United States Office of Pestichta and Toxic Subttancas
Environmental Protection Office of Pesticide Programs (TS-786C)
Agency Washington. DC 20460
vvEPA Pesticide
Fact Sheet
Name of Chemical:
Reason for Issuance:
Date Issued: ^ . _ _„.
_ - _. .. December 1, 1984
Fact Sheet Number:
60
1. Description of the chemical
Generic name: 1-chloro-5-(n>ethylamlno)-2-(alpha, alpha, alpha-
t rlf luoro-m-tolyl) -3 (2H) -pyrldazlnone
Cannon name: Norflurazcn
Trade name: Zorlal*, Sollcam* and 'Evltal*
'EPA Shaugnessy Number: 105801
Chemical Abstract Service Registry Number (CAS): 27314-13-2
Year of Initial registration: 1971
Pesticide Type: Herbicide
Chemical Family: Pluorlnated pyrldazlnone
U.S. & foreign producer: Sandoz -Inc.
2. Use patterns and formulations
Application sites: Norflurazon is registered for use as a selective
preemergent herbicide to control germinating annual grasses and
broadleaf weeds In cranberries, cotton, soybeans, almonds, apples,
apricots, cherries, citrus (all), filberts, hops, nectarines,
peaches, pears, pecans, plums, prunes, walnuts, and noncrop areas
such as storage areas, airports and rlghts-of-way.
Types of formulations: Norflurazon is the sole active ingredient
in the following: 97% active ingredient (a.l.) technical
manufacturlng-use-product, 80% a.l. wettable powder, 50/6 a.l flowable,
and 5% a.l. granular.
Types and methods of applications: Band or broadcast ground application
to soil surface. Aerial application is registered for cotton,
cranberry and soybean use.
Application rates: 0.5 to 8 Ib. a.l. per acre (A):
cranberries 1-8 Ib. a.i./A; cotton and soybeans 1-2 Ib.
a.i./A (split application 0.5-1.0 Ib. a.l./A); tree fruit, nut
tree, citrus and hops 2-1 Ib. a.l./A; and noncrop sites 1-8 Ib.
a.i./A.
Usual carrier: Water
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3. Science Findings
Sunii .ry science stat nent:
?krflurazai has a low acute toxicity and is not an eye or skin
irritant or a skin sensitizer. The subchronlc, chronic feeding,
and reproduction studies did not produce results of toxicological
concern. Norflurazon is not considered to be an oncogen or a
teratogen. mutagenicity studies reviewed thus far are negative.
Norflurazon appears to be mobile in mineral soils and 1n bile
In soils with hig i organic xT teria1 and is persistent in soil.
Norflurazon is relatively non-toxic to avian test species and is
moderately to slightly toxic to aquatic (fresh water and marine)
organisms. Data are available to determine and establish tolerances
for residues of norfiurazon and its desmethyl metabolite in over
half of the commodities with established tolerances. Based
on the established tolerances and the 6—month dog feeding study
the percent of the accepatable daily intake utilized is 39%.
Chemical characteristics:
Norflurazon is a buff—white odorless crystalline solid. The melting
point is 177 ± 3° C. The solubility of norflurazon at 25° C is 5 grams (g)/
100 milliliters (ml) in acetone, insoluble in carbon disulfide,
14.2 g/100 ml in ethyl alcohol, 0.25 gIl 00 ml in xylol, and 28 parts per
million (ppm) (w:w) in water. The vapor pressure is < 1 x 10 Torr
(25°C). Norflurazon is quite stable in dilute acidic or basic aqueous
solution and storage stability is greater than 2 years. No unusual
handling characteristics were noted.
Toxicological characteristics:
Acute studies indicate the following:
Rat acute oral was 9,000 milligrams (mg)/kilogram (kg), Toxicity
Category IV.
Rabbit acute dermal was > 20,000 mg/kg, Toxicity Category IV.
Male rat acute inhalation of 80% WP was ) 200 mg/Liter (L)/
1 hour, Toxicity Category IV.
Not an eye or skin irritant, Toxicity Category IV.
Not a skin sensitizer.
