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Unrt«d StM« OHw* at PVIICMM* and Toxic Sutaunoi
Envfconmntal Prottction Offic* «f P«tk»d« Profnma (TS-7MC)
A. DC 2O460 •
• vvEPA Pesticide
Fact Sheet
540/FS-89-054
Name of Chemical: Fiurprimidoi
Reason for Issuance: New Chemical Registration
Date Issued: FEE 22 1939
Fact Sheet Number: 202
DESCRIPTION OF CHEMICAL
Generic Name : alpha- (l-methy 1 ethy 1) -alpha-[ 4- (trif luoronjethyoxy)
phenyl]-5-pyrimidinemethanol
\
Common Name: Fiurprimidoi
Trade Name: Gutless
EPA Shaughnessy Codes: 125701-3
Chemical Abstracts Service (CAS) Number: 56425-91-3
Year of Initial Registration: 1989
Pesticide Type: Plant Growth Regulator
U.S. and Foreign Producers: Elanco Products Company, Division of
Eli Lilly and Company
USE PATTERNS AND FORMULATIONS
Application Sites: Turfgrasses and ornamental trees
Types and Methods of Application:
Boom-type sprayer to turfgrasses and specialized
injection equipment to ornamental trees.
Application Rates:
50% wettable powder;
Cool season turfgrasses
Late Spring - Early Summer 1.5 - 3 Ibs./ai/A
Late Summer - Early Fall 1.5 - 3 Ibs./ai/A
Warm season turfgrasses
Late Spring - Early Summer 0.75 - 3 Ibs./ai/A
Late Summer - Early Pall 0.75 - 3 Ibs./ai/A
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Poa annua
Late Spring - Early Summer 1-1.5 Ibs./ai/A
Late Summer - Early Fall 1 - 1.5 Ibs./ai/A
99% technical powder;
Ornamental trees - 0.5 - 1.50 grams per inch
tree diameter
Types of Formulations:
50% wettable powder (WP) end-use product marketed in
water soluble packets and 99% technical powder (TP)
end-use product marketed in one quart bottles.
Major Uses:
Turfgrasses: End-use formulation is a plant growth
regulator which reduces internode and leaf elongation
in cool and warm season turfgrasses.
Ornamental trees: End-use formulation is a plant
growth regulator for reduction of growth and pruning
frequency.
Usual Carrier:
50% formulation - water
99% formulation - alcohol
SCIENCE FINDINGS
Summary Science Statement;
Chronic feeding/oncogenicity studies were conducted in both
the rat and mouse. Hepatocellular changes in the males including
enzyme induction, fatty change, hepatocellular eosinophilic
change and focal atypia were observed in the rat study. A core-
supplementary mouse study showed increased absolute and relative
liver weight in females. Although both the rat and mouse study
are core-supplementary for oncogenicity due to inadequate dose
selection, they both satisfy the requirement for oncogenicity
testing in one species for the requested non-food uses. No
oncogenic potential was observed at any dose level in either of
these two studies. New rat and mouse studies (which achieve the
Maximum Tolerated Dose - MTD) will be required for any food use
registrations.
A 1-year dog study showed adrenal changes including
decreased plasma cortisol response to adrenal corticc-tropine
hormone (ACTH) stimulation (males), decreased relative
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and absolute adrenal weight (males) and degenerative changes of
the adrenal cortex (males and females). This study satisfies the
requirement for a chronic oral study in one species.
Decreased body weight and food consumption were observed in
the rabbit and rat teratology studies. In addition the rat
teratology study showed increased mortality, stained perigenital
area and snout, chromodacryorrhea, decreased muscle tone,
hypoactivity and alopecia. Rat and rabbit teratology
requirements have been satisfied.
The requirements for a 90-day feeding study have been
satisfied. A subchronic oral rat study showed an increased
hepatic enzyme induction in males (significant and dose increases
in p-nitroanisol o-demethylase activity). The subchronic oral
mouse study indicated an increased incidence of hepatocellular
hypertrophy in the males.
