United States
Environmental Protection
Agency
                    Office of Prevention, Pesticide
                    and Toxic Substance (7501C)
   SEPA
Common Name

Chemical Name:



EPA Chemical Code:

Chemical Abstracts
Service (CAS) Number:

Chemical Class:

Registrations:



Pesticide Type:

Mode of Action:

Route of Exposure:

Registrant
                                                  Difenacoum
                                                  New Rodenticide
                                                  September 2007
     Pesticide

     Fact Sheet

        Name of Chemical:
        Reason for Issuance:
        Date Issued:
  Description of Chemical
Difenacoum
3-[3-(l,l'-biphenyl)-4-yl-l,2,3,4-tetrahydro-l-naphthalenyl]-
4-hydroxy-2//-l -benzopyran-2-one CAS)
3 -[3 -(1,1 '-biphenyl)-4-yl-1,2,3,4-tetrahydro-1 -naphthalenyl]-
4-hydroxy-2//-1 -benzopyran-2-one (IUPAC)
119901

56073-07-5
4-hydroycoumacin class of anticoagulants

Difenacoum Technical
 EPA Reg. No. 47629-12
 Difenacoum Rat and Mouse Pellets, 0.005%
 EPA Reg. No. 47629-14
Rodenticide

Disrupt clotting ability of blood (anticoagulant)

Ingestion

Woodstream Corporation

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I. USE PATTERN AND FORMULATIONS
Difenacoum belongs to the 4-hydroxycoumarin class of anticoagulants and is a pesticide
intended to control commensal rodents (Norway rat, roof rat, and house mice) in and
around buildings and inside of transport vehicles. In Europe, it has been marketed as a
"second generation anticoagulant", a designation that it shares with brodifacoum,
bromadiolone, and difethialone (rodenticides first registered in the United States in
1980's or 1990's).  First generation anticoagulants are warfarin and its sodium salt,
diphacinone and its sodium salt, and chlorophacinone (rodenticides first registered in the
1950's, 1960's, or 1970's).  Difenacoum's route of exposure is by ingestion, and its
mode of action is the disruption of the clotting of the blood. European countries have
registered this rodenticide since the 1970's.

The registrant, Woodstream of Lilitz, Pennsylvania, has two initial registrations, a
Difenacoum Technical, EPA Reg. No. 47629-12 and Difenacoum Rat and Mouse Pellets,
EPA Reg. No.47629-14, as a loose pellet formulation at 0.005% (50 ppm).
Fable 1. Summary of Proposed Directions for Uses of Difenacoum.
Formulation
[EPA Reg. #[
Method of
Application
Use Sites
Application Rate
Timing of Application
For Control of Norway Rats, Roof Rats, and House Mice
Difenacoum Rat
and Mouse Pellets
(0.005% a.i.)
#47629-14











By hand,
spoon, and
ready-to-use
place packs











In and around
periphery of homes;
industrial,
commercial and
public buildings;
transport vehicles
(trains, ships,
airplanes); and
alleys.

All baits are to be
placed out of the
reach of children,
pets, domestic
animals, and non-
target wildlife, or in
tamper-resistant bait
stations.
Rats: 3 to 7 ounces of
bait per placement
(15-30 feet intervals)
Treating borrows: 1 to 2
ounces of bait applied
with spoon

Mice: 0.5 to 1 ounce of
bait per placement
(8- 12 feet intervals)







Highest bait consumption
is expected to occur on the
first day or two after
treatment. Continue
baiting until all signs or
evidence of rodent activity












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II. SCIENCE FINDINGS

1. Chemical Nomenclature and Physical/Chemical Properties:

Table 2 presents the nomenclature of Difenacoum, and Table 3 presents the
physical/chemical characteristics of Difenacoum:
 Table 2. Difenacoum Nomenclature.
 Chemical Structure
 Common Name
Difenacoum, diphenacoum
 Molecular Formula
 Molecular Weight
444.5
 IUPAC Name
3-(3-biphenyl-4-yl-l,2,3,4-tetrahydro-l-naphthyl)-4-hydroxycoumarin
 CAS Name
3-[3-( 1,1 '-biphenyl)-4-yl-1,2,3,4-tetrahydro-1 -naphthalenyl]-4-hydroxy-27/-l -
benzopyran-2-one	
 CAS Registry Number
56073-07-5
 Technical Product
Difenacoum Technical (99.0% w/w, EPA Registration No. 47629-12
 End-use Product
Difenacoum Rat and Mouse Pellets (0.005% w/w), EPA Registration # 47629-14
 Chemical Class
Anticoagulant Rodenticide
 ! Not yet registered.
Table 3. Physicochemical Properties of Technical Grade Difenacoum.
Parameter
Melting Point/Range
PH
Relative Density (20.5C)
Water Solubility (20C)
Solvent Solubility (g/L at 20C)
Value
21 1.0 - 215.0C (98.7% w/w)
Not available
1.27 (98.7% w/w)
<0.05 mg/L at pH 4
1.7mg/LatpH7
61 mg/L at pH 9
Acetone 7.6
Propan-2-ol 1.5
Ethyl acetate 3.7
Toluene 1.2
Methanol 1.2
Hexane 0.01
Dichloromethane 19.6
Reference
MRID 46750965

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Table 3. Physicochemical Properties of Technical Grade Difenacoum.
Parameter
Vapor Pressure (25C)
Dissociation Constant (pKa)
Octanol/Water Partition Coefficient (Log[Pow])
UV/Visible Absorption Spectrum
Wavelength of peak (nm)
Absorbance
Molar Extinction Coefficient
Value
6.7xl(rv-5.4xlO-|4Pa
4.5
7.6
310.6
0.267
17,100
259.4
0.664
46,600
Reference

2. Toxicology Summary

Tables 4 (Acute Toxicity Profile - Difenacoum) and Table 5 (Subacute, Chronic, Other
Toxicity Profile - Difenacoum) summary the toxicological studies that support
Woodstream's initial registrations.
Table 4 Acute Toxicity Profile - Difenacoum
Guideline
No.
870.1100
870.1100
870.1100
870.1200
870.1300
870.2400
870.2500
870.2600
Study Type
Acute oral - rat
Acute oral - rat
Acute oral - rat and mouse
Acute dermal - rat
Acute inhalation - rat
Acute eye irritation - rabbit
Acute dermal irritation - rabbit
Skin sensitization - guinea pig
MRTO(s)
46750935
46750936
46766206
46750938
46750939
46750940
46750941
46750942
Results
LDjo= 1.8 rag/kg (0.003646 mg/L
(c5+2)
1/3 conjunctival irritation
immediately after. No
positive irritation at 24-
hours.
No irritation at the 24-hour
observation.
Not a sensitizer
Toxicity
Category
I
I
I
I
I
IV
IV
N/A

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Table 5 Subchronic, Chronic and Other Toxicity Profile - Difenacoum
Guideline
No.
Non-
guideline





870.3100










870.3700a





870.3700b








870.5100


870.5100


870.5300




Study Type

6-Week oral
toxicity (dog)





90-Day oral
toxicity (rat)









Prenatal
developmental in
rodents (rat)



Prenatal
developmental in
non-rodents
(rabbit)





Gene mutation -
bacterial reverse
mutation assay
Gene mutation -
bacterial reverse
mutation assay
Gene mutation -
in vitro
mammalian cell
gene forward
mutation assay
M RID No. (year)/
Classification /Doses
46750944 (1994)
Acceptable/nonguideline
0,0.01,0.025,0.05,0.1,0.2
mg/kg/day



46766207 (1991)
Unacceptable/guideline
0, 0.01, 0.02/0.09, 0.03
mg/kg/day







46766208 (1994)
Acceptable/guideline
0,0.01,0.03,0.09
mg/kg/day


46750947 (1994)
Acceptable/guideline
0,0.001,0.005,0.015
mg/kg/day





46750948 (1995)
Acceptable/guideline

46766209 (1986)
Acceptable/nonguideline

46750952 (1995)
Acceptable/guideline



Results

NOAEL = Not determined
LOAEL = 0.01 mg/kg/day based on changes in
blood coagulation, particularly increased
prothrombin time beginning on day 30.
All animals exposed to > 0.025 mg/kg/day were
sacrificed early due to increased coagulation
times and/or clinical evidence of hemorrhage.
NOAEL = Cannot be determined
LOAEL = Cannot be determined

No effect on coagulation at 0.01 mg/kg/day
This study was classified unacceptable due to
inadequate number of animals/sex/dose. There
were no surviving males after day 78. The dose
level for the 0.02 mg/kg/day animals was
increased to 0.09 mg/kg/day on Day 65 (F) or 66
(M). Hematology data are not available for the
low dose group.
Maternal NOAEL = 0.03 mg/kg/day
Maternal LOAEL = 0.09 mg/kg/day based on
vaginal bleeding and increased kaolin-cephalin
time.
Developmental NOAEL = 0.09 mg/kg/day
Developmental LOAEL = Not observed
Maternal NOAEL = 0.005 mg/kg/day
Maternal LOAEL = 0.015 mg/kg/day based on
changes in blood coagulation (increased
prothrombin and kaolin-cephalin times).
All animals in the 0.015 mg/kg/day group were
sacrificed to prevent or minimize fatal maternal
hemorrhage.
Developmental NOAEL = 0.015 mg/kg/day
Developmental LOAEL = Not observed
Negative.


Negative.


Negative.