Subchronic studies indicated the following:
In a 6—month dog feeding study, the primary effects seen
were congestion of the liver, hepatocyte swelling, increased
liver weight, and an increase in colloidal vacuole in thyroid
at 450 ppm. The No Observed Effect Level (NOEL) was 150 ppm.
Levels tested were 0, 50, 150 and 450 ppm.
In a 90—day rat feeding study, the primary effects were
hypertrophic change in the thyroid glands at 2,500 ppm. The
NOEL was 500 ppm. Levels tested were 0, 250, 500 and 2,500 ppm.
In a 28—day mouse feeding study, diffuse and smooth granular
livers and increased liver/body weight ratios were observed
at 2,520 ppm. The NOEL was 420 ppm. Levels tested: 0, 70,
210, 420 and 2,520 ppm.
A 14—day inhalation study in the rat was submitted. Levels
tested were 0.1, 1.0, and 10.0 mg/L. The NOEL was 10 mg/L.
A 21—day dermal toxicity study in the rabbit was performed
on 80% WP (Wettable Powder) norfiurazon. Levels tested were
750 mg/kg/day and 2000 mg/kg/day. The NOEL was > 2000 mg/kg/day.
The chronic studies indicated the following:
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Chronic—feeding studies:
A 2—year rat feeding study was conducted using technical
norfiurazon. Rats were fed dietary levels of 2, 15, 125,
375 and 1025 ppm. In the high dose group histopathological
alterations included an increase in the number of chromophobe
adenomas of the pituitary, nodular or cortical hypertrophy in
adrenals and nephritis and/or casts in kidneys of the male rats;
and fatty changes in adrenals, edometritis and squamous
metaplasia of the uterus, cystic ovaries and hyaline casts
and/or nephritis in kidneys of the females. A NOEL was
demonstrated at 375 ppm. Norfiurazon doinonstrated no
tu rigenic effect in the test animals in any of the dose
levels tested.
In a 2—year feeding study, mice were fed 0, 0 (double control),
85, 340 and 1360 ppm of technical norfiurazon. Histopathological
alterations included hepatoma/hyperplasia — hypertrophy in the
liver at 1360 ppm. The NOEL level observed was 340 ppm.
There was no significant increase in these lesions in the
lower levels over that of the control. The failure to
induce such lesions in the other long term studies permits
the conclusion that this is not a potential carcinogenic response,
but a toxic response to rather high level of chemical insult.
Reproduction studies:
A 3—generation reproduction study was conducted in the rat.
Norflurazon was fed at dietary levels of 0, 125, 375 and 1025
ppm for three generations. At 1025 ppm norflurazon caused
reduced fertility, gestation and viability indices. No
teratogenic effects were seen at any dose tested. The NOEL
was established at 375 ppm.
In a 1—generation reproduction study in the mouse, norfiurazon
was fed at dietary levels of 0, 0, 85, 170 and 340 ppm.
No adverse findings were observed in any of the doses
tested. The NOEL was established at 340 ppm.
Teratogenicity studies:
Pregnant rabbits were fed a diet containing 0, 10, 30, and 60
mg/kg norfiurazon on gestation days 6 through 15. Norflurazon
was not teratogenic at 60 mg/kg/day. Maternal body weight was
decreased at 60 mg/kg. Fetotoxic effects seen at 30 and 60
mg/kg/day were decreased weight and incomplete ossified
variations. Maternal toxic NOEL was observed at 30 mg/kg/day.
Fetotoxic NOEL was observed at 10 mg/kg/day.
In the second teratology study, pregnant rats were fed 0, 100,
200 and 400 mg/kg/day of norflurazon on gestation days 6 through
15. Norfiurazon was not embryotoxic or teratogenic. The NOEL
was 400 mg/kg/day.
Mutagenicity studies:
In two Ames mutagenic assays, norflurazon was tested in Samonella
typhimurium strains, TA—1535, TA—1537, TA—1538, TA—98, TA—100 and
D—4 Saccharomyces cerevisiae strain. The doses employed ranged
from 0.1 micrograms (ug) to 500 ug per plate. The compound was tested
directly in the presence of liver microsomal enzyme preparation from
Aroclor induced rats. Norfiurazon did not demonstrate mutagenic
activity.