\
A 21-day dermal toxicity study (rabbit) noted slight
transient dermal irritation. This data requirement has been
fulfilled.
The requirements for a 2 generation reproductive study have
been satisfied. The Parental Systemic Toxicity in a 2 generation
reproduction study showed increased incidence of non-neoplastic
hepatocellular alteration including fatty change and vacuolation
(males) and increased susceptibility to stress factors.
Decreased mating, fertility, fetal survival (stillbirths),
neonatal survival and neonatal body weight in both sexes and in
both generations were observed at the Reproductive NOEL. Other
parental signs of toxicity included increasedsusceptibility to
stress (pregnant females) resulting in death, increased relative
liver weight (males and females), depressed body weight, weight
gain and food consumption (males and females).
Subchronic, oncogenicity and teratogenicity studies are not
usually required for the requested registration use patterns.
However, due to the structural similarity of flurprimidol to
compounds of toxicological concern (fenarimol, triarimol, and
nuarimol), these studies were required for registration.
Oncogenicity studies were requested based on flurprimidol's
similarity to an oncogenic compound (triarimol) and
teratogenicity studies were requested based on it's similarity to
compounds (triarimol and fenarimol) associated with developmental
concerns.
Mutagenicity tests for gene mutation, chromosomal aberration
and direct DNA damage were evaluated. Flurprimidol had no effect
on induction of unscheduled DNA synthesis or chromosomal
aberration. It was also negative for mutagenic activity.
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The hydrolysis, aerobic and anaerobic soil metabolism,
leaching and adsorption/desorption, terrestrial field
dissipation, and accumulation studies are acceptable and fulfills
the data requirements for proposed turf use. Environmental fate
data demonstrates that flurprimidol is stable and moderately
mobile. Based upon evaluation of the environmental fate data for
the currently proposed uses, the Ground Water Team recommends no
prospective ground water monitoring study be required. A study
may be required if the use of the chemical is expanded to
terrestrial food crops.
The aqueous photodegradation study is considered less than
adequate by itself to support registration. However, when
evaluated with other acceptable photolysis studies on chemicals
of the same class, these data demonstrate a degradation pathway
consistent with other studies. This study is not required for
the proposed tree injection use. As such, this data requirement
is satisfied for turf use since the chemical dissipates rapidly
on turf. However, in the case of bare loam soil where crops are
generally grown, the chemical may not dissipate rapidly and is
therefore subject to photodegradation. Accordingly, a repeat
photodegradation study is required for future (food) uses of
flurprimidol.
*
Avian acute, avian dietary, freshwater fish, freshwater
invertebrate and acute contact toxicity studies have been
fulfilled. Studies indicate that flurprimidol is slightly toxic
to birds, aquatic invertebrates, and both warmwater and coldwater
species.
Chemical Characteristics of the Technical Material
Physical State: crystalline solid
Color: buff to off-white, white to pale yellow
Odor: none - slightly aromatic
Molecular Weight: 312.3
Empirical Formula: GIS^IS^^*^
Boiling Point: 264 degrees Celsius
Melting Point: 93 to 95 degrees Celsius
Vapor Pressure: 3.64 x 10~7 mmHg @25 degrees Celsius
Density: 0.83 to 0.88 g/cc
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Octanol/Water Partition Coefficient:
•w
9.33
pH: In D-H20 6.5 to 8.9
various
Solubility in
water, pH 4
water, pH 7
water, pH 10
Acetone
Acetonitrile
Toluene
Chloroform
Dichloromethone
Methanol
Heavy Aromatic Naphtha
xylene
1-Chlorobutane
n-Hexane
Methyl Cellosolve
Cyclohexane
Ethyl Acetate
Cyclohexane
isophorone
Acetophenone
Monochlorotoluene
(90% ortho, 10% para)
*Solubilities determined at ambient
Celsius.