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Table 5 Subchronic, Chronic and Other Toxicity Profile - Difenacoum
Guideline
No.
870.5375

870.5375

870.5395


870.5395


870.5550

870.5550

870.7485





Study Type
Cytogenetics - in
vitro mammalian
cell chromosome
aberration test
Cytogenetics - in
vitro mammalian
cell chromosome
aberration test
Cytogenetics -
mammalian
erythrocyte
micronucleus test
(rat)
Cytogenetics -
mammalian
erythrocyte
micronucleus test
(mouse)
Other effects -
unscheduled
DNA synthesis
in mammalian
cells in culture
Other effects -
unscheduled
DNA synthesis
in mammalian
cells in culture
Metabolism and
pharmacokinetics
(rat)





MRID No. (year)/
Classification /Doses
46750950 (1995)
Acceptable/guideline

46766210 (1986)
Acceptable/guideline

46766211(1996)
Acceptable/guideline


46766212 (1987)
Acceptable/guideline


46773601 (1996)
Acceptable/guideline

46766214 (1990)
Acceptable/guideline

46766216 (1996)
Acceptable/guideline
0.051 or0.54mg/kg





Results
Positive for chromosomal aberrations in cultured
human lymphocytes with and without S9
activation, with a variable dose-response.

Positive for chromosomal aberrations in Chinese
hamster lung cells with and without S9
activation, with a variable dose-response.

Negative.


Negative.


Negative.

Negative.

Groups of 4 female SD rats were given a single
oral gavage dose of radiolabled difenacoum.
Absorption: Rapid; reached mean peak blood
level for each dose group 4 hours after dosing.
Distribution: Radioactivity was present in all
tissues examined. At necropsy (168 hours), the
majority of the unexcreted dose was present in
the liver (37.6%/20.6% mean radioactivity from
administered low/high dose), with smaller
amounts in the carcass (17.2%/13.5%; low/high
dose), the GI tract (4.0%/2.7%; low/high dose),
and pancreas (1 . 1%/1 .2%; low/high dose).
Metabolism: Absorbed difenacoum is
extensively metabolized, with both parent
compound and up to 4 metabolites present in the
liver at 7 days after dosing. In the liver, 4
metabolites were found in low dose animals and
2 metabolites were found in high dose animals.
Both the parent compound and two of the
hepatic metabolites are eliminated in the faeces
within the first 24 hours, along with a polar
metabolite(s).
Elimination: At 24 hours, 17.7%/19.8%

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Table 5 Subchronic, Chronic and Other Toxicity Profile - Difenacoum
Guideline
No.

Study Type

MRID No. (year)/
Classification /Doses

Results
(fgces), 1.4%/1.2% (urine), and 0.36%/0.06%
(expired CCM of the radioactivity from the
administered low/high dose, respectively, was
recovered. By 168 hours, 39.9%/50.9% (feces)
and 1.9%/1.44% (urine) of the radioactivity from
the administered low/high dose, respectively,
was recovered.

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Table 5    Subchronic, Chronic and Other Toxicity Profile - Difenacoum
Guideline
   No.
   Study Type
     MRTO No. (year)/
   Classification /Doses
                   Results
870.7485
Metabolism and
pharmacokinetics
(rat)
46766215 (2002)
Acceptable/nonguideline
0.57 mg/kg (cis isomer) or
0.55 mg/kg (trans isomer)
Groups of 4 female SD rats were given a single
oral gavage dose of radiolabled cis or trans-
difenacoum.
Absorption:  Reached plateau in plasma 8-24
hours after  dosing, followed by slow elimination
phase. Peak blood level of the cis-isomer (0.21
\ig equiv/ml) was approximately 2.5 times
greater than the trans-isomer (0.08 ng equiv/ml)
at 8 hours.
Distribution:  Radioactivity was present in all
tissues examined. At 96 hrs, the highest levels
were found in the liver (19-22% of the
administered dose of cis-isomer; 22-29% trans),
carcass (13.9-16.3% cis; 11.9-13.5% trans),
pancreas (1.2-1.8% cis; 1.3-1.4% trans), and GI
tract, including stomach, intestines,  cecum, and
content (4-4.2% cis; 3.1-4.3% trans).
Metabolism: Not investigated hi this study.
Elimination: Within 96 hours, the  radioactivity
was recovered mostly in the feces (41% of the
administered dose of cts-isomer; 44.5% trans),
with small amounts in urine (0.5% cis; 0.6%
trans).	
870.7485
Metabolism and
pharmacokinetics
(rat)
46750957(1987)
Acceptable/nonguideline
1.2 mg/kg
32 male Alpk:AP rats were given a single oral
gavage dose of radiolabled difenacoum and were
sacrificed in groups of three at 1,4 and 8 days,
and 2,4, 8, 12 and 26 weeks after dosing.
Absorption: The concentration of radioactivity
in the blood and tissues was highest 24 hours
after dosing, which was the earliest
measurement.
Distribution:  The highest concentration of
radioactivity, expressed as % of the dose, was
found in the liver (42%), followed by the
pancreas (0.48%), kidney (0.22%), and salivary
glands (0.09%), with lower concentrations in the
blood and fat.  Whole body autoradiography
showed that radioactivity levels were similarly
distributed and not significantly reduced (except
for the GI tract) at 5 days after dosing.
Metabolism:  The cis: trans ratio of difenacoum
in the liver at 24 hours was 64:36, while the ratio
of administered difenacoum was 44:56, which
suggests that the tran-isomer was being
preferentially metabolized or eliminated. Five
metabolites were found hi the liver, accounting
for 53% of the total radioactivity in the liver
extract, but these were not identified.
Elimination:  Elimination from the liver was
biphasic, with a rapid phase during days 1-8
accompanied by a reduction in clotting factor

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Table 5    Subchronic, Chronic and Other Toxicity Profile - Difenacoum
Guideline
   No.
   Study Type
     MRTO No. (year)/
   Classification /Doses
                   Results
                                                           synthesis (t Vl = 3 days), followed by a slower
                                                           terminal phase during days 28-182 (t v, = 118
                                                           days). Similar biphasic elimination was found in
                                                           the kidney and salivary glands, but not the
                                                           pancreas. The relative rate of elimination was
                                                           liver, fat, and blood > kidney > salivary glands >
                                                           pancreas.
870.7485
Metabolism and
pharmacokinetics
(species)
44742901 (1992)
Unacceptable/guideline
Irrespective of dose, most of an orally
administered radiolabeled fenazaquin was in rat
excreta (89.5-107.7%) at 168 hours with
approximately 20% of the radiolabel in urine.
After initial uniform distribution, about 0.5-1.6%
of the dose was in the carcass and below 0.04%
of the dose in each tissue. There was no
radiolabel in the expired air and no evidence for
bioaccumulation.  Based on excretion and tissue
residue data, bioavailability is conservatively
estimated at about 20% of an administered dose.

Non-metabolized fenazaquin was higher in feces
(1.0-15.0% of administered dose) than in urine
(below 0.5% of dose) and some of the major
metabolites were identified including AN-1
(urine) in addition to  the fecal metabolites F-l,
F-2 and F3. The metabolic pathway of
fenazaquin involved cleavage of the ether bond,
resulting in the formation of the respective
alcohol (4-OH quinazoline metabolite) and
carboxyl acid (AN-1) derivatives. Other
biotransformation reactions included oxidation
of one  of the methyl groups on the alkyl side
chain to produce either an alcohol (F-l)  or
carboxylic acid (F-2)  metabolites. Finally,
hydroxylation at the O-ether alkyl moiety of F-l
or the 2-position of the quinazoline ring of F-2
resulted in F-l A and F-3 metabolites,
respectively.

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2. Environmental Fate Summary
Difenacoum bait consists of blue-green cylindrical pellets.  It has very low solubility and
low vapour pressure, but is very persistent.

Table 6 summarizes the environmental fate studies supporting Difenacoum.

Table 6.      Fate and Transport Parameters for Difenacoum.
Parameter
Hydrolysis t1/2 (days)
Aqueous Photolysis t,/2 (days)
Atmospheric Photolysis t,/2 (days)
Aerobic Soil tin (days)
Aerobic Aquatic t,,, (days)
Anaerobic Soil t,,, (days)
Anaerobic Aquatic t,;, (days)
LogK^
LogK_
Value
Stable
1000
80
0.14
0.34
0.30
0.087
439


Stable
2.1-2.3
6.45
Comments
pH5
pH7
pH9
pH5
pH7
pH9
N/A (low vapor pressure,
solid bait placed on ground)

not provided
not provided
after 49 days

Calculated from Kow
3. Environmental Effects Summary

A. Primary Terrestrial Hazards Studies

Table 7 summarizes acute oral toxicity studies on difenacoum for the Northern bobwhite
and mallards.

Table 7.  Acute oral toxicity of difenacoum to Northern bobwhite and mallards.
Species
Northern bobwhite
(Colinus virginianus)
Mallard
(Anas platyrhynchos)
%ai
91.1
94.6
LD50
(mg/kg bw)
66
(56 ?; 140
5)
>2000
Observation
period (days)
28
21
Study
date
1980
1996
MRID no.
46750922
46750921
                                      10

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Table 8 summaries sub-acute dietary toxicity studies on Difenacoum for mallards and the
ring-necked pheasant.

