Ca;l-In Response Form(s), If you
choose this option, these are the only forms that you are required to complete.
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If you chose to voluntarily cancel your product, further sale and distribution of your
product after, the effective date of cancellation must be in accordance with the Existing Stocks
provisions of this Notice, which are contained in Section IV-C.
b. Use Deletion -
, You may avoid the requirements of this Notice by eliminating the uses of your product
to which the requirements apply. If you wish to amend your registration to delete uses, you
must submit the Requirements Status and Registrant's Response Form (Attachment 3),'a *
completed application for amendment, a copy of your proposed amended labeling, and all
other information required for processing the application. Use deletion is option number 7
under item 9 in the instructions for the Requirements Status and Registrant's Response'Forms.
You must also complete a Data'Call-In Response Form by signing the certification, item
number 8. Application forms for amending registrations may be obtained from the
Registration Support Branch, Registration Division, Office of Pesticide Programs EPA bv
calling (703) 308-8358. ,
If you choose to delete the use(s) subject to this Notice or uses subject to specific data
requirements, further sale, distribution, or use of your product after one year from the due
date of your 90 day response, is allowed only if the product bears an amended label.
c. Generic Data Exemption - . -
ซ. ,---.. , .
Under section 3(c)(2)(D) of FIFRA, an applicant for registration of a product is
exempt from me requirement to submit or cite generic data concerning an active ingredient if
the active ingredient in the product is derived exclusively from purchased, registered pesticide
products containing the active ingredient. EPA has concluded, as an exercise of its discretion,
that it normally will not suspend the registration of a product which would qualify and
continue to qualify for the generic data exemption in section 3(c)(2)(D) of FIFRA. To qualify,
all of the following requirements must be met:
(i). The active ingredient in your registered product must be present solely because of
incorporation of another registered -product which contains the subject active ingredient
and is purchased from a source not connected with you;
(ii). Every registrant whoisthe ultimate source of the active ingredient in your
; product subject to this DGI must be in compliance with the requirements of this Notice
arid must remain in compliance; and
' ' - ' '
(iii). You must have provided to EPA an accurate and current "Confidential Statement
of Formula" for each of your products to which this Notice applies.
To apply for the Generic Data Exemption you must submit a completed Data Call-in
Response Form, Attachment 2 and all supporting documentation. The Generic Data Exemption
is item number 6a on the Data Call-In Response Form. If you claim a generic data exemption
you are not required to complete the Requirements Status and Registrant's Response Form.
Generic Data Exemption cannot be selected as an option for responding to product specific
data requirements.
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If you are granted a Generic Data Exemption, you rely on the efforts of other persons
to provide the Agency with the required data. If ir registrants) who have committed to
generate and abmit the required data fail to take , :, r*opriate steps to meet requirements or are
no longer in compliance with this Data Call-in Nouce, the Agency will consider that both they
and you are not compliance and will normally initiate proceedings to suspend the registrations
of both your and their produces), unless you commit to submit and do submit the required
data within the specified time. In such cases the Agency generally will not grant a time
extension for submitting the data.
d. Satisfying the Generic Data Requirements of this Notice
There are various options available to satisfy the generic data requirements of this
Notice. These options are discussed in Section ffl-C.l. of this Notice and comprise options 1
through 6 of item 9 in the instructions for the Requirements Status and Registrant's Response
Form' and item 6b on the Data Call-In Response Form. If you choose item 6b (agree to satisfy
thegeneric data requirements), Y"-J must submit the Data Call-In Response Form and the
Requirements Status and Registr. .t's Response Form as well as any other information/data
pertaining to the option chosen to"address the data requirement. Your response must be on the
forms marked "GENERIC" in item number 3.
e. Request for Generic Data Waivers.
Waivers for generic data are discussed in Section ni-D.l. of this Notice and are
covered by options 8 and 9 of item 9 in the instructions for the Requirements Status and
Registrant's Response Form. If you choose one of these options, you must submit both forms
as well as any other information/data pertaining to the option chosen to address the data
requirement.
2. Product Specific Data Requirements
The options for responding to this Notice for product specific data are: (a) voluntary
cancellation, (b) agree to satisfy the product specific data requirements imposed by this Notice
or (c) request a data waiver(s).
A discussion of how to respond if you choose the Voluntary Cancellation option is
presented below. A discussion of the various options available for satisfying the product
specific data requirements of this Notice is contained in Section ffl-C.2. A discussion of
options relating to requests for data waivers is contained in Section ffl-D.2.
Two forms apply to the product specific data requirements one or both of which must
be used in responding to the Agency, depending upon your response. These forms are the
Data-Call-in Response Form, and the Requirements Status and Registrant's Response Form,
for product specific data (contained in Attachments 2 and 3, respectively). The Data Call-in
Response Perm must be submitted as part of every response to this Notice. In addition, one
CODV of the Requirements Status and Registrant's Response Form also must be submitted for -
each product listed on the Data Call-In Response Form unless the voluntary cancellation option
is selected. Please note that the company's authorized representative is required to sign the
first page of the Data Call-In Response Form and Requirements Status and Registrant's
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Response Form (if this form is required) and initial any subsequent pages. The forms contain
separate detailed instructions on the response options. Do not.alter the printed material. If you
have questions or need assistance in preparing your response, call or write the contact
person(s) identified in Attachment 1.
a. Voluntary Cancellation
You may avoid the requirements of this Notice by requesting Voluntary cancellation of
your product(s) containing the active,ingredient that is the subject of this Notice. If you wish
to voluntarily cancel your product, you must submit a completed Data Call-In Response Form.
indicating your election of this option. Voluntary cancellation is item number 5 on both the
Generic and Product Specific Data Call-In Response Forms. If you choose this
option, you must complete both Data Call-In response forms. These are the only forms that
you are required to complete. ~
If you choose to voluntarily cancel your product, further sale and distribution of your
product after the effective date of cancellation must be in accordance with the Existing Stocks
provisions of this Notice which are contained in Section IV-C.
b. Satisfying the Product Specific Data Requirements of this Notice.
There are various options available to satisfy the product specific data requirements of
this Notice. These options are discussed in Section DI-C.2. of this Notice and comprise
options 1 through 6 of item 9 in the instructions for the product specific Requirements Status
and Registrant's Response Form and item numbers 7a and 7b (agree to satisfy the product
specific data requirements for anMUP or EUP as applicable) on the product specific Data
Call-in Response Form. Note that the options available for addressing product specific~data
requirements differ slightly from those options for fulfilling generic data requirements.
Deletion of a use(s) and the low volume/minor use option are not valid options for fulfilling
product specific data requirements. It is important to ensure that you are using the correct
forms and instructions when completing your response to the Reregistration Eligibility
Decision document.
" '' ' '' " ' !'' ..'/-.-". ,.: . ;
e. Request for Product Specific Data Waivers.
Waivers for product specific data are discussed in Section m-D.2. of this Notice and
are covered by option 7 of item 9 in the instructions for the Requirements Status and
Registrant's Response Form. If you choose this option, 'you. inust submit the Data Call-in
Response Form and the Requirements Status and Registrant's Response Form as well as any
other information/data pertaining to the option chosen to address the data requirement. Your
response must be on the forms marked "PRODUCT SPECIFIC" in item number 3.
m-C SATISFYING THE DATA REQUIREMENTS OF THIS NOTICE
1. Generic Data
If you acknowledge on the Generic Data Call-in Response Form that you agree to
satisfy the generic data requirements (i.e. you select item number 6b), then you must select
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one of the six options on the Generic Requirements Status and Registrant's Response Form
related to data production for each data requirement. Your option selection should be entered
under item number 9, "Registrant Response." The rix options related to data production are
the first six options discussed under item 9 in the iniiructions for completing the Requirements
Status and Registrant's Response Form. These six options are listed immediately below with
information in parentheses to guide you to additional instructions provided in this Section. The
options are:
(1) I will generate and submit data within the specified timeframe (Developing
Data)
(2) I have entered into an agreement with one or more registrants to develop data
jointly (Cost Sharing)
(3) I have made offers to cost-share (Offers to Cost Share)
(4) I am submitting an existing study that has not been submitted previously to the
Agency by anyone (Submitting an Existing Study)
(5) I am submitting or citing data to upgrade a study classified by EPA as partially
acceptable and upgradeable (Upgrading a Study)
"(6) I am citing an existing study that EPA has classified as acceptable or an existing
study that has been submitted but not reviewed by the Agency (Citing an
Existing Study)
Option 1. Developing Data
If you choose to develop the required data it must be in conformance with Agency
deadlines and with other Agency requirements as referenced herein and in the attachments. All
data generated and submitted must comply with the Good Laboratory Practice (GLP) rule (40
CFR Part 160), be conducted according to the Pesticide Assessment Guidelines (PAG) and be
in conformance with the requirements of PR Notice 86-5. In addition, certain studies require
Agency approval of test protocols in advance of study initiation. Those studies for which a
protocol must be submitted have been identified in the Requirements Status and Registrant's
Response Form and/or footnotes to the form. If you wish to use a protocol which differs from
the options discussed in Section H-C of this Notice, you must submit a detailed description of
the proposed protocol and your reason for wishing to use it. The Agency may choose to reject
a protocol not specified in Section n-C. If the Agency rejects your protocol you will be
notified in writing, however, you should be aware that rejection of a proposed protocol will
not be a basis for extending the deadline for submission of data.
