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Flurprimidol (Cutless) - EPA Pesticide Fact Sheet 2/89

EPA Pesticide Fact Sheet
Name of Chemical:  Flurprimidol
Reason for Issuance:  New Chemical Registration
Date Issued:  FEB 22 1989
Fact Sheet Number:  202

                         1. DESCRIPTION OF CHEMICAL

- Generic Name:  alpha-(1-methylethyl)-alpha-[4-(trifluoromethyoxy)
  phenyl]-5-pyrimidinemethanol
- Common Name:  Flurprimidol
- Trade Name:  Cutless
- 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

                    2. 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 lbs./ai/A
      - Late Summer - Early Fall 1.5 - 3 lbs./ai/A
    - Warm season turfgrasses
      - Late Spring - Early Summer 0.75 - 3 lbs./ai/A
      - Late Summer - Early Fall 0.75 - 3 lbs./ai/A
    - poa annua
      - Late Spring - Early Summer 1 - 1.5 lbs./ai/A
      - Late Summer - Early Fall 1 - 1.5 lbs./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

                      3. 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 cortice-tropine hormone (ACTH)
stimulation (males), decreased relative 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.  n 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 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).

     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.

     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:  Cl5Hl5F3N202
- 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
- Octanol/Water Partition Coefficient:  Kw = 9.33
- pH:  In D-H20 6.5 to 8.9

Solubility in various solvents:
  water, pH 4                     120 to 140 ppm @25 degrees Celsius

  water, pH 7                     120 to 140 ppm @25 degrees Celsius
  water, pH 10                    120 to 140 ppm @25 degrees Celsius
  Acetone                         *700 to 800 mg/mL
  Acetonitrile                    *200 to 300 mg/mL
  Toluene                         *75 to 100 mg/mL
  Chloroform                      *800 to 900 mg/mL
  Dichloromethone                 *800 to 900 mg/mL
  Methanol                        *700 to 800 mg/mL
  Heavy Aromatic Naphtha          *25 o 35 mg/mL
  Xylene                          *100 to 200 mg/mL
  1-Chlorobutane                  *100 to 200 mg/mL
  n-Hexane                        *1 to 2 mg/mL
  Methyl Cellosolve               *700 to 800 mg/mL
  Cyclohexane                     *2 to 3 mg/mL
  Ethyl Acetate                   *500 to 600 mg/mL
  Cyclohexane                     *400 to 500 mg/mL
  Isophorone                      *400 to 500 mg/mL
  Acetophenone                    *400 to 500 mg/mL
  Monochlorotoluene               *400 to 500 mg/mL
  (90% ortho, 10% para)

*Solubilities determined at ambient temperature, 20 to 22 degrees
Celsius.

- 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.
- 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:  LD50 914 mg/kg
   (male); LD50 709 mg/kg (female)
  - Acute Dermal Toxicity:  Toxicity Category III; Rat:  LD50 > 500
    mg/kg (male and female)
  - Primary Dermal Irritation:  Toxicity Category IV; Slight dermal
    irritant
  - Primary Eye Irritation:  Toxicity category III; Moderate eye
    irritant
  - Dermal Sensitization:  Not a sensitizer
  - Acute Inhalation:  Toxicity Category IV; Rat:  LD50 > 5.231 mg/L
    (male and female)
- The toxicity base for the technical product supports registration of
  this compound for the requested uses.

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 mg/kg/day
(females) of flurprimidol.  The systemic No-Observable- Effect-Level
(NOEL) was 1.68 mg/kg/day and the Lowest-Effect- Level (LEL) was 6.04
mg/kg/day based on increased hepatic enzyme induction in males
(significant and dose increases in p- nitroanisol O-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 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 l-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 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
0-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 0, 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/
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 E. coli.
Flurprimidol did not induce chromosome aberrations in 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:  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.

     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 dat,a 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 LC50 > 2000 mg/kg
- Avian dietary toxicity:  bobwhite quail LC50 > 5000 ppm
                           mallard duck LC50 > 5000 ppm
- Freshwater fish acute toxicity: bluegill sunfish LC50 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 EC50
  .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.

                        6. 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

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 FACT 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.