Table 8. Sub-acute dietary toxicity of difenacoum in mallard and ring-necked
pheasant.
Species
Mallard
(Anas platyrhynchos)
Ring-necked pheasant
(Phaisianus colchicus)
%
ai
91.1
96.5
LCso
(ppm)
18.9
57
Observation
period (days)
40
19
Study date
1980
2000
MRID no.
46750926
46766204
Table 9 summaries feeding tests conducted on difenacoum and other anticoagulant
rodenticides.

Table 9.  Adverse Effects of Difenacoum and Other Anticoagulant Baits Fed to
Adult Leghorn Chickens for up to 15 Days (adapted from Lund 1981)
Anticoagulant
Difenacoum
(50 ppm)
Brodifacoum
(50 ppm)
Bromadiolone
(50 ppm)
Warfarin
(250 ppm)
Avg. intake per bird3
Bait (g)
611
(458-835)
362
(252-443)
496
(329-684)
922
(584-1232)
ai (mg/kg)
19
(13.5-28.3)
10.5
(7.1-15.0)
12
(5.9-16.9)
149
(132-171)
Mortality
2/4
4/4
2/4
0/3
Adverse effects
loss of appetite;
hemorrhage from day 5
death from day 6
loss of appetite;
hemorrhage from day 6
none
1 range is given in parentheses
Table 10 summarizes a chronic toxicity on difenacoum to the Japanese quail.

Table 10. Chronic toxicity of difenacoum in Japanese quail.
Species
Japanese quail
(Coturnix coturnix
japonicd)
%
ai
96.7
NOAEC
(ppm)
>0.100
Observation
period (days)
140
Study date
2005
MRID no.
46799101
                                      11

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Table 11 summarizes the acute oral toxicity test on Difenacoum to the laboratory rat.

Table 11.  Acute oral toxicity of difenacoum to the laboratory rat.
Species
Laboratory rat
(Rattus norvegicus)
%ai
98.7
LD50
(mg
ai/kg)
1.8 c?
2.6$
Observation
period (days)
14
Study date
1995
MRID no.
46750935
46750936
Table 12 summaries a chronic/developmental toxicity test on Difenacoum to the
laboratory rat and rabbit.

Table 12.  Chronic/developmental toxicity of difenacoum to the laboratory rat and
rabbit.


Species

Rabbit
(Orycytolagus
cuniculus)

Laboratory rat
(Rattus
norvegicus)



Laboratory rat
(Rattus
norvegicus)




O/ 0,'
/O 31

98.5

982



NR1




LOAEL/NOAEL
(mg ai/kg-bw/day)
Maternal: 0.01 5 /
0.005
Fetus: 0.015
(highest dose
tested)
Maternal:
0.09/0.03
Fetus: 0.09 (highest
dose tested)



0.1/0.03



Exposure/
Observation
period (days)

Days 8-20
post mating

Days 7-16
post mating



Exposure =
90 days




Study
date

1994

1994



NR




Effects Observed


Increased coagulation time in
dams at 0.015 dose level.
No fetal effects observed.

Vaginal bleeding and
increased kaolin-cephalin
time in dams at 0.09 dose
level.
No fetal effects observed.
Dosed at 0.03, 0.1, 0.2 mg
ai/kg bw/day. 10% death
(males) and increase in
prothrombin time and
thrombin time (males and
females) at medium dose.
55% mortality, increase in
thrombin and prothrombin
time in females, signs of
toxicity at high dose.
'Not Reported.
B. Aquatic Hazards Studies

All aquatic freshwater fish and invertebrate tests show Difenacoum to be very highly
toxic to those species. This active is also toxic to algae.

Table 13 summaries freshwater acute toxicity tests on Difenacoum.
                                       12

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Table 13. Acute toxicity of difenacoum to freshwater fish.

Species


Rainbow trout
(Oncorhynchus mykiss)

Bluegill sunfish
(Lepomis macrochirus)

%ai


96.3

96.3
LCso
(Ppb)


64

258

Exposure duration
(h)
96
(renewal after 48
h)
96
(renewal after 48
h)

Study
date

1995

1995

MRID no.


46750919

46750920
Table 14 summaries freshwater invertebate toxicity tests on Difenacoum.
Table 14. Acute toxicity of difenacoum to aquatic invertebrates.
Species
Waterflea
(Daphnia magna)
%ai
61.4%cw
38.6%
trans
96.3
ECso
(Ppb)
520
610
Exposure
duration (h)
48
48
Study date
1991
1995
MRID no.
46750918
46750917
Table 15 summaries a toxicity test on Difenacoum to algae.

Table 15.  Toxicity of difenacoum to aquatic plants.
Species
Green alga
(Selenastrum
capricornutum)
%ai
96.3
6\A%cis
38.6%
trans
EC50 1 NOAEC
(ppb)
320 / 250
(growth curve)
>2500
(growth curve)
Exposure
duration (h)
72
96
Study date
1995
1991
MRID no.
46750929
46766205
C. Secondary Hazards Studies

The Agency reviewed several secondary hazard studies on birds and mammals (or their
summaries) and found evidence that difenacoum, like related anticoagulants, are capable
of producing toxicity effects secondarily.

Table 16summaries adverse effects of difenacoum and other anticoagulants to barn owls
exposed to rats fed toxic bait.
                                       13

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Table 16.  Adverse Effects of Difenacoum and Other Anticoagulants to Barn Owls
Anticoagulant
Days
exposed
No. tested/
no. dead
Sublethal effects
Observed
Second-generation anticoagulants:
Difenacoum (50 ppm)
Brodifacoum (50 ppm)
Bromadiolone (50 ppm)
1
3
6
10
1
3
6
10
1
3
6
10
1/0
2/0
1/0
2/0
1/0
2/2
1/1
2/2
1/0
2/0
1/0
2/1
the 3 owls offered rats for 6 or 10 days
survived but all hemorrhaged
(1 severely)
none reported in the lone survivor
none reported
First-generation anticoagulants:
Diphacinone (50 ppm)
Chlorophacinone (50 ppm)
Fumarin (250 ppm)
10
10
10
2/0
2/0
2/0
none reported
none reported
none reported
Table 17 summaries another bam owl study (Gray et. Al, 1992) showing adverse effects
of difenacoum and other anticoagulants to barn owls exposed to mice fed toxic bait.
Table 17. Secondary toxicity in Barn Owls (Gray c
Survival Status
Anticoagulant
consumed
(ug/day)
Cumulative
consumption
(mg/kg owl bw)
:t al. (1992) .
Residue Concentration (mg/kg)
Liver
Fat
Muscle
Difenacoum (50 ppm):
Survived (n=3)
Died(n=l)
36-128
101
1.6-5.5
3.7
0.06-0.14
0.25
<0.01
0.01
0.01
0.01
Brodifacoum (50 ppm):
Survived (n=3)
Died(n=l)
52-99
133
1.9-3.3
5.5
0.55-0.69
1.67
O.01-0.01
0.13
0.02
0.04
Flocoumafen" (50 ppm):
                                      14

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Survived (n=2)
Died (n=2)
39-43
56-85
1.8-1.9
2.2-2.8
0.51-0.52
0.57 - 0.70
0.01
0.07 - 0.08
0.04 - 0.06
0.05 - 0.06
 Flocoumafen is not registered in the U.S.

In studies with mammals, Shore et al. (2003) present data on residues in polecats
(Mustela putorius) accidentally killed on roads in England.  Livers were analyzed for
residues of second-generation anticoagulant rodenticides, including difenacoum,
bromadiolone, flocoumafen, and brodifacoum. Of 100 carcasses collected for all three
studies between 1992 and 1999, 31 contained residues of at least one second-generation
anticoagulant. Difenacoum was the most prevalent compound, having been detected in
26 animals.

D. Characterization of Toxicokinetics

 Absorption, distribution and excretion of difenacoum are similar to that reported for
other second-generation anticoagulants (brodifacoum, flocoumafen, bromadiolone).
Difenacoum appears to be well absorbed following oral administration.

      Difenacoum is slowly eliminated. Urinary and fecal excretion during a 7-d period
       after dosing of female rats, fecal and urinary excretion accounted for only 57 and
       39%, respectively, of a dose of 0.05 and 0.54 mg/kg of [14C]-difenacoum.
       Excretion was greatest during the 24 h period after dosing and was very slow
       thereafter.

      Difenacoum and/or its metabolites are widely distributed in body tissues. The
       concentration of radioactivity was above the limit of detection in all 15 tissues
       analyzed in excretion studies, with highest concentrations found in the liver and
       pancreas.

      The concentration in fat was relatively low. Difenacoum is highly lipophilic, but
       that does not significantly affect tissue distribution due to a high affinity for
       specific binding sites in tissues.

      Elimination from tissues is biphasic, with an initial rapid phase during the first
       few days after dosing followed by a very slow phase. The slow elimination from
       tissues is consistent with the slow fecal elimination found during an excretion
       study.

      The trans-isomer is either less well absorbed or more rapidly eliminated from rats
       than is the c/s-isomer, though the differences are not great.

     Difenacoum is partly excreted in feces as metabolites, and metabolites also
       constitute part of the residue in liver. Neither the extent of fecal excretion nor the
      proportion of metabolites in faeces is dose dependent, but the proportions of
       difenacoum and its metabolites in liver are both dose and time dependent.
                                       15

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E. Incidents in United Kingdom
Table 18 illustrates the potential for difenacoum to affect a wide range of nontarget
organisms secondarily.