A progress report must be submitted for each study within 90 days from the date you
are required to commit to generate or undertake some other means to address that study
requirement, such as making an offer to cost share or agreeing to share in the cost of
developing that study. This 90-day progress report must include the date the study was or will
be initiated and, for studies to be started within 12 months of commitment, the name and
address of the laboratories) or individuals who are or will be conducting the study.
In addition, if the time frame for submission of a final report is more than 1 year,
interim reports must be submitted at 12 month intervals from the date you are required to
commit to generate or otherwise address the requirement for the study. In addition to the other
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information specified^! the preceding paragraph, at a minimum/a brief description of current
activity on and the status of the study must be included as well as a full
description of any problems encountered since the last progress report.
The time frames in the Requirements Status and Registrant's Response Form are the
time frames that the Agency is allowing,for the submission of completed study reports or
protocols. The noted deadlines run from the date of the receipt of this Notice by the registrant.
If the data are not'submitted by the deadline, each registrant is subject to receipt of a Notice of
Intent to Suspend the affected registration(s).
If you cannot submit the data/reports to the Agency in the time required by this Notice
and intend to seek additional time to meet the requirements^), you must submit a request to
the Agency which includes: (1) a detailed description of the expected difficulty and (2) a
proposed schedule including alternative dates for meeting such requirements on a step-by-step
basis. You must explain any technical or laboratory difficulties and provide documentation
from the laboratory performing the testing. While EPA is considering your request, the
original deadline remains. The Agency will respond to your request in writing. If EPA does
not grant your request, the original deadline remains. Normally, extensions can be requested
only in cases of extraordinary testing problems beyond the expectation or control of the
registrant. Extensions will not be given in submitting the 90-day responses. Extensions will
not be considered if the request for extension is not made in a timely fashion; in no event shall
an extension request be considered if it is submitted at or after the lapse of the subject
deadline.
Option 2. Agreement to Share in Cost to Develop Data
If you choose to enter into an agreement to share in the cost of producing the required
data but will not be submitting the data yourself, you must provide the name of the registrant
who will be submitting the data. You must also provide EPA with documentary evidence that
an agreement has been formed. Such evidence may be your letter offering to join in an
agreement and the other registrant's acceptance of your offer, or a written statement by the
parties that an agreement exists. The agreement to produce the data need not specify all of the
terms of the final arrangement between the parties or the mechanism to resolve the terms.
Section 3(c)(2)(B) provides that if the parties cannot resolve the terms of the agreement they
may resolve their differences through binding arbitration.
Option 3. Offer to Share in the Cost of Data Development
If you have made an offer to pay in an attempt to enter into an agreement or amend an
existing agreement to meet the requirements of this Notice and have been unsuccessful, you
may request EPA (by selecting this option) to exercise its discretion not to suspend your
registration(s), although you do not comply with the data submission requirements of this
Notice. EPA has determined that as a general policy, absent other relevant considerations, it
will not suspend the registration of a product of a registrant who has in good faith sought and
continues to seek to enter into a joint data development/cost sharing program, but the other
registrants) developing the data has refused to accept the offer. To qualify for this option, you
must submit documentation to the Agency proving that you have made an offer to another
registrant (who has an obligation to submit data) to share in the burden of developing that
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data. You must also submit to the Agency a completed EPA Form 8570-32, Certification of
Offsr to Cost Share in the Development of Data, Attachment 7. In addition, you must
de~ -nstrate that i?*e. other egistrant to whom the offer was made has not accepted your offer
to ir into a cost-sharing agreement by including a copy of your offer and proof of the other
re^ rurant's receipt of that offer (such as a certified mail receipt). Your offer must, in addition
to anything else, offer to share in the burden of producing the data upon terms to be agreed to
or, failing agreement, to be bound by binding arbitration as provided by FIFRA section
3(c)(2)(B)0ii) and must not qualify this offer. The other registrant must also inform EPA of its
election of an option to develop and submit the data required by this Notice by submitting a
Data Call-in Response Form and a Requirements Status and Registrant's Response Form
committing to develop and submit the data required by this Notice.
In order for you to avoid suspension under this option, you may not withdraw your
offer to share in the burden of developing the data. In addition, the other registrant must fulfill
its commitment to develop and submit the data as required by this Notice. If the other
registrant fails to develop the data or for some other reason is subject to suspension, your
registration as well as that of the other registrant normally will be subject to initiation of
suspension proceedings, unless you commit to submit, and do submit, the required data in the
specified time frame. In such cases, the Agency generally will not grant a time extension for
submitting the data.
Option 4. Submitting an Existing Study
If you choose to submit an existing study in response to this Notice, you must
determine that the study satisfies the requirements imposed by this Notice. You may only
submit a study that has not been previously submitted to the Agency or previously cited by
anyone. Existing studies are studies which predate issuance of this Notice. Do not use this
option if you are submitting data to upgrade a study. (See Option 5).
You should be aware that if the Agency determines that the study is not acceptable, the
Agency will require you to comply with this Notice, normally without an extension of the
required date of submission. The Agency may determine at any time that a study is not valid
and needs to be repeated.
To meet the requirements of the DCI Notice for submitting an existing study, all of the
following three criteria must be clearly Met: ,
a. You must certify at the time that the existing study is submitted that the raw
data and specimens from the study are available for audit and review and you
must identify where they are available. This must be done in accordance with
the requirements of the Good Laboratory Practice (GLP) regulation, 40 CFR
Part 160. As stated in 40 CFR 160.3 'Raw data1 means any laboratory
worksheets, records, memoranda, notes, or exact copies thereof, that are the
result of original observations and activities of a study and are necessary for the
reconstruction and evaluation of the report of that study. In the event that exact
transcripts of raw data have been prepared (e.g., tapes which have been
transcribed verbatim, dated, and verified accurate by signature), the exact^copy
or exact transcript may be substituted for the original source as raw data. 'Raw
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c.
data' may include photographs, microfilm or microfiche copies, computer
printouts, magnetic media, including dictated observations, and recorded data
from automated instruments." The term "specimens", according to 40 CFR
160.3, means "any material derived from a test system for examination or
analysis." ,.
Health and safety studies completed after May 1984 also must also contain all
GLP-required quality assurance and quality control information, pursuant to the
requirements of 40 CFR Part 160. Registrants also must certify at the time of
submitting the existing study that such GLP information is available for post
May 1984 studies by including an appropriate statement on or attached to the
study signed by an authorized official or representative of the registrant.
You must certify that each study fulfills the acceptance criteria for the Guideline
relevant to the study provided in the FIFRA Accelerated Reregistration Phase 3
Technical Guidance and that the study has been conducted according to the
Pesticide Assessment Guidelines (PAG) or meets the purpose of the PAG (both
available from NTIS). A study not conducted according to the PAG may be
submitted to the Agency for consideration if the registrant believes that the
study clearly meets the purpose of the PAG. The registrant is referred to 40
CFR 158.70 which states the Agency's policy regarding acceptable protocols. If
you wish to submit the study, you must, in addition to certifying that the
purposes of the PAG are met by the study, clearly articulate the rationale why
you believe the study meets the purpose of the PAG, including copies of any
supporting information or data. It has been the Agency's experience that studies
completed prior to January 1970 rarely satisfied the purpose of the PAG and
that necessary raw data usually are not available for such studies.
If you submit an existing study, you must certify that the study meets all requirements
of the criteria outlined above.
If EPA has previously reviewed a protocol for a study you are submitting, you must
identify any action taken by the Agency on the protocol and must indicate, as part of your
certification, the manner in which all Agency comments, concerns, or issues were addressed
in the final protocol and study.
