f/EPA
United States
Environmental Protection
Agency
Office of Prevention, Pesticides
and Toxic Substances
(7501C)
Pesticide
Fact Sheet
Name of Chemical: Diflufenzopyr
Reason for Issuance: Conditional Registration
Date Issued: January 28,1999
DESCRIPTION OF CHEMICAL
Generic Name:
Common Name:
Trade Name:
Chemical Abstracts
Service (CAS) Number:
Year of Initial
Registration:
Pesticide Type:
Chemical Family:
U.S. Producer:
2-(l-[([3,5-difluorophenylamino]carbonyl)-hydrazono]ethyl)-3-
pyridinecarboxylic acid
Diflufenzopyr
Distinct Herbicide
EPA Shaughnessy Code: 005107
109293-97-2
1999
Herbicide
Semicarbazone
BASF Corporation
USE PATTERNS AND FORMULATIONS
Application Sites:
Types of Formulations:
Diflufenzopyr is registered for use on field corn.
99% technical product (acid); 93% manufacturing use product
(sodium salt); wettable granular end use product containing
21.4% sodium diflufenzopyr and 55% sodium dicamba
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Types and Methods
of Application:
Application Rates:
Carrier:
Ground application using standard commercial sprayers
Use rates on field corn range from 4 to 8 ounces of formulated
product (0.05 to 0.10 pounds active ingredient, diflufenzopyr)
per acre per application. The maximum number of
applications per season is two with a total of no more than 10
ounces product (0.12 pounds active ingredient) per acre.
Water
3.
SCIENCE FINDINGS
Summary Science Statements
Diflufenzopyr is the first active ingredient from a chemical class called semicarbazones. The review
of product chemistry, environmental fate, toxicology, ecological effects and residue chemistry data
have been completed. Based on available data, diflufenzopyr has been determined to be of low
toxicity to humans, birds, aquatic organisms, mammals, and bees. Acute toxicology studies place
technical-grade diflufenzopyr in Toxicity Category HI. It is neither teratogenic nor carcinogenic.
Additionally, the data indicate no significant risk to non-target organisms, and diflufenzopyr is not
expected to pose a risk of groundwater contamination.
Chemical Characteristics
PROPERTY
Physical State
Color
Odor
Melting Point
Density
Solubility (Water)
TECHNICAL
powder, solid
off-white
no odor
135.5°C;decomp. @155°C
0.24g/mL@25°C
63 ppm @ pH 5; 5850 ppm
(a), pH7; 10,546 ppm (a), pH9
END-USE
rod-like, granular solid
tan
N/A
N/A
0.63g/mL@25°C
N/A
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PROPERTY
Vapor Pressure
Octanol/Water Partition
Coefficient
PH
TECHNICAL
l.Ox 10-7kPa@20°Cand
25°C
average Kow =1.09(pH
dependent)
3.90
END-USE
N/A
N/A
8.51
Toxicology Characteristics
Acute Toxicity (Diflufenzopyr Technical)
Acute Oral Toxicity in Rats - LD50 > 5000 mg/kg in males and females; Toxicity Category IV
Acute Dermal Toxicity in Rabbits - LD50 > 5000 mg/kg in males and females; Toxicity Category
IV
Acute Inhalation Toxicity in Rats - LC50 > 2.93 mg/L in males and females; Toxicity Category
IV
Primary Eye Irritation in Rabbits - Mild irritation resolved within 48 hours in 4/6 rabbits; Toxicity
Category HI
Primary Dermal Irritation in Rabbits - Non-irritating; Toxicity Category IV
Primary Dermal Sensitization in Guinea-Pigs - Did not exhibit any sensitization potential.
Acute Toxicity (Diflufenzopyr Manufacturing Use Product)
Acute Oral Toxicity in Rats - LD50 = 4800 mg/kg in males and 3300 mg/kg in females; Toxicity
Category HI
Acute Dermal Toxicity in Rabbits - LD50 > 5000 mg/kg in males and females; Toxicity Category
IV
Acute Inhalation Toxicity in Rats - LC50 > 5.21 mg/L in males and females; Toxicity Category
IV
Primary Eye Irritation in Rabbits - Slight to mild irritation resolved within 48 hours in all eyes;
Toxicity Category HI
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Primary Dermal Irritation in Rabbits - Very slight irritation resolved within 24 hours in all rabbits;
Toxicity Category IV
Primary Dermal Sensitization in Guinea-Pigs - Did not exhibit any sensitization potential.