Table 18. Wildlife incidents involving difenacoum recorded in the UK's Wildlife
Incident Investigation Scheme.
Year
2006
2005
2004
2003
2002
2001
2000
1999
1998
No. Incidents
363
15
20
11
24
8
15
19
9
Species Involved2
cat, stoat, weasel, dog, buzzard, kestrel, barn owl,
pigeons, peacock
red kite, fox, ferel
buzzard, kestrel, red kite, badger, fox, grey squirrel, rat, bantam
chicken, cat, dog, goose
blackbird, buzzard, crow, house sparrow, red kite,
badger, fox, pony, cat, dog
crow, dove, red kite, badger, rabbit, cat, dog
buzzard, feral pigeon, red kite, fox, cat, dog
sparrowhawk,


Buzzard, red kite, badger, pine marten
buzzard, red kite, badger, fox, cat, dog
buzzard, house sparrow, red kite, tawny owl, fox,
cat, dog
buzzard, pheasant, dog, cat
                                       16

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III. HUMAN HEALTH EFFECTS RISK ASSESSMENT
A. Toxicological Doses and Endpoints for Difenacoum in Human Risk Assessments

Table 19 summaries the lexicological doses and endpoints for difenacoum in non-
occupational human health risk assessments.
Table 19. Toxicological Doses and Endpoints for Difenacoum for Use in Non-Occupational Human
Health Risk Assessments.
Exposure/
Scenario
Acute
Dietary (All
Populations)
Chronic
Dietary (All
Populations)
Incidental
Oral
(Episodic)
Dermal
(Short-
Term)
Inhalation
(Short-
Term)
Cancer
Point of
Departure
Uncertaint
y Factors
Level of Concern
for Risk
Assessment
Study and Toxicological Effects
Dietary endpoints were not selected because difenacoum is strictly a non-food use
chemical.
Dietary endpoints were not selected because difenacoum is strictly a non-food use
chemical.
NOAEL=
0.005
mg/kg/day
NOAEL=
0.005
mg/kg/day
Dermal
absorption
rate= 4%
NOAEL=
0.005
mg/kg/day
Default
inhalation
absorption
rate= 100%
UFA= lOx
UFH= lOx
UFA= lOx
UFH= lOx
UFA= lOx
UFH= lOx
Residential LOG
forMOE=100
Residential LOG
forMOE=100
Residential LOC
forMOE=100
Developmental toxicity study in
rabbits
LOAEL = 0.015 mg/kg/day based
on changes in blood coagulation
(increased prothrombin and kaolin-
cephalin times).
Developmental toxicity study in
rabbits
LOAEL = 0.015 mg/kg/day based
on changes in blood coagulation
(increased prothrombin and kaolin-
cephalin times).
Developmental toxicity study in
rabbits
LOAEL = 0.015 mg/kg/day based
on changes in blood coagulation
(increased prothrombin and kaolin-
cephalin times).
Classification: N/A
Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response
data  and  used  to  mark the beginning of extrapolation  to  determine risk associated  with  lower
environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest
observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from animal to human
(interspecies).  UFH = potential variation  in  sensitivity among members  of the human population
(intraspecies). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.
                                          17

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Table 20 summaries the lexicological doses and endpoints for difenacoum in
occupational human health risk assessments.
Table 20. Summary of Toxicological Doses and Endpoints for Difenacoum for Use in Occupational
Human Health Risk Assessments.
Exposure/
Scenario
Dermal
(Short-
Term)
Inhalation
(Short-
Term)
Cancer
Point of
Departure
NOAEL=
0.005
mg/kg/day
Dermal
absorption
rate= 4%
NOAEL=
0.005
mg/kg/day
Default
inhalation
absorption
rate= 100%
Uncertaint
y Factors
UFA= lOx
UFH=10x
UFA= lOx
UFH=10x
Level of Concern
for Risk
Assessment
Occupational LOC
forMOE=100
Occupational LOC
forMOE=100
Study and Toxicological Effects
Developmental toxicity study in
rabbits
LOAEL = 0.015 mg/kg/day based
on changes in blood coagulation
(increased prothrombin and kaolin-
cephalin times).
Developmental toxicity study in
rabbits
LOAEL = 0.015 mg/kg/day based
on changes in blood coagulation
(increased prothrombin and kaolin-
cephalin times).
Classification: N/A
Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response
data  and   used to  mark the  beginning of  extrapolation to determine risk associated  with lower
environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest
observed adverse effect level.  UF = uncertainty factor. UFA =  extrapolation from animal to  human
(interspecies).   UFn = potential variation  in sensitivity among  members of the human population
(intraspecies). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

B. Residential Exposure and Risk

Since  difenacoum  is  strictly  a non-food use  rodenticide  and  since,  based on its
physicochemical properties, no measurable concentrations of difenacoum are expected in
drinking water, only residential exposure could be included in an aggregate assessment.
Therefore, a separate aggregate risk assessment was not conducted.

1. Residential Handlers Exposure and Risk

An assessment for mixer/loader scenarios was not performed, since both formulations
(pellets and place packs)  are considered "ready-to-use".  Since the dermal and inhalation
endpoints are the  same, dermal and inhalation doses  were combined to calculate a total
MOE for applicator scenarios.  All applicator scenarios resulted in total MOEs greater
than the level  of concern (MOEs >  100) at the baseline level, as indicated in Table 21.
                                         18

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Table 21. Residential Handler Short-term Exposure and Risk for Difenacoum At Baseline (No Gloves
Scenario

Difenacoum
(0.005% a.i.)
pellets
Reg.# 47629-
XX
Difenacoum
(0.005% a.i.)
placepacks
Reg.# 47629-
XX
Use Site

In and around
homes, commercial,
industrial and
public buildings; rat
burrows
In and around
homes, commercial,
industrial and
public buildings
Dermal
Unit
Exposure
(mg/lb) *

103.77
Inhalation
Unit
Exposure
(mg/lb) "
Application
Rate"
(Ib ai/site)
Site
Treated c
(sites/day)
% Dermal
Absorption
.
Dermal
Dose "
(mg/kg/day)
Dermal
MOEf
Inhalation
Dose e
(mg/kg/day)
Inhalation
MOEg
Total
MOE"
Applicator
0.47
0.0000218
(7 oz prod,
= 794
pellets)
0.0000094
(3 oz place
pack)
2
4
4
2.6E-6
1.1E-6
1900
4500
2.9E-7
1.26E-7
17,000
40,000
1700
4100
a.  PHED Version 1.1 Scenario 17: Granular Bait Dispersed by Hand; Dermal unit exposure (baseline- no gloves) = 5.67 + 62 + (3.61/0.1)= 103.77
b.  Application Rate based on proposed registered label for Difenacoum .
 According to registrant one pellet weighs 0.25 grams,  lounce (28.35 g)/0.25 g = 113 pellets; 113x7 ounces = 794 pellets/7 oz
c.  Number of bait sites set, treated per day
d.  Short-term Dermal Dose  (mg/kg/day) = [ Rate (Ib ai/A) x UE (mg /Ib ai) x  Sites Treated (A/day)] x % dermal absorption / BW (70 kg)
e.  Short-term Inhalation Dose (mg/kg/day) = [ Rate (Ib ai/A) x UE (mg /Ib ai) x Sites Treated (A/day)] / BW (70 kg)
f.  Short-term Dermal MOE = [Dermal NOAEL (0.005 mg/kg/day)]/ Dermal Dose (mg/kg/day)
g.  Short-term Inhalation MOE = [Inhalation NOAEL (0.005 mg/kg/day)] / Inhalation Dose (mg/kg/day)
h.  Total MOE = NOAEL (0.005 mg/kg/day) / Dermal Dose (mg/kg/day) + Inhalation Dose (mg/kg/day)
                                                                       19

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2. Postapplication Dermal Exposure

EPA did not conduct a separate quantitative an adult, short-term, postapplication dermal
exposure (adult clean-up and bait disposal) assessment because is would be similar to the
to applicator exposure (adult bait application).

EPA did not conduct a quantitative child, short-term dermal postapplication exposure
assessment because, although incidental child dermal contact could occur, EPA does not
consider this exposure to be a routine behavior on a regular basis. It considers this
exposure to be an episodic event.

3. Postapplication Episodic Incidental Ingestion of Bait

      EPA considers ingestion of granules to be an episodic event and not a routine
       behavior. EPA conducted this risk assessment because of the high incidence of
       episodic oral exposures (>15,000/year) for existing rodenticides on the market.
       Difenacoum Rat and Mouse Pellets pose the risk of incidental ingestion of pellets.
       The episodic oral MOE for incidental ingestion of granules by children is 0.3.
       Even though the Agency's level of concern is exceeded for episodic ingestion of
       difenacoum by children,  the human health risk from  the use of difenacoum will
       not be significantly different compared to other registered rodenticides with
       similar use patterns and mode of action. Additionally, the product label will
       include directions for application of the bait in areas  inaccessible to children and
       pets
Table 22. Postapplication Exposure and Risk for Incidental Ingestion of Granules of Difenacoum.
Scenario
Difenacoum Rat and Mouse Pellets
RegNo47629-XX
IgR
(g/day)
5
F
0.00005
CF1
(mg/g)
1000
Dose"
(mg/kg/day)
0.016667
MOEb
0.3
"Dose = IgRx F x CF1 H- BW
b MOE = NOAEL (0.005 mg/kg/day)/Dose
C. Occupational Exposure and Risk

1. Handlers Exposure and Risk

All Difenacoum applicator scenarios resulted in MOEs that are not of concern (MOEs >
100).