If you know of a study pertaining to any requirement in this Notice which does not
meet the criteria outlined above but does contain factual information regarding unreasonable
adverse effects, you must notify, the Agency of such a study. If such study is in the Agency's
files, you need only cite it along with the notification.If not in the Agency's files, youmust
submit a summary and copies as required by PR Notice 86-5.
Option 5. Upgrading a Study ;
If a study has been classified as partially acceptable and upgradeable, you may submit
data to upgrade that study. The Agency will review the data submitted and determine if the
requirement is satisfied. If the Agency decides the requirement is not satisfied, you may still
be required to submit new data normally without any time extension. Deficient, but
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upgradeable studies will normally be classified as supplemental. However, it is important to
note that not ail studies classified as supplemental are upgradeable. If you have questions
regarding the clas fication of a study or whether a study may be upgraded, call or write the
contact person lisa J in Attachment 1. If you submit data to upgrade an existing study you
must satisfy or supply information to correct all deficiencies in the study identified by EPA.
You must provide a clearly articulated rationale of how the deficiencies have been remedied or
corrected and why the study should be rated as acceptable to EPA. Your submission must also .
specify the MRID number(s) of the study which you are attempting to upgrade and must be in
conformance with PR Notice 86-5. .
Do not submit additional data for the purpose of upgrading a study classified as
unacceptable and determined by the Agency as not capable of being upgraded.
This option also should be used to cite data that has been previously submitted to
upgrade a study, but has not yet been reviewed by the Agency. You must provide the MRID
number of the data submission as well as the MRID number of the study being upgraded.
The criteria for submitting an existing study, as specified in Option 4 above, apply to
all data submissions intended to upgrade studies. Additionally, your submission of data
intended to upgrade studies must be accompanied by a certification that you comply with each
of those criteria,- as well as a certification regarding protocol compliance with Agency
requirements.
Option 6. Citing Existing Studies '
If you choose to cite a study that has been previously submitted to EPA, that study
must have been previously classified by EPA as acceptable, or it must be a study which has
not yet been reviewed by the Agency. Acceptable toxicology studies generally will have been
classified as "core-guideline" or "core-minimum." For ecological effects studies, the
classification generally would be a rating of "core." For all other disciplines the classification
would be "acceptable." With respect to any studies for which you wish to select this option,
you must provide the MRID number of the study you are citing and, if the study has been
reviewed by the Agency, you must provide the Agency's classification of the study.
If you are citing a study of which you are not the original data submitter, you must
submit a completed copy of EPA Form 8570-31, O -i .iication with Respect to Data
Compensation Requirements.
2. Product Specific Data
if you acknowledge on the product specific Data Call-in Response Form that you agree
to satisfy the product specific data requirements (i.e. you select option 7a or 7b), then you
must select one of the six options on the Requirements Status and Registrant's Response Form
related to data production for each data requirement. Your option selection should be entered
under item number 9, "Registrant Response." The six options related to data production are
the first six options discussed under item 9 in the instructions for completing the Requirements
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Status and Registrant's Response Form. These six options are listed immediately below with
information in parentheses to guide registrants to additional instructions provided in this
Section. The options are:
> (1) I will generate and submit data within the specified time-frame (Developing
,.'-. Data) ' ":- : ; _ .,.' ; - ;, ,.. , _ ; - -....- -._--.
(2) I have entered into an agreement with one or. more registrants to develop data
Jointly (Cost Sharing)
(3) I have made offers to cost-share (Offers ,to Cost Share)
(4) I am submitting an existing study that has not been submitted previously to the
, Agency by anyone (Submitting an Existing Study)
(5) I am submitting or citing data to upgrade a study classified by EPA as partially
acceptable and upgradeable (Upgrading a Study)
(6) I am citing an existing study that EPA has classified as acceptable or an existing
study that has been
submitted but not reviewed by the Agency (Citing an Existing Study)
Option 1. Developing Data - The requirements for developing product specific data are the
same as those described for generic data (see Section ffl.C.1, Option 1) except that normally
^protocols or progress reports are required.
Option 2. Agree to Share in Cost to Develop Data - If you enter into an agreement to cost
share, the same requirements apply to product specific data as to generic data (see Section
m.C.l, Option 2). However, registrants may only choose this option for acute toxicity data
and certain efficacy data and only if EPA has indicated in the attached data tables that your
product and at least one other product are similar for purposes of depending on
the same data. If this is the case, data may be generated for just one of the products in the
group. The registration number of the product for which data will be submitted must be noted
in me agreement to cost share by me registrant selecting this option.
Option 3. Offer to Share in the Cost of Data Development -The same requirements for
generic data (Section m.C.l., 'Option .3) apply to this option. This option only applies to acute
toxicity and certain efficacy data as described in option 2 above.
Option 4. Submitting an Existing Study - The same requirements described for generic data
(see Section m.C.l., Option 4) apply to this option for product specific data.
Option 5, Upgrading a Study - The same requirements described for generic data (see Section
m.C.l., Option 5),apply to this option for product specific data.
Option 6. Citing Existing Studies ~ The same requirements described for generic data (see
Section m.C.l., Option 6) apply to this option for product specific data.
Registrants who select one of the above 6 options must meet all of the requirements
described in the instructions for completing the Data Call-In Response Form and the
Requirements Status and Registrant's Response Form, and in the generic data requirements
section (m.C.l.)j"as appropriate.
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m-D REQUESTS FOR DATA WAIVERS
1. Generic Data
There are two types of data waiver responses to this Notice. The first is a request for a
low volume/minor use waiver and the second is a waiver request based on your belief that the
data requirements) are not appropriate for your product.
a. Low Volume/Minor Use Waiver ,
Option 8 under item 9 on the Requirements Status and Registrant's Response
Form. Section 3(c)(2)(A) of FIFRA requires EPA to consider the appropriateness of
requlnng data for low volume, minor use pesticides. In implementing this provision,
EPA considers low volume pesticides to be only those active ingredients whose total
production volume for aU pesticide registrants is small. In determining whether to grant a low
volume, minor use waiver, the Agency will consider the extent, pattern and volume of use, the
economic incentive to conduct the testing, the importance of the pesticide, and the exposure
and risk from use of the pesticide. If an active ingredient is used for both high volume and low
volume uses, a low volume exemption will not be approved. If all uses of an active ingredient
are low volume and the'combined volumes for all uses are also low, then an exemption may be
granted, depending on review of other information outlined below. An exemption will not be
granted if any registrant of the active ingredient elects to conduct the testing. Any registrant
receiving a low volume minor use waiver must remain within the sales figures in their forecast
si-nooning the waiver request in order to remain qualified for such waiver. If granted a
wii ver, a registrant will be required, as a condition of the waiver, to submit annual sales
reports. The Agency will respond to requests for waivers in writing.
To apply for a low volume, minor use waiver, you must submit the following
information, as applicable to your produces), as part of your 90-day response to this
Notice:
01). Total company sales (pounds and dollars) of all registered product(s)
containing the active ingredient. If applicable to the active ingredient, include foreign
sales for those products that are not registered in this country but are applied to sugar
(cane or beet), coffee, bananas, cocoa, and other such crops. Present the above
information by year for each of the past five years. ,
(ii) Provide an estimate of the sales (pounds and dollars) of the active
ingredient for each major use site. Present the above information by year for each of
the past five years. ,
(iii) Total direct production cost of produces) containing the active ingredient
by year for the past five years. Include information on raw material cost, direct labor
cost, advertising, sales and marketing, and any other significant costs listed separately.
(iv) Total indirect production cost (e.g. plant overhead, amortized plant and
equipment) charged to product(s) containing the active ingredient by year for the past
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five years. Exclude all non-recurring costs that were directly related to the active
ingredient, such as costs of initial registration and any data development.
(v) A list of each data requirement for which you seek a waiver. Indicate the
type of waiyer sought and the estimated cost to you (listed separately for each data
requirement and associated test) of conducting the testing needed to fulfill each of these
data requirements.