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A reverse mutagenicity assay using Salmonella typhimurium strains
TA—1535, TA—1537, ThS—1538, TA—98 and T—100, also E. coil , WP2 hcr
strain (tryptophanrequiring strain) was conducted. The doses
employed ware 5, 10, 50, 100, 1,000 and 5000 ug per plate.
NorflUrazon was negative in this test.
Metabolism studies:
( 3 H, 14 c)— norfiurazon was adtninisted by gavage to 10 male
Wistar strain rats at a dose of 10 mg per day for 15 days.
Approximately 17 percent of the administed dose was excreted
in the urine and about 57 percent in the feces. Small amounts
of the parent compound ware isolated from the urine (0.1%) and
and larger amounts from the feces (5.4%). Only traces of
radioactivity were present in the tissues examined. Three
major pathways seem to be operative in detoxification of
norfiurazon in the rat: Desmethylatlon, yielding desmethyl
metabolite of norfiurazon; a hydroxylation process involving
the replacement of chlorine on carbon—4 of the pyridazinon
ring; and conjugation through sulfur introduced at carbon—
4 of the pyridazinon ring.
Physiological and biochemical behavioral characteristics:
Norf]urazon is absorbed by the roots of weeds as they germinate and is
translocated to the growing parts where it inhibits carotenoid biosysnthesis
resulting in chlorophyll photodegradation in susceptible species. On
emergence from the soil, the weed seedlings turn white or pinkish, become
necrotic and die.
Environmental characteristics:
Norflurazon residues appear to be relatively mobile in most mineral
soils and immobile in soils with high organic matter. The half—life
in soils ranges from 38 days to 731 days.
Ecological characteristics:
Avian studies:
Acute oral (Mallard duck) > 2510 mg/kg.
Acute dietary (Bobwhite quail) > 10,000 mg/kg.
Acute dietary (Mallard duck) > 10,000 mg/kg.
Reproduction (Mallard duck and bobwhite quail) was not
affected up to 40 ppm dietary exposure (highest dose tested).
Aquatic species studies:
Daphnia magna acute 48 hour no effect level was 15 ppm (the
highest level tested due to solubility of norflurazon
technical).
Daphnla magna chronic life cycle minimum treshold concentration
was > 1.0 < 2.6 ppm due to effect on offspring production.
Bluegill sunfish 96—hour acute was 16.3 ppm.
Rainbow trout 96—hour acute was 8.1 ppm.
Fathead minnow partial chronic maximum toxicant concentration
(MATC) > 1.1 < 2.1 ppm based on growth.
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Rainbow trout partial chronic MATC was > 0.77 < 1.5 ppm based
upon survival and growth.
Atlantic oyster larvae acute NOEL was 10 ppm.
Tolerance assessments:
U.S. tolerances for residues of norflurazon and its desmethyl metabolite
in or on raw agricultural commodities are as follows [ 40 CFR 180.356(a)J:
Commodities Maximum Residue Limit (ppm)
Almond, hulls 1.0
Almonds, meat 0.1
Apricots 0.1
Apples 0.1
Cattle, fat 0.1
Cattle, meat 0.1
Cattle, meat—by—products (mbyp) 0.1
Cherries 0.1
Citrus fruit 0.2
Cottonseed 0.1
Cranberries 0.1
Filberts 0.1
Goats, fat 0.1
Coats, meat 0.1
Goats, mbyp 0.1
Hogs, fat 0.1
Hogs, meat 0.1
Hogs, mbyp 0.1
Hops, green 1.0
Horses, fat 0.1
Horses, meat 0.1
Horses, mbyp 0.1
Milk 0.1
Nectarines 0.1
Pecans 0.1
Peaches 0.1
Pears 0.1
Plums (fresh prunes) 0.1
Poultry, fat 0.1
Poultry, meat 0.1
Poultry, mbyp 0.1
Sheep, fat 0.1
Sheep, meat 0.1
Sheep, mbyp 0.1
Soybeans 0.1
Soybean forage 1.0
Soybean hay 1.0
Walnuts 0.1
U.S. tolerances for indirect residues of norflurazon and its desmethyl
metabolite in raw agricultural commodities when present as a result of
application to cotton when peanuts are a replacement or follow—up crop
are as follows [ 40 FR §180.356(b)]:
Commodities Maximum Residue Limit (ppm)
Peanuts 0.2
Peanut, hay 0.5
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Peanut, hulls 0.5
Peanut, vines 0.5
A food additive tolerance has been established for residues of
norfiurazon and its desmethyl metaboUte in dried hops at 3.0 ppm
[ 21 GFR §193.324J.