2. Postapplication Exposure and Risk
                                        20

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All postapplication scenarios resulted in MOEs that are not of concern at the baseline
level (MOEs> 100).
IV. ECOLOGICAL FATE AND EFFECTS RISK ASSESSMENT

A. Potential Primary Risks

Acute Risk to Birds - Using the mallard LC50 of 18.9 ppm, the dietary RQ for
difenacoum bait formulated at 50 ppm is 2.6.  This value exceeds the acute avian LOCs
of 0.1 for listed species and 0.5 for non-listed species. These LOCs are also exceeded if
the ring-necked pheasant LCso of 57 ppm is used; this value results in an RQ of 0.88.
These RQ values indicate a concern for acute risk to birds resulting from primary
exposure.

The dietary RQ exceeds the acute LOG for perching birds of a wide range of weights,
often after one day. EPA concludes that if birds are exposed via direct consumption of
bait, acute risk to birds is likely. These findings concur with those of the Rapporteur
Member State in the draft CA Report.

Chronic Risks to Birds - EPA has concluded that there is a chronic risk is a concern for
birds, although there is uncertainty with the actual calculated RQ value.

Acute Risks to Wild Mammals - EPA's comparative risk assessment for the rodenticide
cluster used 25-g and 100-g rodents and 1000-g mammals to estimate the dose, amount of
bait, and number of pellets needed to provide one LDso dose. These values are also used
here, along with 15-g and 35-g rodents, in keeping with standard EFED procedures in
estimating acute risk to wild mammals. In all cases, the  dose-based RQ is above the
acute risk LOCs for listed (LOG = 0.1) and non-listed (LOG = 0.5) mammals.  Based on
these numbers, acute risk is presumed for wild mammals that would consume bait
directly. These results agree with the findings presented by the Rapporteur Member State
in the CA Report.

Chronic Risks to Wild Mammals - The CA Report uses the 90-day rat repeated-dose
toxicity test NOAEC to calculate chronic risk to wild mammals. EFED policy is to use a
mammalian teratogenicity study if a two-generation rat reproduction study is not
available.  EFED concludes that chronic risk resulting from primary exposure to
difenacoum is a concern for wild mammals.  These findings agree with those of
mammalian chronic risk due to primary exposure in the CA Report.

2. Potential Secondary Risks to Birds and Non-Target Mammals

The potential for risk to birds and non-target mammals resulting from secondary
exposure to second-generation anticoagulants was identified in EFED's comparative risk
assessment. Since difenacoum is a second-generation anticoagulant, there is sufficient
                                      21

-------
reason to expect that avian and mammalian risk will result from secondary and tertiary
exposure to difenacoum.

The feeding studies with barn owls provide the best evidence that predatory birds will be
affected by anticoagulant properties of difenacoum if they feed on contaminated animals.
They also provide further evidence that difenacoum is similar to bromadiolone in terms
of secondary risks and that information from other second-generation anticoagulants
provides further evidence of the potential risk.

Similar types of feeding studies with mammals are not available for difenacoum, but
studies were also presented that demonstrate difenacoum exposure in carnivorous
mammals found killed along roadsides or trapped on game farms. Difenacoum is
retained in the liver of birds for some time.

Incidents involving birds and difenacoum in the UK also indicate the potential for
difenacoum to cause risk from secondary exposure. Predatory, scavenging, and/or
omnivorous birds are included among the bird species associated with difenacoum in the
UK incident reports, indicating the occurrence of secondary exposure and its effects on
wildlife.  The CA determined that acute and chronic risk is possible due to secondary
poisoning.

3. Relationship of Difenacoum Toxicity to First- and Second-Generation Anti-
Coagulants

EPA compared difenacoum to other anticoagulants based on acute toxicity, hepatic half-
life, and avian and mammalian RQs. They concluded that the toxicity of difenacoum to
most taxa is more similar to the second-generation anticoagulants than to the first-
generation anti-coagulants. The liver half-life of difenacoum is also very consistent with
those of the other second-generation anticoagulants.
                                       22

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Table 23.  Difenacoum compared to other anticoagulants based on acute toxicity, hepatic half-life, and avian and mammalian
RQs.


2nd Generation Anti-Coagulants
Difenacoum1
Brodifacoum
Bromadiolone
Difethialone
1st Generation Anti-Coagulants
Diphacinone
Chlorophacinone
Warfarin
Acute Toxicity
Mallard LD50
Bobwhite LD50
Mallard LC50
Bobwhite LC50
R-n. Pheasant LC50
Rat LD50
Mouse LDso
Rbow trout LC50 (ppb)
Bluegill LC50 (ppb)
Daphnid EC50 (ppb)
>2000
66
19
nd
57
1.8-2.6
0.8
64
258
520
0.26
nd
2.0
0.8
nd
0.4 -0.6
0.4
15
25
980
nd
138-170
158 - 440
38
nd
0.6-0.8
1.7
240
3000
240 - 2000
nd
0.26
1.4
0.56
nd
0.3-0.8
0.5-1.3
51
75
4
3158
>400
906
>5000
nd
2-7
2-340
2600
7500
1800
Nd
258
172
56
Nd
3-11
1-17
450
710
640
620
>2150
890
625
nd
2.5 - 680
4-40
88,000
> 16,000
> 17,000

Rat hepatic half-life (days)
128
1132-350
170-318
74 - 126
32
Nd
262
 All values based on studies summaries in the difenacoum dossier provided by the registrant or in the CA Report. The studies that produced these values have not
been subjected to standard EFED data evaluations.
2 Fisher etal. 2003.
                                                                23

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V. EFFICACY

Difenacoum has been used in Europe for over 30 years, and targets the same commensal
rodent species (Norway rat, roof rat, and house mouse) proposed for the U.S. registration.
European and US field data was submitted in support of the registration. The
Registration Division also confirmed with Dr. Bobby Corrigan, a nationally known
expert on rodent control, that there will be little if any difference in the efficacy of
difenacoum on "European" rodents compared to "American" rodents.

Rats and mice are serious public health pests since they are hosts for vector transmitted
diseases such as plague, murine typhus and Lyme disease. As an anticoagulant,
difenacoum will not provide a new mode of action but it does provide a new bait
formulation as a tool for rodent control. Since bait acceptance is critical to the efficacy of
rodenticides, difenacoum bait provides the applicator with another choice of formulation
which may prove to be more attractive to rodent pests in some situations.
Contact Person at USEPA;

Dan Peacock
Environmental Protection Agency
Office of Pesticide Programs
Registration Division (7504P)
Insecticide-Rodenticide Branch
1200 Pennsylvania Ave., NW,
Washington, DC 20460-0001

Office Location and telephone number:

7262, Potomac Yard South
2777 South Crystal Dr.
Arlington V.A. 22202
703-305-5407

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.
                                       24

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APPENDIX I:
GLOSSARY OF TERMS AND ABBREVIATIONS
ADNT
a.i.
aPAD
ARI
BCF
CAS
ChE
ChEI
cPAD
%CT
DAT
DEEM-FCID

DNA
DNT
DIT
DWLOC
EC
EEC
EPA
FQPA
GLC
GLN
LD50
LOAEL
LOAEC
LOC
LOD
LOQ
mg/kg/day
mg/L
Acute delayed neurotoxicity
Active Ingredient
Acute Population Adjusted Dose
Aggregate Risk Index
Bioconcentration Factor
Chemical Abstracts Service
Cholinesterase
Cholinesterase inhibition
Chronic Population Adjusted Dose
Percent crop treated
Days after treatment
Dietary Exposure Evaluation Model - Food Consumption
Intake Database
Deoxyribonucleic acid
Developmental neurotoxicity
Developmental immunotoxicity
Drinking Water Level of Comparison.
Emulsifiable Concentrate Formulation
Estimated Environmental Concentration. The estimated
pesticide concentration in an environment, such as a terrestrial
ecosystem.
U.S. Environmental Protection Agency
Food Quality Protection Act
Gas Liquid Chromatography
Guideline Number
Median Lethal Concentration. A statistically derived
concentration of a substance that can be expected to cause
death in 50% of test animals. It is usually expressed as the
weight of substance per weight or volume of water, air or feed,
e.g., mg/1, mg/kg or ppm.
Median Lethal Dose. A statistically derived single dose that
can be expected to cause death hi 50% of the test animals when
administered by the route indicated (oral, dermal, inhalation).
It is expressed as a weight of substance per unit weight of
animal, e.g., mg/kg.
Lowest Observed Adverse Effect Level
Lowest Observed Adverse Effect Concentration
Level of Concern
Limit of Detection
Limit of quantitation
Milligram Per Kilogram Per Day
Milligrams Per Liter
                                    25

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MOE
MRID

MTD
NA
NOEC
NOEL
NOAEL
NOAEC
NPDES
OP
OPP
OPPTS
PAD
PAG
PAM
PHED
PHI
ppb
PPE
ppm
PRZM/
EXAMS
RAC
RBC
RED
REI
RfD
SCI-GROW
SF
TGAI
UF
uL/g
USDA
WPS
Margin of Exposure
Master Record Identification (number), EPA's system of
recording and tracking studies submitted
Maximum tolerated dose
Not Applicable
No Observable Effect Concentration
No Observed Effect Level
No Observed Adverse Effect Level
No Observed Adverse Effect Concentration
National Pollutant Discharge Elimination System
Organophosphate
EPA Office of Pesticide Programs
EPA Office of Prevention, Pesticides and Toxic Substances
Population Adjusted Dose
Pesticide Assessment Guideline
Pesticide Analytical Method
Pesticide Handler's Exposure Data
Preharvest Interval
Parts Per Billion
Personal Protective Equipment
Parts Per Million