Acute Toxicity (Distinct Herbicide)
Acute Oral Toxicity in Rats - LD50 = 1600 mg/kg in males and 2100 mg/kg in females;
Toxicity Category HI
Acute Dermal Toxicity in Rabbits - LD50 > 5000 mg/kg in males and females; Toxicity Category
IV
Acute Inhalation Toxicity in Rats - LC50 > 5.34 mg/L for males and females; Toxicity Category
IV
Primary Eye Irritation in Rabbits - Mild to moderate irritation (resolved within 7 days in all eyes);
Toxicity Category HI
Primary Dermal Irritation in Rabbits - Very slightly irritating (resolved within 48 hours in 5/6
rabbits and within 72 hours in all rabbits); Toxicity Category IV
Primary Dermal Sensitization in Guinea-Pigs - Strongly positive as a skin sensitizer.
Subchronic Toxicity
In a subchronic study in rats, Wistar rats were fed test diets containing technical diflufenzopyr at
dose levels of 0, 1000, 5000, 10,000 and 20,000 ppm for a period of 13 weeks. The NOAEL was
set at 5000 ppm (equal to 352 mg/kg bw/day for males, and 431 mg/kg bw/day for females) based
on lower mean body weight gain and decreased food efficiency in the 10,000 and 20,000 ppm
groups, both sexes. Additional findings were decreased food intake; slight increases in cholesterol
and alanine aminotransferase (ALAT); and slightly lower chloride. Histopathological findings were
an increased incidence of foamy macrophages in the lungs in the 10,000 and 20,000 ppm groups and
testicular atrophy in the 20,000 ppm group. Following the 4-week recovery period, the only
treatment-related effects which showed partial or no evidence of recovery were foamy macrophages
in the lungs and testicular atrophy.
In a subchronic study in mice, CD-I mice were dosed with diflufenzopyr at 0, 350, 1750, 3500
and 7000 ppm in the diet for 13 weeks. The NOEL was determined to be the highest dose tested of
7000 ppm (1225 mg/kg/day in males and 1605 mg/kg/day in females) as no clear toxic effects were
observed.
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In a subchronic study in dogs, diflufenzopyr was administered to beagle dogs in the diet at dose
levels of 0, 1500, 10,000, or 30,000 ppm for 13 weeks. The LOAEL for this study is 10,000 ppm
(403 mg/kg/day in males and 424 mg/kg/day in females), based on the occurrence of erythroid
hyperplasia in the bone marrow, extramedullary hemopoiesis in the liver, and hemosiderin deposits
in Kupffer cells. The NOAEL is 1500 ppm (58 mg/kg/day in males and 59 mg/kg/day in females)
In a subchronic dermal toxicity study, technical diflufenzopyr was administered by dermal
application to male and female New Zealand White rabbits at dose levels of 0, 100, 300 and 1000
mg/kg bw per application. Duration of application was 6 hours a day, daily for 21 to 24 consecutive
days. The NOAEL for systemic toxicity was determined to be 1000 mg/kg bw/day, since there were
no apparent signs of treatment-related systemic effects observed in male or female rabbits at any
dose level tested. A NOAEL for dermal effects could not be determined since local dermal irritation
was observed at all dose levels tested (there were no corresponding findings upon histopathological
examination).
Chronic Toxicity/Carcinogenicity
In a chronic toxicity study in dogs, diflufenzopyr was administered to beagle dogs in the diet at
dose levels of 0, 750, 7500, or 15,000 ppm for 52 weeks. The LOAEL for this study is 7500 ppm
(299 mg/kg/day for males and 301 mg/kg/day for females), based on erythroid hyperplasia in the
bone marrow in bone sections, reticulocytosis, and increased hemosiderin deposits in the liver,
kidneys, and spleen. The NOAEL is 750 ppm (26 mg/kg/day for males and 28 mg/kg/day for
females).
In a mouse carcinogenicity study, male and female CD-I mice were fed test diets containing
technical diflufenzopyr at dietary concentrations of 0, 700, 3500 and 7000 ppm for a period of 78
weeks. The NOAEL for systemic toxicity was determined to be 7000 ppm (equal to 1037 mg/kg
bw/day for males and 1004 mg/kg bw/day for females). There were no treatment-related effects
observed at any dose level tested in male rats. There was a slight, but statistically significantly lower
mean overall body weight gain for females in the 7000 ppm group, due primarily to decreased
gain/increased weight loss during the second year of the study. In the absence of any other treatment-
related findings, this was not considered to be an adverse, lexicologically significant finding. There
was no evidence of oncogenic potential of diflufenzopyr for male or female mice at any dose level
tested.