solvents:
120 to 140 ppn> §25
120 to 140 ppm @25
120 to 140 ppm @25
*700 to 800 mg/mL
*200 to 300 mg/mL
*75 to 100 mg/mL
*800 to 900 mg/mL
*800 to 900 mg/mL
*700 to 800 mg/mL
*25 to 35 mg/mL
*100 to 200 mg/mL
degrees
degrees
degrees
Celsius
Celsius
Celsius
*100 to
*1 to 2
*700 to
*2 to 3
*500 to
*400
*400
*400
*400
to
to
to
to
200 mg/mL
mg/mL
800 mg/mL
mg/mL
600 mg/mL
mg/mL
mg/mL
mg/mL
mg/mL
500
500
500
500
temperature, 20 to 22 degrees
Stability: Stable in glass or polyethylene container
Oxidizing or Reducing Action:
Oxidizing or reducing action reagent:
Ammonium dihydrogen phosphate - no gas
evolution, no temperature rise over 24 hours.
Reagent: Potassium permanganate - no gas
evolution, no temperature rise over 24 hours.
Reagent: Zinc dust 100 mesh - no gas
evolution, no temperature rise over 24 hours.
Corrosion Characteristics:
Not corrosive to low density polyethylene
films and high density polyethylene
containers.
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Explodability:
No positive results were obtained in 10
repetitive drops at 20 inches with an eight
pound hammer.
Toxicology Characteristics
Acute Studies
Acute Oral Toxicity: Toxicity Category III
Rat: LD5Q 914 mg/kg (male)
LD50 709 mg/kg (female)
Acute Dermal Toxicity: Toxicity Category in
Rat: LD5Q > 500 mg/kg (male and female)
Primary Dermal irritation: Toxicity Category IV
Slight dermal irritant
Primary Eye Irritation: Toxicity category ill
Moderate eye irritant
Dermal Sensitization:
Not a sensitizer
Acute Inhalation: Toxicity Category IV
Rat: LD5Q > 5.231 mg/L (male and female)
The toxicity base for the technical product supports
registration of this compound for the requested use«.
Subchronic Studies
A 90-day feeding study in rats treated to 0, 1.68, 6.04,
20.39, 68.34 mg/kg/day (males) and 0, 1.98, 7.13, 24.37, 78.47
ing/kg/day (females) of f lurprimidol. The systemic No-Observable-
Effect-Level (NOEL) was 1.68 mg/kg/day and the Lowest-Effect-
Level (LED was 6.04 mg/kg/day based on increased hepatic enzyme
induction in males (significant and dose increases in p-
nitroanisol 0-demthylase activity). At 24.37 mg/kg/day there was
increased relative and absolute ovarian (female) and relative
liver (male) weight. At 68.34 mg/kg/day, there was increased
absolute liver weight (males).
A 90-day feeding study in the mouse, treated with 0, 15,
67.5 and 300 mg/kg/day of technical flurprimidol. The NOEL was
15 mg/kg/day and the LEL was 67.5 mg/kg/day based on increased
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incidence of hepatocellular hypertrophy in the males. At 300
mg/kg/day, there was evidence of enzyme induction, increased
liver weight and hepatocellular hypertrophy in females.
A subchronic dermal study (21-day) was conducted in the
rabbit. Groups of 5 rabbits/sex/group were treated by dermal
exposure to 0, 500, or 1000 mg/kg/day of flurprimidol. The
systemic NOEL was greater than or equal to 1000 mg/kg/day and
the LEL was greater than 1000 mg/kg/day. The NOEL for dermal
irritation was less than 500 mg/kg/day and the LEL was less than
or equal to 500 mg/kg/day based on slight transient dermal
irritation.