Tier II Surface Water Computer Model
Raw Agriculture Commodity
Red Blood Cell
Reregistration Eligibility Decision
Restricted Entry Interval
Reference Dose
Tier I Ground Water Computer Model
Safety Factor
Technical Grade Active Ingredient
Uncertainty Factor
micrograms
Micrograms Per Liter
Microliter per gram
United States Department of Agriculture
Worker Protection Standard
                                   26

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APPENDIX II:
Citations Considered to be Part of the Data Base Supporting the Registration of
Difenacoum
35806     Mendenhall, V.M.; Pank, L.F. (1979) Secondary Poisoning of Owls by Anticoagulant
           Rodenticides. (U.S. Fish and Wildlife Service, Patuxent and Denver Wildlife Research
           Centers, unpublished study)

80242     Mendenhall, V.M.; Pank, L.F. (1979) Secondary Poisoning of Owls by Anticoagulant
           Rodenticides. (U.S. Fish and Wildlife Service, Patuxent Wildlife Research Center;
           unpublished study; CDL 245704-M)

94694     Mendenhall, V.M.; Pank, L.F. (1980) Secondary poisoning of owls by anticoagulant
           rodenticides. Wildlife Society Bulletin 8(4):311- 315. (Also~ln~unpublished
           submission received Feb 7, 1982 under 12455-34; submitted by Bell Laboratories,
           Madison, Wis.; CDL 246741-C)

157732    Pank, L.; Hirata, D. (1976) Primary and Secondary Toxicity of Anti- coagulant
           Rodenticides: Job Completion Report: Work Unit DF 103.7. Unpublished study
           prepared by US Fish and Wildlife Service, Denver Wildlife Research Center. 23 p.

40077200  Chempar (1987) Data on Bromadiolone for Maki Products: Toxicity and Efficacy
           Reports. Compilation  of 9 Studies.

40077207  Hoppe, A.; Krambias, A. (1982) The response of captive Chukar par- tridges to the
           ingredients and anticoagulant poisons used in ro- dent baits in Cyprus. P. 639-646 in
           Proceedings of a conference on the organization and practice of Vertebrate Pest
           Control; Aug 30-Sept  3,1982, Elvetham Hall, Hampshire, England.

46750800  Woodstream Corp. (2006) Submission of Product Chemistry and Efficacy Data in
           Support of the Experimental Use Permit of Difenacoum Rat and Mouse Pellets.
           Transmittal of 3 Studies.

46750801  Harrison, E.  (2006) Difenacoum Rat and Mouse Pellets: Product Identity and
           Composition, Formulation Process, Discussion of Potential Impurity Formation and
           Certified Limits. Unpublished study prepared by Lewis & Harrison. 17 p.

46750802  Poche, R. (2005) Comparison of Toxicity of Difenacoum Bait (0.005%) to Norway
           Rats (Rattus norvegicus) and House Mice (Mus musculus): Final Report. Project
           Number: N05003. Unpublished study prepared by Genesis Laboratories, Inc. 23 p.

46750803  Mach, J. (2006) House Mouse (Mus musculus) Anticoagulant Dry Bait Laboratory
           Test Using Woodstream GS3 Pellet Bait, Containing 50 ppm Difenacoum: Three-Day
           Test. Project Number: 05030. Unpublished study prepared by Genesis Laboratories,
           Inc. 89 p.

46750900  Woodstream Corp. (2006) Submission of Product Chemistry, Toxicity, Fate,
           Environmental Fate, Exposure and Risk Data in Support of the Application for
           Registration  of Difenacoum Technical. Transmittal of 50 Studies.

46750901  Harrison, E.  (2005) Difenacoum Technical: Product Identity and Composition,
           Manufacturing Process, Discussion of Potential Impurity Formation and Certified
           Limits. Unpublished study prepared by Woodstream Corp. 31 p.

46750902  Cura, C.; Craig, W. (2000) Difenacoum:  Product Chemistry of Difenacoum: Analytical
           Profile of 5 Batches. Project Number: 17949, DF/959/0075, 333361, Unpublished
           study prepared by Inveresk Research International. 83 p.
                                         27

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46750903 Russell, S. (1996) Difenacoum: Determination of Physico-chemical Properties: Final
          Report. Project Number: 355/7/1014, 355/7. Unpublished study prepared by Corning
          Hazleton (Europe). 60 p.

46750904 Greenwood, J. (2000) Difenacoum: Evaluation of Thermal Properties by Differential
          Scanning Calorimetry. Project Number: 355/50, 355/50/D2141. Unpublished study
          prepared by Covance Laboratories, Ltd. 16 p.

46750905 Harrison, E.  (2005) Product Chemistry Data Waiver Requests for Difenacoum, a New
          Rodenticide  Active Ingredient. Unpublished study prepared by Woodstream Corp. 5
          P-
46750906 Edwards, D. (1996) Difenacoum: Determination of Spectroscopic Properties: Final
          Report. Project Number: 355/43/1014, 355/43. Unpublished study prepared by
          Corning Hazleton (Europe) and University of York. 29 p.

46750907 Hogg, A. (2003) Difenacoum: Physico-Chemical Testing with Difenacoum: Estimation
          of Adsorption Coefficient. Project Number: 21677, 341765, 4176A. Unpublished study
          prepared by Inveresk Research  International. 47 p.

46750908 Lewis, C. (1992) (Carbon 14)-Difenacoum: Aged Soil Leaching: Final Report. Project
          Number: 38/168, 7066, P6732D. Unpublished study prepared by Hazleton Uk. 62 p.

46750910 Lewis, C. (1992) Difenacoum: Hydrolysis Study (Final Report). Project Number: 7031,
          38/166. Unpublished study prepared by Hazleton Uk. 96 p.

46750912 Hall, B.; Jackson, R.; Priestley, I. (1992) Difenacoum: Photolysis in Buffered Aqueous
          Solutions. Project Number: 8704, 381614. Unpublished study prepared by Inveresk
          Research International. 123 p.

46750914 Lewis, C. (1992) (Carbon 14)- Difenacoum: A Study of the Degradation in Two Soils:
          Final Report. Project Number: 38/167, 6927. Unpublished study prepared by Hazleton
          Uk. 78 p.

46750916 Penwell,  A. (2004) Difenacoum: Determination of Anaerobic Biodegradability. Project
          Number: BL7788/B. Unpublished study prepared by Astrazeneca Uk Ltd. 24 p.

46750917 Wyness, L. (1995) Difenacoum:  Acute Toxicity to Daphnia magna: Final Report.
          Project Number: 355/18/1018. Unpublished study prepared by Corning Hazleton
          (Europe). 38 p.

46750918 Kent, S.; Tapp, J.; Sankey, S.; et. al. (1991) Difenacoum: Acute Toxicity to Daphnia
          magna. Project Number: BL4314/B, V480/B. Unpublished study prepared by Imperial
          Chemical Industries, Ltd.  19 p.

46750919 Wyness, L. (1995) Difenacoum:  Acute Toxicity to Oncorhynchus mykiss: Final Report.
          Project Number: 355/17/1018. Unpublished study prepared by Corning Hazleton
          (Europe). 32 p.

46750920 Wyness, L. (1995) Difenacoum:  Acute Toxicity to Lepomis macrochirus: Final Report.
          Project Number: 355/23/1018. Unpublished study prepared by Corning Hazleton
          (Europe). 32 p.

46750921 Nolan-Smith, S. (1997) Difenacoum: Acute Oral Toxicity to Mallard Duck: Final
          Report. Project Number: 355/39/1007. Unpublished study prepared by Covance
          Laboratories, Ltd. 60 p.

46750922 Ross, D.; ROberts, N.; Fairley, C. (1980) The Acute Oral Toxicity (LD50) of
          Difenacoum  to the Bobwhite Quail. Project Number: ICI/309/WL/8076, CTL/C/932.
          Unpublished study prepared by Huntingdon Life Sciences, Ltd. 20 p.
                                         28

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46750923  Nolan-Smith, S. (1998) Difenacoum: Acute Dietary Toxicity to Bobwhite Quail: Final
           Report. Project Number: 355/41/1007. Unpublished study prepared by Covance
           Laboratories, Ltd. 60 p.

46750924  Nolan-Smith, S. (2000) Difenacoum: Acute Dietary Toxicity to Mallard Duck: Final
           Report. Project Number: CLE/355/40, CLE/355/40/D1141, DF/959/0077. Unpublished
           study prepared by Covance Laboratories, Ltd. 67 p.

46750925  Ross, D.; Roberts, N.;  Fairley, C. (1980) The Subacute Dietary Toxicity (LC50) of
           Difenacoum to the Bobwhite Quail. Project Number: 56/79,  ICI/305/791197.
           Unpublished study prepared by Huntingdon Life Sciences, Ltd. 16 p.

46750926  Ross, D.; Roberts, N.;  Fairley, C. (1980) The Subacute Dietary Toxicity (LC50) of
           Difenacoum to the Mallard Duck. Project Number: CTL/C/888, ICI/304/791198.
           Unpublished study prepared by Huntingdon Life Sciences, Ltd. 19 p.