In a combined chronic toxicity/carcinogenicity study, male and female Wistar rats were fed test
diets containing technical diflufenzopyr at dietary concentrations of 0, 500, 1500, 5000 and 10,000
ppm for a period of 104 weeks. The NOAEL for systemic toxicity was set at 5000 ppm (equal to
236 mg/kg bw/day for males and 323 mg/kg bw/day for females). Treatment-related effects in the
10,000 ppm group were significantly lower body weight and body weight gains throughout the study
period and decreased food efficiency. There was no evidence of oncogenic potential of diflufenzopyr
at any dose level tested.
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Developmental Toxicity
In a developmental toxicity study, technical diflufenzopyr was administered by gavage to female
Sprague Dawley rats at dose levels of 0, 100, 300, or 1000 mg/kg/day from days 6 through 15 of
gestation. The maternal NOAEL is 300 mg/kg/day and the maternal LOAEL is 1000 mg/kg/day
based on decreases in food consumption and weight gain. Developmental effects, characterized as
significantly lower fetal body weights in males(15%) and skeletal variations, exhibited as
incompletely ossified and unossified sternal centra and reduced fetal ossification sites for caudal
vertebrae, were observed at 1000 mg/kg/day. The developmental LOAEL is 1000 mg/kg/day, based
on decreased fetal body weights and skeletal variations. The developmental NOAEL is 300
mg/kg/day.
In a developmental toxicity study, technical diflufenzopyr was administered by gavage to female
New Zealand White rabbits at dose levels of 0, 30, 100, or 300 mg/kg/day from days 6 through 19
of gestation. The maternal LOAEL is 100 mg/kg/day, based on minimal reductions in body weight
gain with no reduction in food consumption and clinical signs of toxicity (abnormal feces). The
maternal NOAEL is 30 mg/kg/day. Developmental effects, characterized as significant increases in
the incidence of supernumerary thoracic rib pair ossification sites occurred at the 300 mg/kg/day
dose. No treatment-related developmental effects were noted at the low and mid doses. The
developmental LOAEL is 300 mg/kg/day based on increased skeletal variations (supernumerary rib
ossification sites). The developmental NOAEL is 100 mg/kg/day.
Reproductive Toxicity
In a 2-generation reproduction study, technical diflufenzopyr was administered continuously in
the diet to Wistar at dose levels of 0, 500, 2000 or 8000 ppm in the diet. The systemic LOAEL is
2000 ppm (113.1-175.9 mg/kg/day) based on reduced body weight gain, increased food
consumption, and increased seminal vesicle weights. The systemic NOAEL is 500 ppm (27.3-42.2
mg/kg/day). The reproductive LOAEL is 8000 ppm (466.2-742.0 mg/kg/day) based on lower live
birth and viability indices, total pre-perinatal loss, reduced body weights and body weight gain
during lactation, a higher proportion of runts, and a higher percentage of offspring with no milk in
the stomach. The reproductive NOAEL is 2000 ppm (113.1-175.9 mg/kg/day).
Mutagenicity
Four acceptable mutagenicity studies were available for review: a microbial (Salmonella
typhimurium) mutagenicity assay; an in vitro mammalian (mouse lymphoma) cell gene mutation
assay; an in vivo mouse bone marrow micronucleus assay; and an unscheduled DNA synthesis assay.
Diflufenzopyr was negative for mutagenic potential in all assays.
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Neurotoxicity
In an acute neurotoxicity study, diflufenzopyr was administered by gavage to Crl:CD BR rats at
dose levels of 0, 125, 500 or 2000 mg/kg. Diflufenzopyr had no definite impact on neurotoxic
responses, although a few abnormalities were observed in the functional battery on the day of dosing.
A decrease in immediate righting responses that was observed in several males in all treatment
groups was not concentration-dependent. Nasal staining was observed in more rats in the 2000
mg/kg treatment groups (6 males; 3 females), but was not considered a definite or significant
response to treatment. Lower mean brain weights in all female treatment groups lacked associated
macroscopic and microscopic histopathological changes, and were only 4-5% lower than the control
brain weight. Mean locomotor activities for the 2000 mg/kg female treatment groups were decreased
on Days 7 and 14 after dosing, but the pattern of activity for the individual animals was similar to
the individual controls over time. There were no definite treatment-related differences in body
weights or food consumption in any of the treatment groups. There was no evidence of treatment-
related neuropathology in the 2000 mg/kg treatment group. A LOAEL was not established. The
NOAEL for acute neurotoxicity is 2000 mg/kg (the limit dose).