Chronic Studies
Rodent Feeding Studies
A 2-year study in rats treated with either 0, 1.0, 3.6, 12.1
and 41.2 mg/kg/day of flurprimidol technical for males and 0,
1.2, 4.4, 14.5, and 49.3 mg/kg/day for females the NOEL was 3.6
mg/kg/day and the LEL was 12.1 mg/kg/day based upon
hepatocellular changes in males including enzyme induction, fatty
change, hepatocellular eosinophilic change and focal atypia. At
41.2 mg/kg/day there was also a transient body weight and weight
gain decrease (males), increased cholesterol and triglycerides
(males and females) increased hepatic enzyme induction and liver
weight, fatty change and hepatocellular eosinophilic change
(females). No oncogenic potential was observed at any dose
level.
A 2-year core-supplementary study in mice treated with
either 0, 1.4, 10.5 or 79.9 mg/kg/day of flurprimidol, the
systemic NOEl was 1.4 mg/kg/day. The LEL was 10.5 mg/kg/day
based on increased absolute and relative liver weight in the
males. No oncogenic potential was observed at any dose level.
Although both the rat and the mouse study are supplementary
for oncogenicity due to inadequate dose selection, they both
satisfy the requirement for oncogenicity testing in one species
for the requested non-food use. There was no indication of
oncogenic potential at any dose level in either study.
New rat and mouse studies will be required for any food use
registrations.
Non-rodent Feeding Study
A 1-year dog study treated with flurprimidol at doses of 0,
0.5, 1.5, 7.0 and 30.0 mg/kg/day, the NOEl was 7.0 mg/kg/day and
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8
the LEL was 30.0 mg/kg/day Highest Dose Tested (HDT) based on
adrenal changes including decreased plasma cortisol response to
ACTH stimulation (males and degenerative changes of the adrenal
cortex (males and females). The histopathology was limited to
the zona fasciculata of the adrenal cortex and was characterized
by eosinophilic degeneration, vacuolation and cortical atrophy.
There was a slight increase in hepatic p-nitroanisole o-
demethylase activity (males).
Teratology Studies
A rabbit teratology study using doses of 0, 1.7, 9 and 45
mg/kg/day of flurprimidol had a maternal toxicity NOEl of 9
mg/kg/day and the LEL was 45 mg/kg/day based on decreased body
weight and food consumption.
A rat teratology study using doses of Of 2.5, 10, 45 or 200
mg/kg/day of flurprimidol had a maternal toxicity NOEL of 10
mg/kg/day and a LEL of 45 mg/kg/day based on decreased body
weight gain and food consumption. The developmental NOEL was 10
mg/kg/day and the LEL was 45 mg/kg/day based on decreased fetal
weight, increased incidence of hydronephrosis, hydroureter and
numerous developmental skeletal anomalies.
Reproduction Study
A 2 generation reproduction study in the rat treated with
(time weighted average) 0, 1.8, 7.3, and 74 mg/kg/day of
flurprimidol had a parental Systemic Toxicity NOEL of 1.8
mg/kg/day and a LEL of 7.3 mg/kg/day based on increased
incidence of non-neoplastic hepatocellular alterations including
fatty change and vacuolation (males) and increased susceptibility
to stress factors. The Reproductive NOEL was 7.3 mg/kg/c?=iy and
the LEL was 74 mg/kg/day based on decreased mating, fertility,
fetal survival (stillbirths), neonatal survival and neonatal body
weight in both sexes and in both generations. There was an
increased incidence of persistent vaginal estrous and no corpora
lutea. Additional parental signs of toxicity at 74 mg/kg/day
included increased susceptibility to stress (pregnant females)
resulting in death, increased relative liver weight (males and
females), depressed body weight, weight gain and food consumption
(males and females).
Mutagenicity Studies
No mutagenic activity was observed in mammalian cells.
There was also no activity when tested in S_._ typhimurium and £_._
coli. Flurprimidol did not induce chromosome aberrations in
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vitro in Chinese Hamster ovary cells. There was no effect on
the capacity to induce sister chromatid exchanges in bone marrow
cells of Chinese Hamsters. It had no effect on induction of
unscheduled DNA synthesis in rat hepatocytes.