46750928  Harrison, E. (2005) Summary of Environmental Fate and Ecological Effects Studies
           Conducted with Difenacoum, A New Rodenticide Active Ingredient. Unpublished
           study prepared by Woodstream Corp. 15 p.

46750929  Wyness, L (1995) Difenacoum: Inhibition of Growth to the Alga Selenastrum
           Capricornutum: Final Report. Project Number: 355/19/1018, 355/19. Unpublished
           study prepared by Corning Hazleton (Europe). 37 p.

46750931  Mendenhall, V.; Pank,  L. (1980) Secondary Poisoning of Owls by Anticoagulant
           Rodecticides: (Difenacoum, Bromadiolone, Brodifacoum, Diphacinone, Fumarin,
           Chlorophacinone). The Wildlife Society Bulletin 8(4): 311-315.

46750932  Gray, A.; Eadsforth, C.; Dutton, A.; et. al. (1992) Toxicity of  Second Generation
           Rodenticide to Barn Owls: (Brodifacoum, Difenacoum, Flocoumafen). Brighton Crop
           Protection Conference Pests and Diseases: 781-786.

46750933  Newton, I.; Wyllie, I.; Freestone, P. (1990) Rodenticides in British Barn Owls:
           (Difenacoum, Brodifacoum). Environmental Pollution 68:101-117.

46750934  Buckle, A. (2004)  Expert Review of Literature on the Ecotoxicology of Difenacoum
           and Wildlife in the European Union. Unpublished study prepared by Alan Buckle
           Consulting, Ltd. 239 p.

46750935  Gardner, J. (1995) Acute Oral Toxicity Study in the Male Wistar Rat:  Difenacoum:
           Final Report. Project Number: 355/34/1032, 355/34. Unpublished study prepared by
           Corning Hazleton  (Europe). 30 p.

46750936  Gardner, J. (1995) Acute Oral Toxicity Study in the Rat:  Difenacoum: Final Report.
           Project  Number: 355/8/1032, 355/8. Unpublished study prepared by Hazleton Uk. 26
           P-

46750938  Gardner, J. (1995) Acute Dermal Toxicity Study in the Rat: Difenacoum: Final Report.
           Project  Number: 355/9/1032, 355/9. Unpublished study prepared by Hazleton Uk. 29
           P-

46750939  Shepherd, N. (1996) Difenacoum: Single Dose Inhalation (Head-Only) Toxicity in the
           Rat: Final Report.  Project Number: 355/11/1050, 355/11. Unpublished study prepared
           by Corning Hazleton (Europe). 87  p.

46750940  Gardner, J. (1995) Eye Irritation Study in the Rabbit: Difenacoum: Final Report.
           Project Number: 355/024/1032, 355/24. Unpublished study prepared by Hazleton Uk.
           18 p.
                                          29

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46750941 Gardner, J. (1995) Difenacoum: Skin Irritation Study in the Rabbit: Final Report.
          Project Number: 355/010/1032, 355/010. Unpublished study prepared by Hazleton
          Uk. 17 p.

46750942 Denton, S. (1995) Difenacoum: Skin Sensitisation in the Guinea Pig: Final Report.
          Project Number: 355/12/1032, 355/12. Unpublished study prepared by Hazleton Uk.
          30 p.

46750944 Hodge, M. (1994) Difenacoum: 6 Week Oral Toxicity Study in Dogs. Project Number:
          CTL/L/5738, PD0965. Unpublished study prepared by Zeneca Ltd. Central Toxicology
          Lab. 8 p.

46750945 Harrison, E. (2005) Summary of Safety Studies Conducted with Difenacoum, a New
          Rodenticide Active Ingredient. Unpublished study prepared by Woodstream Corp. 15
          P-
46750947 Hodge, M. (1994) Difenacoum: Developmental Toxicity Study in the Rabbit. Project
          Number: CTL/P/4245, RB0631. Unpublished study prepared by Zeneca Ltd. Central
          Toxicology Lab. 100 p.

46750948 Ballantyne, M. (1995) Difenacoum: Reverse Mutation in 5 Histidine-requiring Strains
          of Salmonella typhimurium: Final Report. Project Number: 355/22/1052, 355/22.
          Unpublished study prepared by Hazleton Uk. 46 p.

46750950 Riley, S. (1995) Difenacoum: Induction of Chromosome Aberrations in Cultured
          Human Peripheral Blood Lymphocytes: Final Report. Project Number: 355/21/1052,
          355/21. Unpublished study prepared by Corning Hazleton (Europe). 61 p.

46750952 Clements, J. (1995) Difenacoum: Mutation at the Thymidine Kinase (tk) Locus of
          Mouse Lymphoma L5178Y Cells Using the Microtitre Fluctuation Technique: Final
          Report. Project Number: 355/16/1052, 355/16. Unpublished study prepared by
          Corning Hazleton (Europe). 45 p.

46750957 Bratt, H. (1987) Difenacoum: Elimination from the Tissues of Rats Following
          Administration of a Single Oral Dose. Project Number: CTL/P/1592, UR0193.
          Unpublished study prepared by ICI Americas Inc.  35 p.

46750960 Batten, P. (2002) Difenacoum:  Expert Review of Toxicokinetics. Project Number:
          355/49. Unpublished study prepared by Covance Laboratories, Ltd. 22 p.

46750961 Croucher, A. (1998) Analysis of Difenacoum in Rat Carcasses: Validation of a Method
          and Analysis of Samples: Amended Final Report.  Project Number:
          CLE/355/45/D2140, 355/45,  CLE/355/45/02R. Unpublished study prepared by
          Covance Laboratories, Ltd. 31 p.

46750962 Doran, A.; McGuire, G. (2002) Development and Validation of a Method for
          Determination of Difenacoum in Rat Liver Samples. Project Number: 21009, 300320,
          0032. Unpublished study prepared by Inveresk Research International. 31 p.

46750964 Harrison, E. (2005) Toxicology Data Waiver Requests for Difenacoum, a New
          Rodenticide Active Ingredient. Unpublished study prepared by Woodstream Corp.
          and JSC International. 37 p.

46750965 Sorex Ltd. (2005) Listing of End-Points for  the Active Substance Difenacoum.
          Unpublished study prepared by Sorex Company Limited. 23 p.

46750966 Sorex Ltd. (2005) Risk Characterization for the Active Ingredient, Difenacoum.
          Unpublished study. 46 p.
                                         30

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46750967  MacDonald, E. (2004) Difenacoum Technical: Stability/Storage Stability. Project
           Number: 343846, 23527, 3336A. Unpublished study prepared by Inveresk Research
           International. 44 p.

46766200  Woodstream Corp. (2006) Submission of Fate, Toxicity, Environmental Fate and
           Pesticide Use Data in Support of the Application for Registration of Difenacoum
           Technical. Transmittal of 16 Studies.

46766201  Lewis, C. (1992) (Carbon 14)-Difenacoum: Aged Soil Leaching: Amendment to Final
           Report. Project Number: 38/168, 7066. Unpublished study prepared by Hazleton Uk.
           7 P-

46766202  Lewis, C. (1992) Difenacoum: Hydrolysis Study: Amendment to Final Report. Project
           Number: 38/166R, 7031. Unpublished study prepared by Hazleton Uk. 6 p.

46766203  Lewis, C. (1992) (Carbon 14)-Difenacoum: A Study of the Degradation in Two Soils:
           Amendment to Final Report. Project Number: 38/167R, 6927. Unpublished study
           prepared by Hazleton Uk. 7 p.

46766204  Nolan-Smith, S.; Sharpies,  R. (2000) Difenacoum: Acute Dietary Toxicity to Ring-
           necked Pheasants: Final Report. Project Number: 355/42, 355/42/D1142.
           Unpublished study prepared by Covance Laboratories, Ltd. 63 p.

46766205  Smyth, D.; Tapp, J.; Sankey, S.; et. al. (1991) Difenacoum: Toxicity to the Green
           Alga: Selenastrum capricornutum. Project Number:  V480/A, BL4307/B, FT51/91.
           Unpublished study prepared by Imperial Chemical Industries, Ltd. 21 p.

46766206  Robbins, M. (1998) Acute Oral Toxicity (LD50) Tests with Cis- and Trans- Isomers
           and a Racemic Mixture of Difenacoum. Project Number: 3175/2, 3175/2/2/98.
           Unpublished study prepared by BIBRA Toxicology International. 110 p.

46766207  Horner, J. (1991) Difenacoum: Oral Toxicity Study in Rats. Project Number: BA/90/7,
           Y00441/006, KR1122. Unpublished study prepared  by ICI Central Toxicology Lab. 94
           P-

46766208  Hodge, M. (1994) Difenacoum: Development Toxicity Study in the Rat. Project
           Number: AI/93/0051, 10131, Y00441/006. Unpublished study prepared by Central
           Toxicology Lab. (Syngenta). 79 p.

46766209  Callander, R. (1986) Difenacoum - An Evaluation in  the Salmonella Mutagenicity
           Assay. Project Number: SC/26/85, Y00441/004/003, YV1768. Unpublished study
           prepared by ICI  Central Toxicology Lab. 29 p.

46766210  Wildgoose, J.; Howard, C.;  Clay,  P.; et. al. (1986) Difenacoum: An In vitro
           Cytogenetic  Study in Chinese Hamster Lung Fibroblasts. Project Number:
           CTL7P/1553, SC/27/85, Y00441/004/008/9. Unpublished study prepared by ICI
           Central Toxicology Lab. 31  p.

