norflurazon (Zorial, Solicam) Herbicide Profile 12/84
CHEMICAL FACT SHEET FOR:
FACT SHEET NUMBER: 60
DATE ISSUED: DECEMBER , 1984
1. DESCRIPTION OF THE CHEMICAL
- Generic Name: 4-chloro-5-(methylamino)-2-(alpha, alpha,
- Common Name: norflurazon
- Trade Name: Zorial, Solicam, and Evital
- EPA Shaughnessy Code: 105801
- Chemical Abstracts Service (CAS) Number: 27314-13-2
- Year of Initial Registration: 1974
- Pesticide Type: Herbicide
- Chemical Family: fluorinated pyridazinone
- U.S. and Foreign Producers: 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 rights-of-way.
- Types of formulations: Norflurazon is the sole active ingredient in
the following: 97% active ingredient (a.i.) technical manufacturing-
use product, 80% a.i. wettable powder, 50% a.i. flowable, and 5% a.i.
- 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 lb. a,i. per acre (A): cranberries 4-8
lb. a.i./A; cotton and soybeans 1-2 lb. a.i./A (split application
0.5-1.0 lb. a.i./A); tree fruit, nut tree, citrus, and hops 2-4 lb.
a.i./A; and noncrop sites 4-8 lb. a.i./A.
- Usual carrier: Water
3. SCIENCE FINDINGS
- Norflurazon is a buff-white, odorless, crystalline solid. The melting
point is 177 +/-3 degrees C. The solubility of norflurazon at 25
degrees C is 5 grams (g)/100 milliliters (ml) in acetone, insoluble in
carbon disulfide, 14.2 g/100 ml in ethyl alcohol, 0.25 g/100 ml in
xylol, and 28 parts per million (ppm) (w:w) in water. The vapor
pressure is <1 x 10(-5) Torr (25 degrees C). Norflurazon is quite
stable in dilute acidic or basic aqueous solution, and storage
stability is greater than two years. No unusual handling
characteristics were noted.
- Acute studies indicate the following:
- Rat acute oral LD50: 9,000 milligrams (mg)/kilogram (kg),
Toxicity Category IV.
- Rabbit acute dermal LD50: >20,000 mg/kg, Toxicity Category IV.
- Male rat acute inhalation LC50 of 80% WP: >200 mg/liter (1)/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 effect was 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 were 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) norflurazon. Levels tested were 750
mg/kg/day and 2,000 mg/kg/day. The NOEL was >2,000 mg/kg/day.
- The chronic studies indicated the following:
- Chronic feeding studies:
- A 2-year rat feeding study was conducted using technical
norflurazon. Rats were fed dietary levels of 2, 15, 125, 375,
and 1,025 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, endometritis 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. Norflurazon demonstrated no tumorigenic
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 1,360 ppm of technical norflurazon. Histopathological
alterations included hepatoma/hyperplasia-hypertrophy in the liver
at 1,360 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 a 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 1,025
ppm for three generations. At 1,025 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, norflurazon
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 norflurazon 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. Norflurazon was not embryotoxic or teratogenic.
The NOEL was 400 mg/kg/day.
- Mutagenicity studies:
- In two Ames mutagenic assays, norflurazon was tested in
Salmonella 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 5,000 ug
per plate. The compound was tested directly in the presence of
liver microsomal enzyme preparation from Aroclor-induced rats.
Norflurazon did not demonstrate mutagenic activity.
- A reverse mutagenicity assay using Salmonella typhimurium
strains TA-1535, TA-1537, TA-1538, TA-98, and TA-100, and E.
coli, WP2 hcr strain (tryptophan-requiring strain) was
conducted. The doses employed were 5, 10, 50, 100, 1,000, and
5,000 ug per plate. Norflurazon was negative in this test.
- Metabolism studies:
- (3H, 14C)-norflurazon was administered by gavage to 10 male
Wistar strain rats at a dose of 10 mg/day for 15 days. Approxi-
mately 17% of the administered dose was excreted in the urine,
and about 57% in the feces. Small amounts of the parent
compound were isolated from the urine (0.1%), 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 norflurazon in the rat:
desmethylation, yielding desmethyl metabolite of norflurazon; 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
- Norflurazon is absorbed by the roots of weeds as they germinate and is
translocated to the growing parts, where it inhibits carotenoid
biosynthesis, resulting in chlorophyll photodegradation in susceptible
species. On emergence from the soil, the weed seedlings turn white
or pinkish, become necrotic, and die.