In a subchronic neurotoxicity study, diflufenzopyr was administered in the diet to Crl:CD BR rats
at dose levels of 0,25,75 or 1000 mg/kg/day for 13 weeks. No treatment-related neurotoxicological
effects were observed at any treatment level. A LOAEL for neurotoxicological effects was not
established; the NOAEL was 1000 mg/kg/day for both sexes. Treatment-related toxic effects were
observed at the 1000 mg/kg/day treatment level. The toxicological LOAEL for this study is 1000
mg/kg/day, based on decreased body weight gains for both sexes. The toxicological NOAEL is 75
mg/kg/day.
Metabolism
In a rat metabolism study, [phenyl-U-14C] or [pyridinyl-4,6-14C]diflufenzopyr was administered
to Wistar rats as a single intravenous dose at 1 mg/kg/day, a single oral dose (gavage) at 10 or 1000
mg/kg or a single dose at 10 mg/kg following a 14-day pretreatment with unlabeled diflufenzopyr
at 10 mg/kg. Following oral administration, diflufenzopyr was partially absorbed and rapidly
eliminated. By oral administration, 20 to 44 % of the dose was eliminated in urine and 49 to 79 %
in feces. By contrast, intravenously dosed rats excreted 61-89% of the dose in urine. Biliary
elimination accounted for 3 to 19 % of the dose in all dose groups. Elimination half-life in urine and
feces was 5.2-6.9 hours for all single dose groups and 7.7-10.8 hours for all repeat oral dose groups.
Total radioactive residues in tissues from rats in all dose groups were <3% of the administered dose.
Blood residue levels for all dose groups were <1% of the administered dose at all sampling intervals
through 72 hours post-dose. Diflufenzopyr was eliminated in urine, feces and bile primarily as
unchanged parent compound. Hydrolytic and hydroxylation products were also found in excreta but
in low percentages of the dose.
Metabolism of diflufenzopyr was also conducted in laying hens and lactating goats. The data
showed diflufenzopyr was rapidly eliminated from the animals. With a feeding level of 10 ppm
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equivalent in the diet, residue levels in edible tissues, milk and eggs were less than 0.12 ppm
equivalent. The metabolite profile in rat was similar in hen and goat. The major plant corn
metabolites Ml, M9, and M10 were also found in rat, goat and hen.
Human Exposures and Risks
The chronic Reference Dose (RfD) has been established at 0.26 mg/kg/day, based on the NOAEL
of 0.26 mg/kg/day from the one-year dog feeding study and an uncertainty factor of 100. The acute
RfD has been established at 1.0 mg/kg/day, based on the NOAEL from the rabbit developmental
toxicity study and an uncertainty factory of 100. The population subgroup of concern for acute
effects is females, 13 years of age and older.
Dietary exposure was calculated by using a Theoretical Maximum Residue Concentration (TMRC)
approach, which assumed 100% of field corn commodities contain residues of diflufenzopyr at the
tolerance level of 0.05 ppm. Dietary (food and drinking water) exposures and risks are summarized
below for relevant subgroups:
Population Subgroup
Food
Exposure
(mg/kg/day)
%RfD
Drinking Water
Estimated
Concentration
(ppb)
Drinking
Water Level of
Comparison
(DWLOC)
(ppb)
I. Acute Exposure and Risk:
Females, 13 + years
0.000128
0.01
<3.8
29,970
II. Chronic Exposure and Risk:
Overall U.S. Population
Infants and Children
0.000063
<0.000200
<0.1
0.1
<1.95
<1.95
9,100
2,600
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Environmental Characteristics
STUDY TYPE
Hydrolysis (Half Life)
Photolysis in Water (Half Life)
Photolysis on Soil (Half Life)
Aerobic Soil Metabolism (Half Life)
Aerobic Aquatic Metabolism (Half
Life)
Anaerobic Aquatic Metabolism (Half
Life)
Mobility- Leaching (Parent)
Mobility- Leaching (Metabolites)
Terrestrial Field Dissipation* (Half
Lifel
HALF
LIFE/OTHER
13 days (pH 5)
24 days (pH 7)
26 days (pH 9)
7 days (pH 5)
17days(pH7)
13days(pH9)
14 days
8-10 days
25-26 days
20 days
Mobile - very mobile
(Koc= 18 to 156mL/g)
Mobile - very mobile (Koc for Ml = 199 to
557mL/g; Koc for M9 = 128 to 1087 mL/g)
4 days
* Based on Canadian study; additional Field Dissipation data required.