46766211  Riley, S. (1996)  Difenacoum: Induction of Micronuclei in the  Bone Marrow of Treated
           Rats: Final Report. Project Number: 355/37/1052, 355/37. Unpublished study
           prepared by Corning Hazleton (Europe). 36  p.

46766212  Sheldon, T.; Richardson, C.; Randall, V.; et. al. (1987) Difenacoum: An Evaluation in
           the Mouse Micronucleus Test. Project Number: SC/4/86, Y00441/004/010, 001.
           Unpublished study prepared by ICI Central Toxicology Lab. 27 p.

46766214  Kennelly, J. (1990) Difenacoum: Assessment for the Induction of Unscheduled DNA
           Synthesis in  Rat Hepatocythes in Vivo. Project Number: CTL/P/3017, SR0389.
           Unpublished study prepared by ICI Central Toxicology Lab. 42 p.
                                         31

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46766215  Phillips, J. (2002) An Investigation into the Elimination and Tissue Distribution of the
           (Carbon 14)-Labelled Stereoisomers of Difenacoum Following Oral Administration to
           Rats. Project Number: 3175/3/02, 3175. Unpublished study prepared by TNO BIBRA
           International Ltd. 57 p.

46766216  Phillips, J. (1996) An Investigation in the Absorption, Tissue Distribution and
           Elimination of (Carbon 14)-Labelled Difenacoum Following Oral Administration to
           Rats. Project Number: 1555/2,1555/2/3/96. Unpublished study prepared by BIBRA
           Toxicology International. 69 p.

46766217  Lewis & Harrison (2005) Compilation of Efficacy Studies Conducted with New
           Rodenticide Active Ingredient, Difenacoum. Unpublished study prepared by Lewis &
           Harrison. 558 p.

46773600  Woodstream  Corp. (2006) Submission of Toxicity Data in  Support of the Application
           for Registration of Difenacoum Technical. Transmittal of 1 Study.

46773601  Clare, C. (1996) Difenacoum: Measurement of Unscheduled DNA Synthesis in Rat
           Liver Using an In Vivo/In Vitro Procedure: Final Report.  Project Number: 355/38/1052,
           802657. Unpublished study prepared by Corning Hazleton (Europe). 34 p.

46799100  Woodstream  Corporation (2006) Submission of Toxicity Data in Support of the
           Application for Registration of Difenacoum Technical. Transmittal of 1 Study.

46799101  Under, T. (2006) Avian Reproduction Study with Difenacoum in the Japanese Quail
           (Coturnix coturnix japonica): Final Report. Project Number: 04012. Unpublished study
           prepared by Genesis Laboratories, Inc. 205 p.

46892000  Woodstream  Corp. (2006) Submission of Toxicity Data in  Support of the Application
           for Registration of Difenacoum Technical. Transmittal of 3 Studies.

46892001  Moore, G. (2006) Acute Inhalation Toxicity Study in Rats - Limit Test: Difenacoum
           Pellets. Project Number: 19383, P330. Unpublished study prepared  by Product Safety
           Laboratories. 22 p.

46892002  Moore, G. (2006) Acute Dermal Toxicity Study in Rats - Limit Test: Difenacoum
           Pellets. Project Number: 19382, P322/RAT. Unpublished study prepared by Product
           Safety Laboratories. 14 p.

46892003  Moore, G. (2006) Acute Oral Toxicity Up and Down Procedure in Rats: Difenacoum
           Pellets. Project Number: 19381, P320/UDP. Unpublished  study prepared by Product
           Safety Laboratories. 14 p.

46913700  Woodstream  Corp. (2006) Submission of Efficacy Data in  Support of the Application
           for Registration of Difenacoum Technical. Transmittal of 2 Studies.

46913701  Mach, J.; Under, T. (2006)  Product Performance of Woodstream GS3 Pellet Bait to
           Control House Mice (Mus musculus) at a Natuarally Infested Site Outside of the
           Midwest Region: Final Report. Project  Number: 06003. Unpublished study prepared
           by Genesis Laboratories, Inc. 83 p.

46913702  Mach, J.; Linder, T. (2006)  Product Performance of Woodstream GS3 Pellet Bait to
           Control Norway Rats (Rattus norvegicus) at a Naturally  Infested Site Outside of the
           Southwest Region. Project  Number: 06004. Unpublished study prepared by Genesis
           Laboratories, Inc. 92 p.

46914000  Woodstream  Corporation (2006) Submission of Efficacy Data in Support of the
           Application for Registration of Difenacoum Technical. Transmittal of  2 Studies.
                                          32

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46914001  Mach, J.; Under, T. (2006) Product Performance of Woodstream GS3 Pellet Bait to
           Control Norway Rats (Rattus norvegicus) at a Naturally Infested Site in Colorado:
           Final Report. Project Number: 05033. Unpublished study prepared by Genesis
           Laboratories, Inc. 77 p.

46914002  Mach, J.; Under, T. (2006) Product Performance of Woodstream GS3 Pellet Bait to
           Control House Mice (Mus musculus) at a Naturally Infested Site in Colorado:
           Amended Final Report. Project Number: 05032. Unpublished study prepared by
           Genesis Laboratories, Inc. 96 p.

46916100  Woodstream Corp. (2006) Submission of Product  Chemistry Data in Support of the
           Application for Registration of Difenacoum Technical. Transmittal of 1 Study.

46916101  Wo, C. (2006) Physical and Chemical Characteristics: Color, Physical State, Odor,
           pH, and Bulk Density: Difenacoum Pellets.  Project Number: 20008. Unpublished
           study prepared by Product Safety Laboratories. 12 p.

46961400  Woodstream Corp. (2006) Submission of Efficacy  Data in Support of the Application
           for Registration of Difenacoum Technical. Transmittal of 1 Study.

46961401  Mach, J. (2006) Norway Rat (Rattus norvegicus) Anticoagulant Dry Bait Laboratory
           Test Using Woodstream GS3 Pellet Bait, Containing 50 ppm Difenacoum: Three-day
           Test: Final  Report. Project Number: 05028. Unpublished  study prepared by Genesis
           Laboratories, Inc. 104 p.

46988300  Woodstream Corp. (2006) Submission of Efficacy  Data in Support of the Application
           for Registration of 0.005% Difenacoum Rat and Mouse Pellets. Transmittal of 1
           Study.

46988301  Mach, J. (2006) Norway Rat (Rattus Norvegicus) Anticoagulant Dry Bait Laboratory
           Test Using Woodstream GS3 Pellet Bait, Containing 50 ppm Difenacoum: Three-day
           Test: Final  Report. Project Number: 05028. Unpublished  study prepared by Genesis
           Laboratories, Inc. 104 p.

47041700  Woodstream Corp. (2006) Submission of Efficacy  Data in Support of the Application
           for Registration of Difenacoum Technical. Transmittal of 1 Study.

47041701  Mach, J. (2007) Product Performance of Woodstream GS3  Pellet Bait to Control Roof
           Rats (Rattus rattus) at a Naturally Infested Site Outside of the Southwest Region:
           Final Report. Project Number: 06005. Unpublished study prepared by Genesis
           Laboratories, Inc. 101 p.

47098400  Woodstream Corp. (2007) Submission of Product  Chemistry Data in Support of the
           Application for Registration of Difenacoum Technical and the Experimental Use of
           Difenacoum. Transmittal of 2 Studies.

47098401  Sinning, D. (2006) Physical and Chemical Characteristics of Difenacoum Technical:
           Stability. Project Number:  2720/103. Unpublished  study prepared by Case Consulting
           Laboratories, Inc. 18 p.

47098402  Harrison, E. (2007) Enforcement Analytical Method - Analysis of Difenacoum in a
           Typical End-Use Product. Unpublished study prepared by Woodstream Corp.  11 p.

47220300  Woodstream Corp. (2007) Submission of Product  Chemistry and Efficacy Data in
           Support of the Application for Registration of Difenacoum Rat and Mouse Block.
           Transmittal of 4 Studies.

47220301  Sinning, D. (2007) Physical and Chemical Characteristics of Difenacoum Block:
           Color, Physical State, Odor, pH and Relative Density. Project Number: 2720/134.
           Unpublished study prepared by Case Consulting Laboratories, Inc. 7 p.
                                          33

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47220302 Levey, C. (2007) Product Specific Chemistry Difenacoum Rat and Mouse Block.
          Project Number: WS/06B/1. Unpublished study prepared by Genesis Laboratories,
          Inc. 6 p.

47220303 Under, T.; Borchert, J. (2006) House Mouse (Mus musculus) Anticoagulant Wax
          Block Laboratory Test Using WS-06B-1: Three Day Test: Final Report. Project
          Number: 06017. Unpublished study prepared by Genesis Laboratories, Inc. 98 p.

47220304 Under, T. (2006) Norway Rat (Rattus norvegicus) Anticoagulant Dry Bait Laboratory
          Test Using WS-06B-1  Block Bait: Three-day Test: Final Report. Project Number:
          06015. Unpublished study prepared by Genesis Laboratories, Inc. 107 p.
Dan Peacock, Flash Drive, 2gb, P:\Documents\Word, WP, Excel, etc\Difenacoum\Fact
Sheets\Difenacoum, Fact Sheet, 9-24-2007, ver 3,.doc
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