- 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.
- Avian studies:
- Acute oral (mallard duck) LD50: >2,510 mg/kg.
- Acute dietary (bobwhite quail) LD50: >10,000 mg/kg.
- Acute dietary (mallard duck) LD50: >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).
- Daphnia magna chronic lifecycle minimum threshold 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) was >1.1 <2.1 ppm based on growth.
- Rainbow trout partial chronic MATC was >0.77 <1.5 ppm based upon
survival and growth.
- Atlantic oyster larvae acute NOEL was 10 ppm.
- 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)):
Commodities Maximum Residue Limit (ppm)
Almond, hulls 1.0
Almonds, meat 0.1
Cattle, fat 0.1
Cattle, meat 0.1
Cattle, meat byproducts (mbyp) 0.1
Citrus fruit 0.2
Goats, fat 0.1
Goats, 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
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
Soybean forage 1.0
Soybean hay 1.0
- 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 CFR 180.356(b)):
Commodities Maximum Residue Limit (ppm)
Peanut, hay 0.5
Peanut, hulls 0.5
Peanut, vines 0.5
- A food additive tolerance has been established for residues of
norflurazon and its desmethyl metabolite in dried hops at 3.0 ppm (21
CFR 193.324). Feed additive tolerances have been established for
residues of norflurazon and its desmethyl metabolite in citrus
molasses at 1.0 ppm and dried Citrus pulp at 0.4 ppm (21 CFR 561.283).
No Codex Alimentarius 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 norflurazon, based on the
established tolerances, is 0.0877 mg/day for a 1.5 kg diet, and the
percent ADI utilized is 38.98%.
- 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.
Summary Science Statement
- Norflurazon has a low acute toxicity and is not an eye or skin
irritant or a skin sensitizer. The subchronic, chronic feeding, and
reproduction studies did not produce results of toxicological concern.
Norflurazon is not considered to be an oncogen or a teratogen. The
mutagenicity studies reviewed thus far are negative. Norflurazon
appears to be mobile in mineral soils and immobile in soils with high
organic material and is persistent in soil. Norflurazon is relatively
non-toxic to avian test species and is moderately to slightly toxic
to aquatic (freshwater and marine) organisms. Data are available to
determine and establish tolerances for residues of norflurazon 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 acceptable daily intake
utilized is 39%.
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 norflurazon.
- Groundwater contamination potential: Because of the mobility and long
half-life, norflurazon presents a potential for groundwater contamina-
tion. The groundwater studies will be requested in an accelerated
time frame. Due to the inadequate data base, and since norflurazon to
date has not been found in groundwater, no interim restrictions were
imposed. Any future decisions depend on the results of the required
5. SUMMARY OF MAJOR DATA GAPS
- Groundwater studies:
- Hydrolysis, photodegradation, and mobility are required within six
months after receipt of the Guidance Package.
- Metabolism, soil and aquatic (sediment) dissipation are required
within two years after receipt of the Guidance Package.
- Soil, long-term dissipation is required within four years after
receipt of the Guidance Package.
- Short-term studies required to be filled within six 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, oxidizing or reducing
action, explodability, pH, and stability.
- Honeybee acute contact.
- Female rat metabolism.
- Mutagenicity studies for chromosomal aberration and other mechanisms
of mutagenicity are required to be filled within one year after the
receipt of the Guidance Package.
- Long-term studies required to be filled within two 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,
6. CONTACT PERSON AT EPA
Richard F. Mountfort
Product Manager (23)
Environmental Protection Agency (TS-767C)
401 M Street S.W.
Washington, DC 20460
DISCLAIMER: THE INFORMATION PRESENTED IN THIS CHEMICAL INFORMATION FACT
SHEET IS FOR INFORMATIONAL PURPOSES ONLY AND NOT TO BE USED TO FULFILL
DATA REQUIREMENTS FOR PESTICIDE REGISTRATION AND REREGISTRATION.