Fe &additive tolerances have been established for residues of norfiurazon
and its desmethyl metabolite in citrus molasses at 1.0 ppm and dried citrus
pulp at 0.4 ppm [ 21 CFR §561.283J.
No Codex Almentarius or Mexican or Canadian tolerances have been
established for residues of norflurazon on the above commodities.
The acceptable daily intake (ADI) was established using the 6—month
dog feeding study with a no observed effect level of 150 ppm
(3.750 mg/kg/day). Using a 1,000 fold safety factor the ADI is
calculated to be 0.0038 mg/kg/day. The maximum permitted intake
(MPI) for a 60 kg human is calculated to be 0.2250 mg/day. The
current theoretical maximum residue contribution (TMRC) for
norfiurazon, based on the established tolerances, is 0.0877
mg/day for a 1.5 kg diet and the percent ADI utilized is 38.98Z.
Residue studies are adequate to support tolerances established for
almonds, apricots, cherries, cranberries, cottonseed, filberts,
grapes, nectarines, peaches, peanut hulls, pears, pecans, walnuts,
milk, and the fat, meat, and meat—by—products of cattle, goats, hogs,
horses, poultry, and sheep.
‘4. Summary of Regulatory Position and Rationale
Use, formulation, manufacturing process or geographical restrictions: None
are required.
Unique precautionary statements, protective clothing requirements or
reentry intervals: None required.
Risk/benefit review: None of the risk criteria set forth in Title 40 Code
of Federal Regulations §162.11 have been exceeded by norfiurazon.
Gruund Water Potential: Because of the mobility and long half—life,
norflurazon presents a potential for ground water contamination.
The Ground Water Studies will be requested in an accelerated time
frame. Due to the inadequate data base and since norfiurazon to date
has not been found in ground water, no interim restrictions were imposed.
Any future decisions depend on the results of the required studies.
5. Summary of major data gaps and when these are due to be filled
Ground Water Studies:
Hydrolysis, photodegradation and mobility are required within
6 months after receipt of the Guidance Package.
Metabolism, soil and aquatic (sediment) dissipation are required
within 2 years after receipt of the Guidance Package.
Soil, long term dissipation is required within 4 years after
receipt of the Guidance Package.
Short term studies required to be filled within 6 months after
receipt of the Guidance Package:
Product Chemistry: Description of manufacturing process, discussion
of formation of impurities, analysis of product, density, dissociation
constant, octanol/water partition coefficient, oxdizing or reducing
action, explodability, pH and stability.
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Honeybee acute contact.
Female rat metabolism.
Mutagagenicity studies for chromosoinal aberation and other mechanisms of
mutagenicity are required to be filled within 1 year after the receipt of
th8 Guidance Package. -
Long term studies required to be filled within 2 years after the
receipt of the Guidance Package:
Rotational crops.
Plant and animal metabolism.
Analytical methods and stability of residues under storage.
Crop residues studies for soybeans, citrus, apples, plums, hops and
peanuts.
6. Contact person at EPA
Richard F. Mountfort
Product Manager (23)
Environmental Protection Agency (TS—767C)
401 M Street S.W.
Washington, D.C. 20460
(703) 557—1830
DISCLAIMER: The information presented in this Chemical Information
Fact Sheet is for informational purposes only and may
not be used to fulfill data requirements for pesticide
registration and reregistration.
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