V''".'"1 .'..'..'.''' ^' .-'-.-,'"/'Ji .-.' ' /'. -
(vi) A list of each data requirement for which you are not seeking any waiver
and the estimated cost to you (listed separately for each data requirement and associated
test) of conducting the testing needed to fulfill each of these data requirements
(vii) For each of the next ten years, a year-by-year forecast of company sales
(pounds and dollars) of the active ingredient, direct production costs of produces)
containing the active ingredient (following the parameters in item 2 above), indirect
production costs of produces) containing the active ingredient (following the
parameters in item 3 above), and costs of data development pertaining to the active
ingredient. '-,.,'
(viii) A description of the importance and unique benefits of the active
ingredient to users. Discuss the use patterns and the effectiveness of the active
ingredient relative to registered alternative chemicals and non-chemical control
strategies. Focus on benefits unique to the active ingredient, providing information that
is as quantitative as possible. If you do not have quantitative data upon which to base
your estimates, then present the reasoning used to derive your estimates. To assist the
Agency in determining the degree of importance of the active ingredient in terms of its
benefits, you should provide information on any of the following factors, as applicable
to your product(s): "(a) documentation of the usefulness of the active ingredient in
Integrated Pest Management, (b) description of the beneficial impacts on the
environment of use of the active ingredient, as opposed to its registered alternatives,
(c) information on the breakdown of the active ingredient after use and on its
persistence in the environment, and (d) description of its usefulness against a pest(s) of
pubUc health significance.
i ,-',.. ' -
Failure to submit sufficient information for the Agency to make a determination
regarding a request fora low volume/minor use waiver will result in denial of the
request for a waiver.
''.'', . . .''.''.. i -
b. Request for Waiver of Data
Option 9, under Item 9, on the Requirements Status and Registrant's Response
Form. This option may be used if you believe that a particular data requirement should
not apply because the requirement is inappropriate. You must submit a rationale
explaining why you believe the data requirements should not apply. You also must
submit the current label(s) of your produces) and, if a current copy of your
Confidential Statement of Formula is not already on file you must submit a current
copy. ' . '.-. . . ' ..,. '- ; . ' -''....>'".'"'-.:
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' You will be informed of the Agency's decision in writing. If the Agency
determines that the data requirements of this Notice are not appropriate to your
produces), you will not be required to supply the data pursuant to section 3(c)(2)(B). If
EPA determines that the data are required for your produces), you must choose a
method of meeting the requirements of this Notice within the time frame provided by
this Notice. Within 30 days of your receipt of the Agency's written decision, you must
submit a revised Requirements Status and Registrant's Response Form indicating the
option chosen.
2. Product Specific Data . .
If you request a waiver for product specific data because you believe it is
inappropriate, you must attach a complete justification for the request including
technical reasons, data and references to relevant EPA regulations, guidelines or
policies. (Note: any supplemental data must be submitted in the format required by PR
Notice 86-5). This will be the only opportunity to state the reasons or provide
information in support of your request. If the Agency approves your waiver request,
you will not be required to supply the data pursuant to section 3(c)(2)(B) of FIFRA. If
the Agency denies your waiver request, you must choose an option for meeting the data
requirements of this Notice within 30 days of the receipt of the Agency's decision^
You must indicate and submit the option chosen on the product specific Requirements
Status and Registrant's Response Form. Product specific data requirements for product
chemistry, acute toxicity and efficacy (where appropriate) are required for all products
and the Agency would grant a waiver only under extraordinary circumstances. You
should also be aware that submitting a waiver request will not automatically extend the
due date for the study in question. Waiver requests submitted without adequate
supporting rationale will be denied and the original due date will remain in force.
SECTION IV.
CONSEQUENCES OF FAILURE TO COMPLY WITH THIS
NOTICE " ~
IV-A NOTICE OF INTENT TO SUSPEND
The Agency may issue a Notice of Intent to Suspend products subject to this Notice due
to failure by a registrant to comply with the requirements of this Data Call-In Notice, pursuant
to FIFRA section 3(c)(2)(B). Events which may be the basis for issuance of a Notice of Intent
to Suspend include, but are not limited to, the following:
1. Failure to respond as required by this Notice within 90 days of your receipt of
this Notice.
2. Failure to submit on the required schedule an acceptable proposed or final
protocol when such is required to be submitted to the Agency for review.
3. Failure to submit on the required schedule an adequate progress report on a
study as required by this Notice.
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4.
5.
6.
7.
8.
9.
Failure to submit on the required schedule acceptable data as required by this
; Notice.
/ ' . '''",..- . , /
Failure to take a required action or submit adequate information pertaining to
any option chosen to address the data requirements (e.g., any required action or
information pertaining to submission or citation of existing studies or offers,
arrangements, or arbitration on the sharing of costs or the formation of Task
Forces, failure to comply with the terms of an agreement or arbitration
concerning joint data development or failure to comply with any terms of a data
waiver).
Failure to submit supportable certifications as to the conditibns of submitted
studies, as required by Section in-C of this Notice,
Withdrawal of an offer to share in the cost of developing required data.
Failure of the registrant to whom you have tendered an offer to share in the cost
of developing data and provided proof of the registrant's receipt of such offer
or failure of a registrant on whom you rely for a generic data exemption either
to: .. ' ; '* .''.
i. Inform EPA of intent to develop and submit the data required by this Notice
on a Data Call-in Response Form and a Requirements Status and,Registrant's
Response Form. ~~ ~~~~ ~ -.-'.--
ii. Fulfill the commitment to develop and submit the data as required by this
Notice; or
iii. Otherwise take appropriate steps to meet the requirements stated in this
Notice,
unless you commit to submit and do submit the required data in the specified
time frame.
Failure to take any required or appropriate steps, not mentioned above, at any
time following the issuance of this Notice.
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IV-B. BASIS FOR DETERMINATION THAT SUBMITTED STUDY IS
UNACCEPTABLE .
The Agency may determine that a study (even if submitted within the required time) is
unacceptable and constitutes a basis for issuance of a Notice of Intent to Suspend^ The grounds
for suspension include, but are not limited to, failure to meet any of the following:
; 1) EPA requirements specified in the Data Call-in Notice or other documents
incorporated by reference (including, as applicable, EPA Pesticide Assessment
Guidelines, Data Reporting Guidelines, and GeneTox Health Effects Test Guidelines)
regarding the design, conduct, and reporting of required studies. Such requirements
include, but are not limited to, those relating to test material, test procedures, selection
of species, number of animals, sex and distribution of animals, dose and effect levels to
be tested or attained, duration of test, and, as applicable, Good Laboratory Practices.
2) EPA requirements regarding the submission of protocols, including the
incorporation of any changes required by the Agency folio wing review.
3) EPA requirements regarding the reporting of data, including the manner of
reporting, the completeness of results, and the adequacy of any required supporting (or
raw) data, including, but not limited to, requirements referenced or included in this
Notice or contained in PR 86-5. All studies must be submitted in the form of a final
report; a preliminary report will not be considered to fulfill the submission
requirement.
IV-C EXISTING STOCKS OF SUSPENDED OR CANCELLED PRODUCTS
EPA has statutory authority to permit continued sale, distribution and use of existing
stocks of a pesticide product which has been suspended or cancelled if doing so would be
consistent with the purposes of the Act.
The Agency has determined that such disposition by registrants of existing stocks for a
suspended registration when a section 3(c)(2)(B) data request is outstanding generally would
not be consistent with the Act's purposes. Accordingly, the Agency anticipates granting
registrants permission to sell, distribute, or use existing stocks of suspended produces) only in
exceptional circumstances. If you believe such disposition of existing stocks of your produces)
which may be suspended for failure to comply with this Notice should be permitted, you have
the burden of clearly demonstrating to EPA that granting such permission would be consistent
with the Act. You also must explain why an "existing stocks" provision is necessary, including
a statement of the quantity of existing stocks and your estimate of the time required for their
sale, distribution, and use. Unless you meet this burden, the Agency will not consider any
request pertaining to the continued sale, distribution, or use of your existing stocks after
suspension.
If you request a voluntary cancellation of your produces) as a response to this Notice
and your product is in full compliance with all Agency requirements, you will have, under
most circumstances, one year from the date your 90 day response to this Notice is due, to sell,
distribute, or use existing stocks. Normally, the Agency will allow persons, other than the
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registrant such as independent distributors, retailers and end users to sell, distribute or use >
such existing stocks until the stocks are exhausted. Any sale, distribution or use of stocks of
voluntarily cancelled products containing an active ingredient for which the Agency has
particular risk concerns will be determined on a case-by-case basis.
Requests for voluntary cancellation received after the 90 day response period required
by this Notice will not result in the agency granting any additional time to sell, distribute, or
use existing stocks beyond a year from the date the 90 day response was due, unless you
demonstrate to the Agency that you are in full compliance with all Agency requirements,
including the requirements of this Notice. For example, if you decide to voluntarily cancel
your registration six months before a 3-year study is scheduled to be submitted, all progress
reports and other information necessary to establish that you have been conducting the study in
an acceptable and good faith manner must have been submitted to the Agency, before EPA
will consider granting an existing stocks provision. '
SECTION V.