Mutagenicity tests for gene mutation, chromosomal aberration
and DNA repair were negative.
Environmental Characteristics
Hydrolysis
stable at pHs 5,7, and 9
Aerobic Soil Metabolism
degrades with a half-life of > 26 weeks in
sandy loam, silt loam and clay loam soils.
Mobility x
Mobile in bare loam soil
Dissipation
persistent in unvegetated loam (estimated
half-life of 1.5 years)
dissipates rapidly on turf (half-life of 5-21
days)
Accumulation
displays a low bioconcentration factor in
fish with rapid depuration.
The Environmental Fate and Ground Water Branch (EFGWB) have
concluded that the hydrolysis, aerobic and anaerobic soil
metabolism, leaching and adsorption/desorption, terrestrial field
dissipation, and accumulation studies are acceptable and
fulfills the data requirements for proposed turf use.
Review of the Aqueous Photodegradation study noted several
deficiencies. The study is considered less than adequate by
itself to support registration. However, when evaluated with
other acceptable photolysis studies on chemicals of the same
class, these data demonstrate a degradation pathway consistent
with the other studies. This study is not required for the
proposed tree injection use. As such, this data requirement is
satisfied for turf use since the chemical dissipates rapidly on
turf. However, in the case of bare loam soil where crops are
generally grown, the chemical may not dissipate rapidly and is
therefore subject to photodegradation. Accordingly, a repeat
photodegradation study is required for future (food) uses of
flurprimidol.
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10
A repeat of the Aqueous Photodegradation study is requested,
but not as a condition of registration. A new study will remove
any doubt concerning the data and the available study submitted
by the registrant is a passe' protocol. Without a free standing
study, the question of acceptability will continually arise with
every new use and generic review of the chemical.
Ecological Characteristics
Avian acute toxicity:
bobwhite quail
Avian dietary toxicity:
bobwhite quail
mallard duck
LC5Q > 2000 mg/kg
LC50 > 5000 ppm
LC50 > 5000 ppm
Freshwater fish acute toxicity:
bluegill sunfish ^C50 17.2(16.6 and 17.8) ppm
rainbow trout LC50 18.3(17.5 and 19.0) ppm
Freshwater invertebrate toxicity:
Daphnia magna EC50 11.8(10.9 and 12.9) ppm
Acute Toxicity for Green Algae:
Selenastrum capricornutum EC5Q.84 ppm
Acute Contact Toxicity:
honey bee
LD50 > 100 ug/bee
All of the above data requirements have been satisfied.
Flurprimidol is practically non-toxic to birds on an acute and
dietary basis, slightly toxic to aquatic invertebrates, and both
warmwater and coldwater species. The hazard to freshwater algae
is expected to be minimal. In addition flurprimidol is
relatively non-toxic to honey bees.
CONTACT PERSON AT EPA
Robert J. Taylor
Product Manager (25)
Fungicide-Herbicide Branch
Registration Division (TS-767C)
Office of Pesticide programs
Environmental Protection Agency
401 M Street, S. W.
Washington, D. C. 20460
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11
Office location and telephone number:
Room 243, Crystal Mall #2
1921 Jefferson Davis Highway
Arlington, VA 22202
(703) 557-1800
DISCLAIMER: The information in this Pesticide Pact Sheet is a
summary only and is not to be used to satisfy data requirements
for pesticide registration and reregistration. The complete
Registration Standard for the pesticide may be obtained from the
contact person listed above.
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SEPA
United States i
Environmental Protection Agency
Office of Pesticide Program (H7502C)
PMSD. Information Services Branch
401 M Street. SW.
Washington. DC 20460
Official Business
Penalty for Private Use $300
First-CIa:
Postage and Fees
EPA
Permit No. G-35
Paid
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