Potential to Contaminate Drinking Water
Based upon proposed uses, fate characteristics, and model predictions, EPA does not expect
diflufenzopyr to reach drinking water resources in significant quantities.
Ecological Characteristics
Terrestrial
Diflufenzopyr is practically non-toxic on an acute basis to avian species (LD50 > 2250 mg ae/kg;
LC50 > 5620 ppm ai), of low acute toxicity to small mammals (LD50 = 4000 mg/kg) and practically
non-toxic to honey bees (LD50 > 25 jig ae/bee).
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Aquatic - Freshwater
Diflufenzopyr is slightly toxic to practically non-toxic to freshwater organisms (LC50 = 15to> 135
ppm ae).
Aquatic - Estuarine/Marine
Diflufenzopyr is slightly toxic to practically non-toxic to estuarine/marine organisms (LC50 or EC50
= 18.9 to > 138 ppm ae).
Plants
Diflufenzopyr is highly toxic to terrestrial plants. Seedling emergence studies identified the turnip
as the most sensitive dicot species (EC25 = 0.0008 pounds acid equivalent/acre) and ryegrass as the
most sensitive monocot (Shoot Length EC25 = 0.0055 Ibs. ae/A).
Mechanism of Pesticidal Action
Diflufenzopyr is an auxin transport inhibitor. Diflufenzopyr inhibits the polar transport of naturally
occurring auxin (indoleacetic acid, or IAA) and synthetic auxin-like compounds, such as dicamba,
in sensitive plants. Diflufenzopyr's inhibition of auxin transport causes an abnormal accumulation
of IAA and synthetic auxin agonists in meristematic shoot and root regions, disrupting the delicate
auxin balance needed for plant growth. When diflufenzopyr is applied with dicamba, as in the
Distinct Herbicide formulated product, it focuses dicamba's translocation to the meristematic sinks,
where it delivers effective weed control at reduced dicamba rates and across a wider range of weed
species. Sensitive broadleaf weeds exhibit rapid and severe plant hormonal effects (e.g., epinasty)
after application of Distinct; symptoms are visible within hours, and plant death usually occurs
within a few days. Symptomology, in sensitive annual grasses, is characterized by a "herbistatic"
stunting effect on growth. Tolerance in corn occurs through rapid metabolism of diflufenzopyr and
dicamba.
4. SUMMARY OF REGULATORY POSITION AND RATIONALE
Available data provide adequate information to support the conditional registrations of Diflufenzopyr
Technical, Sodium Diflufenzopyr Technical, and Distinct Herbicide for use on field corn.
Use, Formulation, Manufacturing Process or Geographic Restrictions
Restrictions for Use on Corn:
Do not apply more than a total of 10 ounces of Distinct Herbicide (0.125 pounds
diflufenzopyr and 0.313 pounds dicamba) per acre, per season.
Do not apply if corn is more than 24" tall.
Do not apply within 32 days of forage harvest. Do not apply within 72 days of corn
grain and stover harvest.
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Allow a minimum of 15 days between sequential applications of Distinct.
Do not plant any crops within 120 days after the last application of Distinct. In the
event of crop failure, corn can be replanted 7 or more days after application.
Do not use penetrants such as petroleum-based oils or methylated seed oils with
Distinct as crop injury may result.
Do not apply to corn showing injury (leaf phytotoxicity or plant stunting) produced
by any other prior herbicide applications, because this injury may be enhanced or
prolonged.
Do not apply through any type of irrigation system.
Do not treat irrigation ditches or water used for crop irrigation or domestic uses.
This product cannot be used to formulate or reformulate any other pesticide product.
5. SUMMARY OF DATA GAPS
Residue Chemistry Data:
Rotational crop data
Storage stability data
Environmental Fate Data:
Terrestrial field dissipation data (end use product)
Aerobic soil metabolism (metabolites)
Ecological Effects Data:
Tier 2 vegetative vigor
Acute freshwater invertebrate toxicity (end-use product)
Chronic aquatic invertebrate toxicity (end-use product)
Acute freshwater invertebrate toxicity (end-use product)
Avian reproduction test (end-use product)
Fish early life-stage test (end-use product)
6. CONTACT PERSON AT EPA
Joanne I. Miller, Product Manager 23
Herbicide Branch
Registration Division (7505C)
Office of Pesticide Programs
Environmental Protection Agency
401 M Street, SW
Washington, DC 20460
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Office Location and Telephone Number
Room 239, Crystal Mall Building #2
1921 Jefferson Davis Highway
Arlington, VA 22202
(703) 305-6224
DISCLAIMER: The information presented in this Pesticide 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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