REGISTRANTS' OBLIGATION TO REPORT POSSIBLE
UNREASONABLE ADVERSE EFFECTS
Registrants are reminded that FBFRA section 6(a)(2) states that if at any time after a
pesticide is registered a registrant has additional factual information regarding unreasonable
adverse effects on the environment by the pesticide, the registrant shall submit the information
to the Agency. Registrants must notify the Agency of any factual information they have, from
whatever source, including but not limited to interim or preliminary results of studies,
regarding unreasonable adverse effects on man or the environment. This requirement
continues as long as the products are registered by the Agency.
SECTION VI.
INQUIRIES AND RESPONSES TO THIS NOTICE
If you have any questions regarding the requirements and procedures established by
this Notice, call the contact person(s) listed in Attachment 1, the Data Call-in Chemical Status
Sheet. ~ ~ ~
All responses to this Notice must include completed Data Call-in Response Forms
(Attachment 2)and completed Requirements Status and Registrant's Response Forms
(Attachment 3), for both (generic and product specific data) and any other documents required
by this Notice, and should be submitted to the contact person(s) identified in Attachment 1. If
the voluntary cancellation or generic data exemption option is chosen, only the Generic and
Product Specific Data Call-In Response Forms need be submitted.
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The Office of Compliance (OC) of the Office of Enforcement and Compliance
Assurance (OECA), EPA, will be monitoring the data being generated in response to this
Notice.
Sincerely yours,
(7)014,
Lois A. Rossi, Director
Special Review and
Reregistration Division
Attachments
The Attachments to this Notice are:
1- Data Call-In Chemical Status Sheet
2- Generic Data Call-In and Product Specific Data Call-in Response Forms with
Instructions
3- Generic Data Call-in and Product Specific Data Call-in Requirements Status
and Registrant's Response Forms with Instructions
4- EPA Batching of End-Use Products for Meeting Acute Toxicology Data
Requirements for Reregistration
5- List of Registrants Receiving This Notice
6 - Confidential Statement of Formula, Cost Share and Data Compensation Forms
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AMTTROLE DATA CALL-IN CHEMICAL STATUS SHEET
INTRODUCTION V
You have been sent this Product Specific Data Call-in Notice because you have product(s)
containing amitrole.
This Product Specific Data Call-in Chemical Status Sheet contains an overview nf^ta
required by this notice, and point of contact for inquiries pertaining to the reregistration of
amitrole. This attachment is to be used in conjunction with (1) the Product Specific Data Call-Li
Notice, (2) the Product Specific Data Call-In Response Form .(Attachment 2), (3) the
Requirements Status and Registrant's Form (Attachment 3), (4) EPA's Grouping of 'End-Use
Products for Meeting Acute Toxicology Data Requirement (Attachment 4), (5) a list of registrants
receiving this DCI (Attachment 5) and (6) the Cost Share and Data Compensation Forms in
replying to this Amitrole Product Specific Data Call-in (Attachment 6). Instructions and
guidance accompany each form.
DATA REQUIRED BY THIS NOTICE
The additional data requirements needed to complete the database for amitrole are
contained in the Requirements Status and Registrant's Response. Attachment 3 . The Agency has
concluded that additional data on amitrble are heeded for specific products. These data are
required to be submitted to the Agency within the time frame listed. These data are needed to
fully complete the reregistration of all eligible amitrole products.
INQUIRIES AND RESPONSES TO THIS NOTICE
If you have any questions regarding this product specific data requirements and
procedures established by this Notice, please contact Nancy Tompkins at (703) 308-8 172.
' "
. -
All responses
submitted to:
'."'' " "* i L ' " ' - '
to this Notice for the product specific data requirements should be
Nat?.cy Tompkins
CliemicalReview Manager Team 81
Pro4ua Reregistration Branch
Special Review and Reregistration Branch 7508W
Office of Pesticide Programs
U.S. Environmental Protection Agency
Washington, D.C. 20460
RE: AMITROLE
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AMTTROLE DATA CALL-IN CHEMICAL STATUS SHEET
INTRODUCTION
You have been sent this Generic Data Call-In Notice because you have product(s)
containing amitrole. ,
This Generic Data Call-In Chemical Status Sheet contains an overview of data required
by this notice, and point of contact for inquiries pertaining to the reregistration of amitrole. This
attachment is to be used in conjunction with (1) the Generic Data Call-In Notice, (2) the Generic
Data Call-in Response Form (Attachment 2), (3) the Requirements Status and Registrant's Form
(Attachment 2), (4) a list of registrants receiving this DCI (Attachment 5), and (5) the Cost Share
and Data Compensation Forms in replying to this Amitrole Generic Data Call In (Attachment 6).
Instructions and guidance accompany each form.
DATA REQUIRED BY THIS NOTICE
The additional data requirements needed to complete the generic database for amitrole are
contained in the Requirements Status and Registrant's Response. Attachment 3. The Agency has
concluded that additional product chemistry data on amitrole are needed. These data are needed
to fully complete the reregistration of all eligible amitrole products.
INQUIRIES AND RESPONSES TO TfflS NOTICE -
If you have any questions regarding the generic data requirements and procedures
established by this Notice, please contact Mario F. Fiol at (703) 308-8049.
All responses to this Notice for the generic data requirements should be submitted to:
Mario F. Fiol, Chemical Review Manager
Reregistration Branch
Special Review and Registration Division (H7508W)
Office of Pesticide Programs
U.S. Environmental Protection Agency
Washington, D.C. 20460
RE: AMITROLE
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INSTRUCTIONS FOR COMPLETING THE "DATA CALL-IN RESPONSE FORMS"
FOR THE GENERIC AND PRODUCT SPECIFIC DATA CALL-IN
INTRODUCTION
These instructions apply to the Generic and Product Specific "Data Call-In Response
Forms" and are to be used by registrants to respond to generic and product specific Data Call-ins
as part of EPA's Reregistration Program under the Federal Insecticide, Fungicide, and
Rodenticide Act. If you are an end-use product registrant only and have been sent this DCI letter
as part of a RED document you have been sent just the product specific "Data Call-In Response
Forms." Only registrants .responsible for generic data have been sent the generic data response
form. The type of Data Call-In (generic or product specific) is indicated in item number 3
("Date and Type of DCI") on each form. '-.'"<
Although the form is me same for both generic and product specific data, instructions for
completing these forms are different. Please read these instructions carefully before filling out
the forms. , ,
EPA has developed these forms individually for each registrant, and has preprinted these
forms with a number of items. DO NOT use these forms for any other active ingredient.
Items 1 through 4 have been preprinted on the form. Items'5 through 7 must be completed
by the registrant as appropriate. Items 8 through 11 must be completed by the registrant before
submitting a response to the Agency.
The public reporting burden for this collection of information is estimated to average 15
minutes per response, including time for reviewing instructions, searching existing data sources,
gathering and maintaining the data needed, and completing and reviewing the collection of
information. Send comments regarding the burden estimate or any other aspect of this collection
of information, including suggestions for reducing mis burden, to Chief, Information Policy
Branch, Mail Code 2136, U.S. Environmental Protection Agency, 401 M St., S.W., Washington,
D.C. 20460; and to the Office of Management and Budget, Paperwork Reduction Project
2070-0107, Washington, D.C. 20503.
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INSTRUCTIONS FOR COMPLETING THE DATA CALL-IN RESPONSE FORMS
Generic and Product Specific Data Call-In
Item 1. ON BOTH FORMS: This item identifies your company name, number and
address. .
Item 2. ON BOTH FORMS: This item identifies the case number, case name, EPA
chemical number and chemical name. . ,
Item 3. ON BOTH FORMS: This item identifies the type of Data Call-In. The date of
issuance is date stamped.
Item 4. ON BOTH FORMS: This item identifies the EPA product registrations relevant
to the data call-in. Please note that you are also responsible for informing the
Agency of your response regarding any product that you believe may be covered
by this Data Call-in but that is not listed by the Agency in Item 4. You must bring
any such apparent omission to the Agency's attention within the period required
for submission of this response form.
-,'
Item 5. ON BOTH FORMS: Check this item for each product registration you wish to
cancel voluntarily. If a registration number is listed for a product for which you
previously requested voluntary cancellation, indicate in Item 5 the date of that
request. Since this Data Call-in requires both generic and product specific data,
you must complete item 5 on both Data Call-In response forms. You do not need
to complete any item on the Requirements Status and Registrant's Response Forms.
Item 6a. ON THE GENERIC DATA FORM: Check this Item if the Data Call-In is for
generic data as indicated in Item 3 and you are eligible for a Generic Data
Exemption for the chemical listed in Item 2 and used in the subject product. By
electing this exemption, you agree to the terms and conditions of a Generic Data
Exemption as explained in the Data Call-In Notice.
If you are eligible for or claim a Generic Data Exemption, enter the EPA
registration Number of each registered source of that active ingredient that you use
in your product.
Typically, if you purchase an EPA-registered product from one or more other
producers (who, with respect to the incorporated product, are in compliance with
this and any other outstanding Data Call-In Notice), and incorporate that product
into all your products, you may complete this item for all products listed on this
form. If, however, you produce the active ingredient yourself, or use any
unregistered product (regardless of the fact that some of your sources are
registered), you may not claim a Generic Data Exemption and you may not select
this item. - .
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INSTRUCTIONS FOR COMPLETING THE DATA CALL-IN RESPONSE FORMS
Generic and Product Specific Data Call-in
Item6b.
ItemTa.
ItemTb.
ON TBE GENERIC DATA FORM: Check .this Item if the Data Call-in is for
generic data as indicated in Item 3 and if you are agreeing to satisfy the generic
data requirements of this Data Call-In. Attach .the Requirements Status and
Registrant's Response Form that indicates how you will satisfy those requirements.
NOTE: Item 6a and 6b are not applicable for Product Specific Data.
ON THE PRODUCT SPECIFIC DATA FORM: For each manufacturing use
product (MUP) for which you wish to maintain registration, you must "agree to
satisfy the data requirements by responding "yes."
For each end use product (EUP) for which you wish to maintain registration, you
must agree to satisfy the data requirements by responding "yes."
" v ' . . " ' ' , . ."/-
FOR BOTH MUP and EUP products
You should also respond "yes" to this item (7a for MUP's and 7b for EUP's) if
your product is identical to another product and you qualify for a data exemption.
You must provide the EPA registration numbers of your source(s); do not
complete the Requirements Status and Registrant's Response form. Examples of
such products include repackaged products and Special Local Needs (Section 24c)
products which are identical to federally registered products.
If you are requesting a data waiver, answer "yes" here; in addition, on the
"Requirements Status and Registrant's Response" form under Item 9, you must
respond with option 7 (Waiver Request) for each study for which you are
requesting a waiver.
NOTE: Item 7a and 7b are not applicable for Generic Data,
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INSTRUCTIONS FOR COMPLETING THE DATA CALL-IN RESPONSE FORMS
Generic and Product Specific Data Call-In ! ,
/' i
Item 8." ON BOTH FORMS: This certification statement must be signed by an authorized
representative of your company and the person signing must include his/her tide.
Additional pages used in your response must be initialled and dated in the space
provided for the certification.
v '"' . "' - *
Item 9. ON BOTH FORMS: Enter the date of signature.
Item 10. ON BOTH FORMS: Enter the name of the person EPA should cpntact with
questions regarding your response.
Item 11. ON BOTH FORMS: Enter the phone number of your company contact.
Note: You may provide additional infonnation that does not fit on Ibisfoim in a ligiied letter that accoinpanies your response. For example, you
nay wiih to report that your product his already been transferred to another company or that you haie already voluntarily cancelled this
product. For tteie caies, please fupply all relevant details 10 Ibat EPA can ensure that its records aป.
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INSTRUCTIONS FOR COMPLETING THE "REQUIREMENTS STATUS AND
REGISTRANT'S RESPONSE FORMS" FOR THE GENERIC AND PRODUCT
SPECIFIC DATA CALL-IN
INTRODUCTION
. These instructions apply to the Generic and Product Specific "Requirements Status and
Registrant's Response Forms" and are to be used by registrants to respond to generic and product
specific Data Call-in's as part of EPA's reregistration program under the Federal Insecticide,
Fungicide, and Rodenticide Act. If you are an end-use product registrant only and have been
sent this DCI letter as part of a RED document you have been sent just the product specific
"Requirements Status and Registrant's Response Forms." Only registrants responsible for generic
data have been sent the generic data response forms. The type of Data Call-In (generic or
product specific) is indicated in item number 3 ("Date and type of DCI") on each form.
Although the form is the same for both product specific and generic data, instructions for
completing the forms differ, slightly. Specifically, options for satisfying product specific data
requirements do not include (1) deletion of uses or (2) request for a low volume/minor use
waiver. Please read these instructions carefully before filling out the forms, :
EPA has developed these forms individually for each registrant, and has preprinted these
forms to include certain information unique tothis chemical. DO NOT use these forms for any
other active ingredient.
Items 1 through 8 have been preprinted on the form. Item 9 must be completed by the
registrant as appropriate. Items 10 through 13 must be completed by the registrant before
submitting a response to the Agency.
The public reporting burden for this collection of information is estimated to average 3 0
minutes per response, including time for reviewing instructions, searching existing data sources,
gathering and maintaining the data needed, and completing and reviewing tine collection of
information. Send comments regarding the burden estimate or any other aspect of this collection
of information, including suggestions for reducing this burden^ to Chief, Information Policy
Branch, Mail Code 2136, U.S. Environmental Protection Agency, 401 M St., S.W, Washington,
D.C. 20460; and to the Office of Management and Budget, Paperwork Reduction Project
2070-0107, Washington, D.C. 20503.
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INSTRUCTIONS FOR COMPLETING THE "REQUIREMENTS STATUS AND
REGISTRANT'S RESPONSE FORMS"
Generic and Product Specific Data Call-In
'..-'" ' - " - -
Item 1. ON BOTH FORMS: This item identifies your company name, number and
address.
Item 2. ON THE GENERIC DATA FORM: This item identifies the case number, case
name, EPA chemical number and chemical name.
ON THE PRODUCT SPECIFIC DATA FORM: This item identifies the case
number, case name, and the EPA Registration Number of the product for which
the Agency is requesting product specific data.
Item 3. ON THE GENERIC DATA FORM: This item identifies the type of Data
Call-in. The date of issuance is date stamped.
ON THE PRODUCT SPECIFIC DATA FORM: This item identifies the type
of Data Call-In. The date of issuance is also date stamped. Note the unique
identifier number (ID#) assigned by the Agency. This ID number must be used
in the transmittal document for any data submissions in response to this Data Call-
InNotice.
Item 4. ON BOTH FORMS: This item identifies the guideline reference number of
studies required. These guidelines, in addition to the requirements specified in the
Data Call-in Notice, govern the conduct of the required studies. Note that series
61 and 62 in product chemistry are now listed under 40 CFR 158.155 through
158.180, Subpartc.
Item 5. ON BOTH FORMS: This item identifies the study title associated with the
guideline reference number and whether protocols and 1, 2, or 3-year progress
reports are required to be submitted in connection with the study. As noted in
Section IDE of the Data Call-In Notice, 90-day progress reports are required for all
studies. , ~
If an asterisk appears in Item 5, EPA has attached information relevant to this
guideline rererence number to the Requirements Status and Registrant's Response
Form.
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INSTRUCTIONS FOR COMPLETING THE "REQUIREMENTS STATUS AND
REGISTRANT'S RESPONSE FORMS"
Generic and Product Specific Data Call-In
Item 6.
Item?.
ON BOTH FORMS: This item identifies the code associated with the use pattern
of the pesticide. In the case of efficacy data (product specific requirement), the
required study only pertains to products which have the use sites and/or pests
indicated. A brief description of each code follows:
'v .
A Terrestrial food
B Terrestrial feed
C Terrestrial non-food
D Aquatic food
E Aquatic non-food outdoor
F Aquatic non-food industrial
G Aquatic non-food residential
H Greenhouse food
I Greenhouse non-food crop
J Forestry .
K Residential
L Indoor food ,
M Indoor non-food
N Indoor medical ,
6 Indoor residential
ON BOTH FORMS: This item identifies the code assigned to the substance that
must be used for testing. A brief description of each code follows:
EUP
MP
MP/TGAI
PAI
PAI/M
PAI/PAlRA
PAIRA
PAIRA/M
PAIRA/PM
TEP
TEP %
TEP/MET
TEP/PAI/M
TGAI
End-Use Product
Manufacturing-Use Product
Manufacturing-Use Product and Technical Grade Active
Ingredient
Pure Active Ingredient
Pure Active ingredient and Metabolites
Pure Active Indredient or Pute Active
Ingredient Radiolabelled
Pure Active Ingredient Radiolabelled
Pure Active Ingredient Radiolabelled and Metabolites
Pure Active Ingredient Radiolabelled and Plant Metabolites
Typical End-Use Product
Typical End-Use Product, Percent Active Ingredient
Specified ',. ,
Typical End-Use Product and Metabolites
Typical End-Use Product or Pure Active Ingredient and
Metabolites
Technical Grade Active Ingredient
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TGAI/PAI
TGAI/PAIRA
TGAFTEP
MET
IMP
DEGR
Technical Grade Active Ingredient or Pure Active
Ingredient
Technical Grade Active Ingredient or Pure Active
Ingredient Radiolabelled
Technical Grade Active Ingredient or Typical End-Use
Product
Metabolites , .
Impurities
Degradates
See: guideline comment
ItemS. This item completed by the Agency identifies the time frame allowed fpr
submission of the study or protocol identified in item 5.
ON THE GENERIC DATA FORM: The time frame runs from the date of your
receipt of the Data Call-In notice.
ON THE PRODUCT SPECIFIC DATA FORM: The due date for submission
of product specific studies begins from the date stamped on the letter transmitting
the ReregistrationEligibility Decision document, and not from the date of receipt.
However, your response to the Data Call-in itself is due 90 days from the date of
receipt.
Item 9. ON BOTH FORMS: Enter the appropriate Response Code or Codes to show
: how you intend to comply with each data requirement. Brief descriptions of each
code follow. The Data Call-In Notice contains a fuller description of each of these
options. ,
Option 1. ON BOTH FORMS: (Developing Data) I will conduct a new study and
submit it within the time frames specified in item 8 above. By indicating
that I have chosen this option, I certify that I will comply with all the
requirements pertaining to the conditions for submittal of this study as
outlined in the Data Call-in Notice and that I will provide the protocols and
progress reports required in item 5 above.
Option 2. ON BOTH FORMS: (Agreement to Cost Shared I have entered into an
agreement with one or more registrants to develop data jointly. By
indicating that I have chosen this option, I certify that I will comply with
all the requirements pertaining to sharing in the cost of developing data as
outlined in the Data Call-in Notice.
However, for Product Specific I>ata, I understand that this option
is available for acute toxicity or certain en-icacy data ONLY if the Agency
indicates in an attachment to this notice tnat my product is similar enough
to another product to qualify for this option. I certify that another party in
the agreement is committing to submit or provide the required data; if the
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required study is not submitted on time, my product may be subject to
suspension.
" ' ' ' "* '
Option 3. ON BOTH FORMS: (Offer to Cost Share! I have made an offer to enter
into an agreement with one or more registrants to develop data jointly. I
am also submitting a completed "Certification of offer to Cost Share in the
Development of Data" form, I am submitting evidence that I have made
an offer to another registrant (who has an obligation to submit data) to
share in the cost of mat data. I am including a copy of my offer and proof
of the other registrant's receipt of that offer. I am identifying the party
which is committing to submit or provide the required data; if the required
study is not submitted on time, my product may be subject to suspension.
I understand that other terms under Option 3 in the Data Call-In Notice
apply as well.
However, for Product Specific Data, I understand that this option
is available only for acute toxicity or certain efficacy data and only if the
Agency indicates in an attachment to this Data Call-in Notice that my
product is similar enough to another product to qualify for this option.
Option 4. ON BOTH FORMS: (Submitting Existing Datal I will submit an
existing study by the specified due date that has never before been
submitted to EPA. By indicating that I have chosen this option, I certify
ป that this study meets all the requirements pertaining to the conditions for
, submittal of existing data outlined in the Data Call-in Notice and I have
attached the needed supporting information along with this response.
Option 5. , ON BOTH FORMS: (Upgrading a Study) I will submit by the specified
due date, or will cite data to upgrade a study that EPA has classified as
partially acceptable and potentially upgradeable. By indicating that I have
chosen this option, I certify that I have met all the requirements pertaining
to the conditions for submitting or citing existing data to upgrade a study
described in the Data Call-In Notice. I am indicating on attached
Correspondence the Master Record Identification Number (MRID) that
EPA has assigned to the data that I am citing as well as the MRID of the
study I am attempting to upgrade.
' * " * '"''-
Option 6. ON BOTH FORMS: (Citing a Studvl I am citing an existing study that
has been previously classified by EPA as acceptable, core, core minimum,
or a study that has not yet been reviewed by the Agency. If reviewed, I am
providing the Agency's classification of the study.
'. . "' ' ^ " :'' ' ' " ' ' '
However, for Product Specific Data, , I am citing another
registrant's'study. I understand that this option is available ONLY for
acute toxicity or cerjtain efficacy data and ONLY if the cited study was
conducted on my product, an identical product or a product which the
Agency has "grouped" with one or mpre other products for purposes of
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depending on the same data. I may also choose this option if I am citing
my own data. In either case, I will provide the MRID or Accession number
(s). If I cite another registrant's data, I will submit a completed
"Certification With Respect To Data Compensation Requirements" form.
FOR THE GENERIC DATA FORM ONLY; The following three options (Numbers
7. S. and 9\ are responses that apply only to the "Requirements Status and
Registrant's Response Form" for generic data.
Option 7. (Deleting Uses') I am attaching an application for amendment to my
registration deleting the uses for which the data are required.
Option 8. fLow Volume/Minor Use Waiver Request), I have read the statements
concerning low volume-minor use data waivers in the Data CalUn Notice
and I request a low-volume minor use waiver of the data requirement. I am
attaching a detailed justification to support this waiver request including,
among other things, all information required to support the request. I
understand that, unless modified by the Agency in writing, the data
requirement as stated in the Notice governs.
Option 9. (Request for Waiver of Data> I have read the statements concerning data
waivers other than lowvolume minor-use data waivers in the Data Call-in
Notice and I request a waiver of the data requirement. I ani attaching a
rationale explaining why I believe the data requirements do not apply. I am
also submitting a copy of my current labels. (You must also submit a copy
of your Confidential Statement of Formula if not already on file with
EPA). I understand that, unless modified by the Agency in writing, the data
requirement as stated in the Notice governs.
FOR PRODUCT SPECIFIC DATA; The following option (number 7) is a response
that applies to the "Requirements Status sad Registrant's Response Form" for
product specific data. .
Option 7. (Waiver Request) I request a waiver for this study because it is
inappropriate for my product. I am attaching a complete justification for
this request, including technical reasons, data and references to relevant
EPA regulations, guidelines or policies. [Note: any supplemental data must
be submitted in the format required by P.R. Notice 86-5]. I understand that
this is my only opportunity to state the reasons or provide information in
support of my request. If the Agency approves my. waiver request, I will
not be required to supply the data pursuant to Section 3(c) (2) (B) of
FIFRA. If the Agency denies my waiver request, I must choose a method
of meeting the data requirements of this Notice by the due date stated by
this Notice. Li this case, I must, within 30 days-of : y receipt of the
Agency's written decision, submit a revised "Requirements Status" form
specifying the option chosen. I also understand that the deadline for
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submission of data as specified by the original Data Call-in notice will not
change.
Item 10. ONBOTHFORMS: This item must be signed by an authorised representative
of your company. The person signing must include his/her title, and must initial
and date all other pages of this form.
ON BOTH FORMS: Enter the date of signature.
ON BOTH FORMS: Enter the name of the person EPA should contact with
questions regarding your response.
Item 13, ON BOTH FORMS: Enter the phone number of your company contact.
EQffi. Youปปy Provide ซHitional information tha,td^ For example. Vou
maywishtoreportthatyoOTprodnrthasalreadybeentransferteatoanothercompanyorthatyouhaveakeadyvol^ .
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EPA'S BATCHING OF AMITROLE PRODUCTS FOR MEETING
REREGISTRATION ACUTE TOXICITY DATA REQUIREMENTS
In an effort to reduce the time, resources and number of animals needed to fulfill the acute
toxicity data requirements for reregistration of products containing amitrole as the active
ingredient, the Agency has batched products which can be considered similar for purposes of
acute toxicity. Factors considered in the sorting process include each product's active and inert
ingredients (identity, percent composition and biological activity), type of formulation (e.g.,
emulsifiable concentrate, aerosol, wettable powder, granular, etc.), and labeling (e.g., signal
word, use classification, precautionary labeling, etc.). Note that the Agency is not describing
batched products as "substantially similar" since some products within a batch may not be
considered chemically similar or have identical use patterns.
Using available information, batching has beer accomplished by the process described
in the preceding paragraph. Not with-standing the batching process, the Agency reserves the right
to require, at any time, acute toxicity data for an individual product should the need arise.
In conducting the batching PRS identified the following products:
Technical Amitrole [(90.0% al) (Id-No. 33688-5)]. :
Amizol Industrial Herbicide [(90.0% a.i.) (Id. No, 33688-6)].
Amitrol-T Liquid Herbicide [(21.6% a.i.) (Id. No, 33688-7)].
PRS has concluded that there are no acute tox data requirements for Technical Amitrole
(33688-5) and/or Amizol Industrial Herbicide (33688-6). Amizol Industrial Herbicide is similar
to Technical Amitrole.
Acute tox testing of Amitrol-T Liquid Herbicide (33688-7) should be provided by the
registrant for PRS review.
132
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Instructions for Completing the Confidential Statement of Formula
- . . 4 . >
The Confidential Statement of Formula (CSF) Form 8570-4 must be used. Two legible, signed
copies of tiie form are required. Following are basic instructions:
a.
b.
c.
d.
e.
h.
i.
j-
k.
1.
m.
n.
All the blocks on the form must be filled in and answered completely.
If any block is not applicable, mark it N/A.
The CSF must be signed, dated and the telephone number of the responsible party
must be provided.
All applicable information which is on the product specific data submission must
also be reported on the CSF.
All weights reported under item 7 must be in pounds per gallon for liquids and
pounds per cubic feet for solids.
f. Flashpoint must be in degrees Fahrenheit and flame extension in inches.
g. For all active ingredients, the EPA Registration Numbers for the currently
registered source products must be reported under column 12.
The Chemical Abstracts Service (CAS) Numbers for all actives and inerts and all
common names for the trade names must be reported.
For the active ingredients, the percent purity of the source products must be,
reported under column 10 and must be exactly the same as on the source product's
label.
All the weights in columns 13.a. and 13.b. must be in pounds, kilograms, or
grams. In no case will volumes be accepted. Do not mix English and metric
system units (i.e., pounds and kilograms).
All the items under column 13.b, must total 100 percent.
All items under columns 14.a. and 14.b. for the active ingredients must represent
pure active form.
The upper and lower certified limits for ail active and inert ingredients must follow
the 40 CFR 158.175 instructions. An explanation must be provided if the proposed
limits are different than standard certified limits. .:
When new CSFs are submitted and approved, all previously submitted CSFs
become obsolete for that specific formulation.
134
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?/EPA
United State* Environmental Protection Agency
Washington, DC 20460
CERTIFICATION OF OFFER TO COST
SHARE IN THE DEVELOPMENT OF DATA
Form Approved
OMB No. 2070-0106
2070-0057
Approval Expires 3-31-%
Public reporting burden for this collection of information is estimated to average 15 minutes per response ir*
SrrllSfiKS"0 y^tL"8' "W*8 e!(lstinS *"ซ a*"06*, gathering and maintaining the data needed, and
completing and reviewing the collection of Information. Send comments regarding the burden estimate or any other
^S.0!.!1] oซ"f fton of iriformatton preluding suggestions for reducing this burden, to Chief. Information Policy
Sn^ .' ^. ^viroivnentaJ Protection Agency, 401 M St., S.W.. Washington. DC 20460: and to the Office
of Management and Budget, Paperwork Reduction Project (2070-0106), Washington, DC 20503.
Please fill in blanks below. '- ' .
Compuny Number
EPA Reg. No.
I Certify that:
My company is willing jo develop and submit the data required by EPA under the authority of the Federal
Insecticide, Fungicide and RodenfJclde Act (FIFRA), if necessary. However, my company would prefer to
enter into an agreement with one or more registrants to develop jointly or share in the cost of developing
data. - . -'
My firm has offered in writing to enter into such an agreement That offer was Irrevocable and included an
offer to be bound by arbitration decision under section 3(c)(2)(B)(Iii) of FIFRA if final agreement on all
terms could not be reached otherwise. This offer was made to the following firm(s) on the following
oaie\s/: , -
Nam* of Flrm(a)
DM* of Offer
Certification: >
I certify that 1 am duly authorized to represent the company named above, and that the statements that I have made on
this form and all attachments therein are true, accurate, and complete. 1 acknowledge that any knowingly falsa or
misleading statement may be punishable by fine or imprisonment or both under applicable law.
Signature of Company* Authorized Rapretentatlve
Dal*
-------
-------
United States Environmental Protection Agency
Washington, DC 20460
CERTIFICATION WITH RESPECT fO
DATA COMPENSATION REQUIREMENTS
Form Approved
OMB No. 2O7O-O1O7,
2070-0057
.Approval Expires
3-31-96
: reporting burden for this collection of information is estimated to average 15 minutes per response including time for
Iflng instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewina the
Ition of information. Send comments regarding the burden estimate or any other aspect of this collection of information
ing suggestions for reducing this burden to, Chief Information Policy Branch, PM-233, U.S. Environmental Protection '
fcy, 401 M St., S.W., Washington, DC 20460; and to the Office of Management and Budget, Paperwork Reduction Project
1-0106), Washington, DC 20503. ' ' ,
:e fill in blanks below.
my Name . . ' . .
tName ,
Company Number
EPAReg.No.
fythat:
Study ^ in support of re9istration ฐi" reregistratiion under the Federal Insecticide, Fungicide and Rodenticide Act
AHhat is an exclusive use study, I am the original .data submitter, or I have obtained the written permission of the original
uDminer to cite that study. . i ", , . =>
hat for each study cited in support of registration or reregistration under FIFRA that is'NOT anlexclusive use study I am the
i\ data submitter, or I have obtained the written permission of the original data submitter, or I have notified in writing the
ScKSS ^lSoUwmtt?lSaJ ha^^d and have Off6red to: (a) Pa* compensation for those data in accordance with sections
)(F) and 3(c)(2)(D) of FIFRA; and (b) Commence negotiation to determine which data are subject to the compensation
ement of FIFRA and the amount of compensation due, if any. The companies 1 have notified are. (check one)
he companies who have submitted the studies listed on the back of this form or attached sheets, or indicated on the attached
irements Status and Registrants' Response Form,*
'hat I have previously complied with section 3(c)(1)(F) of FIFRA for the studies I have cited in support of registration or
stratipn under FIFRA. ;
re
Date
ind Title (Please Type or Print)
RAL OFFER TO, PAY: I hereby offer and agree to pay compensation to other persons, with regard to the registration or
stration of my products, to the extent required by FIFRA section 3(c)(1)(F) and 3(c)(2)(D), .
re
Date
md Title (Please Type or Print)
8570-31 (4-96)
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APPENDIX E-LIST OF RELATED DOCUMENTS
''.", ' '. - ' -\ - . - --. . ",-'
The following is a list of available documents for Amitrole that my further assist you in
responding to this Reregistration Eligibility Decision document. These documents may be
obtained by the following methods:
Electronic .
File format: Portable Document Fonnat (.PDF) Requires Adobeฎ Acrobat or compatible.
reader. Electronic copies can be downloaded from the Pesticide Special Review
i and Reregislration Information System at 703-308-7224. They also are available ^
on the Internet on EPA's gopher server, GOPHER.EPA.GOV, or using ftp on
FTP.EPA.GOV, or using WWW (World Wide Web) on WWW.EPA.GOV., or
contact Nancy Tompkins at (703) 308-8172.
5 -'.'/" ' ' . . , . '''_-'-
1 PRN6tice86-5.
2. PR Notice 91-2 (pertains to the Label Ingredient Statement).
3. A full copy of this RED document.
4. A copy of the fact sheet for amitrole.
The following documents are part of the Administrative Record for amitrole and may
included in the EPA's Office of Pesticide Programs Public Docket. Copies of these documents
are not available electronically, but may. be obtained by contacting the person listed on the
Chemical Status Sheet.
1. Health and Environmental Effects Science Chapters:
2. Detailed Label Usage Information System(LUIS) Report.
The following Agency reference documents are not available electronically, but may be
obtained by contacting the person listed on the Chemical Status Sheet of this RED document.
' * ' ' ' . " * ' '.'.'
1. -,' The Label Review Manual.
2. -, EPA Acceptance Criteria
141
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